Brain Neoplasms, Brain Neoplasms, Primary, Carcinoma, Non-Small-Cell Lung, Malignant Melanoma, Malignant Neoplasms
Conditions
Keywords
Proto-Oncogene Proteins B-raf, Brain Neoplasms, Melanoma, Carcinoma, Non-Small-Cell Lung, Brain Diseases, Central Nervous System Neoplasms, Enzyme Inhibitors
Brief summary
First-in-human study to assess safety, tolerability, PK, and preliminary activity of PF-07284890 as a single agent and in combination with binimetinib in participants with BRAF V600-mutated advanced solid tumor malignancies with and without brain involvement.
Interventions
DRUGPF-07284890
PF-07284890 will be administered orally, daily for 21 consecutive days (21-day cycle)
DRUGBinimetinib
Binimetinib will be administered together with PF-07284890 orally, 45mg twice daily
DRUGMidazolam
Midazolam will be administered 7 days before start of study drug, on Cycle 1 Day 1, and on Cycle 1 Day 15
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥16 years at the time of consent * Histologically confirmed diagnosis of advanced/metastatic solid tumor including primary brain tumor * Documented evidence of a BRAF V600 mutation in tumor tissue or blood * Confirmation of availability of adequate tumor tissue for submission to the sponsor/central laboratory * Presence or absence of brain involvement unless specified below * Dose Expansion (Part B) * Cohort 1, 2, 3, 4: melanoma with at least 1 parenchymal brain lesion * Cohort 1,3: asymptomatic in the brain for at least 14 days prior to start of study treatment * Cohort 2,4: symptomatic in the brain within 14 days prior to the start of study treatment * Cohort 5: any solid tumor that does not meet requirements for Cohorts 1-4, history of or current leptomeningeal metastases. * Optional Cohort 6 (DDI Sub-study) and 7 (Food-Effect): if brain involvement present, must be asymptomatic * Disease progression despite prior treatment and no acceptable alternative treatment options available unless specified below * Dose Expansion (Part B) * Cohort 1, 2: No prior BRAF inhibitor in the metastatic setting or in the adjuvant setting within 6 months of study treatment * Cohort 3, 4: Required prior BRAF inhibitor in the metastatic setting or in the adjuvant setting within 6 months of treatment * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Exclusion criteria
* Brain metastasis/primary brain tumor requiring immediate local intervention * History of or current leptomeningeal metastases * Any other active malignancy within 2 years prior to enrollment * Radiation therapy to visceral metastases within 14 days prior to study treatment. WBRT within 28 days prior to study treatment. * Systemic anti-cancer therapy or small-molecular therapeutic(s) within 2 weeks prior to start of study treatment; Antibody based agents within 4 weeks prior to start of study treatment. * History or current evidence of RVO or current risk factors for RVO; History of retinal degenerative disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | Cycle 1 (21 Days) | DLT was defined as any adverse event (AE) or abnormal laboratory value which were related to study treatment and assessed as unrelated to disease (disease progression), occurring during the first 21 days of treatment that met at least 1 of the study specified criteria. DLTs were graded according to the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version (v) 5.0. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 542 days; maximum follow-up: 572 days) | An adverse event (AE) was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE. |
| Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days) | The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades. |
| Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days) | The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (CPK) increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades. |
| Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days]) | Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered. |
| Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days]) | A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered. |
| Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days]) | In this outcome measure, dose discontinuations for any drug due to TEAEs were considered. |
| Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b | From date of first dose until CR or PR (maximum treatment exposure: 400 days) | Extracranial response rate was defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Intracranial Response Rate by mRECISTv1.1: Phase 1b | From date of first dose until CR or PR (maximum treatment exposure: 400 days) | Intracranial response rate as assessed using modified RECIST (mRECIST) v 1.1., was defined as the percentage of participants with brain or central nervous system (CNS) involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Overall Response Rate (ORR): Phase 1b | From date of first dose until CR or PR (maximum treatment exposure: 400 days) | ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. |
| Response Rate Using Response Assessment in Neuro-Oncology (RANO) for Primary Brain Tumors: Phase 1b | From date of first dose until CR or PR (maximum treatment exposure: 400 days) | RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for more than or equal to (\>=) 4 weeks; no new lesions; stable or improved non-enhancing (T2/ \[fluid attenuated inversion recovery\] FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; no new lesions; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | CL/F was calculated as Dose/AUCinf. |
| Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose (24 hours post-dose concentration), 1, 2, 4, 6 and 8 hours post dose on C1D15 | T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. In the determination of the t1/2, steady-state was assumed and the pre-dose value was used for the 24-hour post-dose value, which could have enabled the reporting of the t1/2 value higher than 8 hours. |
| Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D1 and C1D15 | Rac was defined as area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,τ) divided by area under the plasma concentration-time curve over the dosing interval from a single dose (AUCsd,τ). |
| Extracranial Response Rate by RECISTv1.1: Phase 1a | From date of first dose until CR or PR (maximum treatment exposure: 542 days) | Extracranial response rate was defined as the percentage of participants with a BOR of CR or confirmed PR in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Intracranial Response Rate by mRECISTv1.1: Phase 1a | From date of first dose until CR or PR (maximum treatment exposure: 542 days) | Intracranial response rate as assessed using modified mRECIST v 1.1., was defined as the percentage of participants with brain or CNS involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| ORR by RECISTv1.1: Phase 1a | From date of first dose until CR or PR (maximum treatment exposure: 542 days) | ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. |
| Overall Response Rate as Per RANO for Brain Tumours: Phase 1a | From date of first dose until CR or PR (maximum treatment exposure: 542 days) | RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for \>= 4 weeks; no new lesions; stable or improved non-enhancing (T2/FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved. |
| Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment/start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 400 days, maximum follow up: 430 days) | An AE was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE. |
| Number of Participants With Hematology Laboratory Abnormalities: Phase 1b | From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 400 days, maximum follow up: 430 days) | The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades. |
| Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b | From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 400 days, maximum follow up: 430 days) | The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, CPK increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades. |
| Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b | During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days]) | Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered. |
| Number of Participants With Dose Reduction Due to TEAEs: Phase 1b | During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days]) | A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered. |
| Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b | During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days]) | In this outcome measure, dose discontinuations for any drug due to TEAEs were considered. |
| Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1 | — |
| Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1 | — |
| AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1 | AUClast was determined using the linear/log trapezoidal method. |
| Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1 (C1D1); 24 hours was only for arms where study drug was administered as QD. | — |
| Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b | From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days) | DCR: percentage of participants with BOR of CR, PR/ SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive disease (PD). PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease. |
| Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b | From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days) | DCR: percentage of participants with BOR of CR, PR or SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target & non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease. |
| Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b | From date of first dose of study treatment until first documentation of PD or death due to any cause or censoring date whichever occurred first (maximum treatment exposure: 400 days) | PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started . In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method. |
| Overall Progression Free Survival (PFS): Phase1b | From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum treatment exposure: 400 days) | PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is smallest on study). In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered a sign of progression. PD for non-target lesions- unequivocal progression of existing non-target lesion. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Overall PFS included evaluation for brain metastasis and extracranial lesions. Analysis was performed using Kaplan-Meier method. |
| Overall Survival (OS): Phase1b | From start of study treatment until death due to any cause or censoring date (maximum treatment exposure: 400 days) | Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants who were still alive at the end of the study or lost to follow-up were censored at the last date they were known to be alive. Analysis was performed using Kaplan-Meier method. |
| Intracranial Duration of Response (DOR) by mRECIST v1.1: Phase1b | From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days) | DOR was defined as the time from date of the first radiographic response (CR or PR) to the earliest documented PD or death due to any cause. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non target lesions. |
| Overall DOR by RECIST v1.1: Phase1b | From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days) | DOR: time from date of first radiographic response (CR/PR) to earliest documented PD/ death due to any cause.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. PD for non-target lesions- unequivocal progression of existing non-target lesions. |
| Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b | From date of first dose until CR or PR (maximum treatment exposure: 400 days) | Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Overall TTR by RECIST v1.1: Phase1b | From date of first dose until CR or PR (maximum treatment exposure: 400 days) | Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response evaluable population. |
| CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | CL/F was calculated as Dose/AUCinf. |
| Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD. | — |
| Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD. | AUClast was determined using the linear/log trapezoidal method. |
| Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD. | T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD. | AUCinf was calculated as AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis. Those outcome measures are either due to either patient(s) has insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined |
| Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD. | CL/F was calculated as Dose/AUCinf. |
| Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD. | Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
| Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15 | — |
Countries
Canada, Israel, United States
Participant flow
Recruitment details
The study consisted of 2 phases: Phase 1a (dose escalation, divided into monotherapy \[PF-07284890 alone\] and combination therapy \[PF-07284890 plus binimetinib\]) and Phase 1b (dose expansion).
Pre-assignment details
A total of 65 participants were enrolled in the study: Phase 1a: 48 participants (monotherapy \[25 participants\] and combination therapy \[23 participants\]) and Phase 1b: 17 participants). No participants were enrolled in Cohort 2 and 6 of Phase 1b.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1a: PF-07284890 50 mg QD Participants received PF-07284890 50 milligrams (mg) oral dose once daily (QD) in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 2 |
| Phase 1a: PF-07284890 100 mg QD Participants received PF-07284890 100 mg oral dose QD in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 4 |
| Phase 1a: PF-07284890 200 mg QD Participants received PF-07284890 200 mg oral dose QD in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 3 |
| Phase 1a: PF-07284890 200 mg BID Participants received PF-07284890 200 mg oral dose twice daily (BID) in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 3 |
| Phase 1a: PF-07284890 300 mg BID Participants received PF-07284890 300 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 10 |
| Phase 1a: PF-07284890 450 mg BID Participants received PF-07284890 450 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 3 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID Participants received PF-07284890 100 mg oral dose QD in combination with binimetinib 45 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 4 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID Participants received PF-07284890 100 mg oral dose BID in combination with binimetinib 45 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 4 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID Participants received PF-07284890 150 mg oral dose BID in combination with binimetinib 45 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 2 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID Participants received PF-07284890 225 mg oral dose BID in combination with binimetinib 45 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 5 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID Participants received PF-07284890 300 mg oral dose BID in combination with binimetinib 45 mg oral dose BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 8 |
| Phase 1b: Cohort 1 Cohort 1 included melanoma participants with asymptomatic brain metastases and no prior B-type Raf proto-oncogene (BRAF) inhibitor therapy. Participants received PF-07284890 300 mg oral dose QD in combination with binimetinib 45 mg BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 1 |
| Phase 1b: Cohort 3 Cohort 3 included melanoma participants with asymptomatic brain metastases and with prior BRAF inhibitor therapy. Participants received PF-07284890 300 mg oral dose QD in combination with binimetinib 45 mg BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 4 |
| Phase 1b: Cohort 4 Cohort 4 included melanoma participants with symptomatic brain metastases and with prior BRAF inhibitor therapy. Participants received PF-07284890 300 mg oral dose QD in combination with binimetinib 45 mg BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 1 |
| Phase 1b: Cohort 5 Cohort 5 included participants with a mixture of tumor types, any brain disease and with or without prior BRAF inhibitor therapy. Participants received PF-07284890 300 mg oral dose QD in combination with binimetinib 45 mg BID in a 21-day cycle. Participants continued treatment until disease progression, participant refusal, unacceptable toxicity, or up to 2 years, whichever occurred first. | 11 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1a | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Phase 1a | Global Deterioration Of Health Status | 0 | 1 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Phase 1a | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 1a | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 1a | Other (Death) | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 1a | Progressive Disease | 2 | 2 | 3 | 1 | 4 | 2 | 3 | 4 | 1 | 0 | 4 | 0 | 0 | 0 | 0 |
| Phase 1a | Study terminated by sponsor | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 1a | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 1 | 1 | 2 | 0 | 0 | 0 | 0 |
| Phase 1b | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Phase 1b | Other (Death) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Phase 1b | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 5 |
| Phase 1b | Study Terminated By Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 |
| Phase 1b | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Phase 1a: PF-07284890 50 mg QD | Phase 1b: Cohort 4 | Phase 1b: Cohort 3 | Phase 1b: Cohort 1 | Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Phase 1b: Cohort 5 | Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Phase 1a: PF-07284890 450 mg BID | Phase 1a: PF-07284890 300 mg BID | Phase 1a: PF-07284890 200 mg BID | Phase 1a: PF-07284890 200 mg QD | Phase 1a: PF-07284890 100 mg QD |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 15.12 | 64.5 Years STANDARD_DEVIATION 0.71 | 31.0 Years | 63.8 Years STANDARD_DEVIATION 12.15 | 57.0 Years | 45.0 Years STANDARD_DEVIATION 13.89 | 42.0 Years STANDARD_DEVIATION 18.71 | 40.5 Years STANDARD_DEVIATION 27.58 | 50.8 Years STANDARD_DEVIATION 12.96 | 57.5 Years STANDARD_DEVIATION 23.35 | 59.8 Years STANDARD_DEVIATION 3.2 | 50.0 Years STANDARD_DEVIATION 7.94 | 55.9 Years STANDARD_DEVIATION 15.95 | 62.7 Years STANDARD_DEVIATION 11.85 | 65.3 Years STANDARD_DEVIATION 12.34 | 56.3 Years STANDARD_DEVIATION 12.61 |
| Ethnicity, Customized Hispanic/ Latino(a) or of Spanish Origin | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity, Customized Not disclosed | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity, Customized Not Hispanic/Latino(a)/of Spanish Origin | 57 Participants | 2 Participants | 0 Participants | 4 Participants | 0 Participants | 6 Participants | 4 Participants | 2 Participants | 11 Participants | 4 Participants | 4 Participants | 3 Participants | 8 Participants | 3 Participants | 3 Participants | 3 Participants |
| Ethnicity, Customized Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not disclosed | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reported | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 56 Participants | 2 Participants | 0 Participants | 4 Participants | 0 Participants | 7 Participants | 3 Participants | 2 Participants | 9 Participants | 4 Participants | 3 Participants | 3 Participants | 9 Participants | 3 Participants | 3 Participants | 4 Participants |
| Sex/Gender, Customized Female | 33 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 5 Participants | 3 Participants | 1 Participants | 3 Participants | 7 Participants | 2 Participants | 0 Participants | 1 Participants |
| Sex/Gender, Customized Male | 30 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 4 Participants | 1 Participants | 6 Participants | 1 Participants | 3 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants |
| Sex/Gender, Customized Not disclosed | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 4 / 4 | 0 / 3 | 2 / 3 | 4 / 10 | 2 / 3 | 2 / 4 | 3 / 4 | 1 / 2 | 4 / 5 | 4 / 8 | 0 / 1 | 3 / 4 | 0 / 1 | 4 / 11 |
| other Total, other adverse events | 2 / 2 | 4 / 4 | 3 / 3 | 3 / 3 | 10 / 10 | 2 / 3 | 4 / 4 | 4 / 4 | 2 / 2 | 5 / 5 | 8 / 8 | 1 / 1 | 4 / 4 | 1 / 1 | 11 / 11 |
| serious Total, serious adverse events | 0 / 2 | 1 / 4 | 0 / 3 | 3 / 3 | 4 / 10 | 2 / 3 | 1 / 4 | 1 / 4 | 1 / 2 | 2 / 5 | 3 / 8 | 0 / 1 | 3 / 4 | 0 / 1 | 3 / 11 |
Outcome results
Primary
Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b
Extracranial response rate was defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Population: Extracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable tumor at baseline and at least one post baseline extracranial assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b | 100.0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Extracranial Response Rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: Phase 1b | 12.5 Percentage of participants |
Primary
Intracranial Response Rate by mRECISTv1.1: Phase 1b
Intracranial response rate as assessed using modified RECIST (mRECIST) v 1.1., was defined as the percentage of participants with brain or central nervous system (CNS) involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Population: Intracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable brain tumor at baseline and at least one post baseline intracranial assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Intracranial Response Rate by mRECISTv1.1: Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Intracranial Response Rate by mRECISTv1.1: Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | Intracranial Response Rate by mRECISTv1.1: Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1b | 0 Percentage of participants |
Primary
Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a
The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (CPK) increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 4 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 3 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 3 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 10 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 4 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 4 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 5 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Chemistry Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 8 Participants |
Primary
Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a
In this outcome measure, dose discontinuations for any drug due to TEAEs were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1a | 1 Participants |
Primary
Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a
Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 3 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 5 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 3 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1a | 5 Participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a
DLT was defined as any adverse event (AE) or abnormal laboratory value which were related to study treatment and assessed as unrelated to disease (disease progression), occurring during the first 21 days of treatment that met at least 1 of the study specified criteria. DLTs were graded according to the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version (v) 5.0.
Time frame: Cycle 1 (21 Days)
Population: The per protocol analysis set included all enrolled participants who had at least one dose of study treatment and either experienced DLT or did not have major treatment deviations during the DLT observation period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1a | 1 Participants |
Primary
Number of Participants With Dose Reduction Due to TEAEs: Phase 1a
A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 542 days])
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 1 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 0 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1a | 2 Participants |
Primary
Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a
The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 542 days; maximum follow-up: 572 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 4 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 3 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 3 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 10 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 4 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 4 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 2 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 5 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Hematology Laboratory Abnormalities of Any CTCAE Grade: Phase 1a | 8 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a
An adverse event (AE) was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 542 days; maximum follow-up: 572 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 0 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 2 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 4 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 3 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 2 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 3 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 3 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 5 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 4 Participants |
| Phase 1a: PF-07284890 300 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 10 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 3 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 2 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 450 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 2 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 4 Participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 3 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 4 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 4 Participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 1 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 1 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 2 Participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 5 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 2 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 2 Participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 3 or 4 TEAEs | 3 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with serious treatment related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Serious TEAEs | 3 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with TEAEs | 8 Participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1a | Participants with Grade 5 TEAEs | 2 Participants |
Primary
Overall Response Rate (ORR): Phase 1b
ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Population: The response evaluable population included all participants who received at least one dose of study treatment and had measurable disease at baseline and at least one post baseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Overall Response Rate (ORR): Phase 1b | 100 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Overall Response Rate (ORR): Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | Overall Response Rate (ORR): Phase 1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Overall Response Rate (ORR): Phase 1b | 11.1 Percentage of participants |
Primary
Response Rate Using Response Assessment in Neuro-Oncology (RANO) for Primary Brain Tumors: Phase 1b
RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for more than or equal to (\>=) 4 weeks; no new lesions; stable or improved non-enhancing (T2/ \[fluid attenuated inversion recovery\] FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; no new lesions; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Population: The response evaluable population analyzed. The outcome measure was to be evaluated only in glioblastoma participants; apart from Cohort 5 all other cohorts did not have any glioblastoma participants. Hence, Overall Number of Participants Analyzed for these cohorts is 0 and for Cohort 5 it signifies participants evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 200 mg BID | Response Rate Using Response Assessment in Neuro-Oncology (RANO) for Primary Brain Tumors: Phase 1b | 50.0 Percentage of participants |
Secondary
Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Rac was defined as area under the plasma concentration-time curve over the dosing interval at steady state (AUCss,τ) divided by area under the plasma concentration-time curve over the dosing interval from a single dose (AUCsd,τ).
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D1 and C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
| Phase 1a: PF-07284890 100 mg QD | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
| Phase 1a: PF-07284890 200 mg QD | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 1.024 Ratio | Standard Deviation 0.11484 |
| Phase 1a: PF-07284890 300 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Ratio | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 1.609 Ratio | Standard Deviation 0.54869 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Ratio | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 1.950 Ratio | Standard Deviation 0.5356 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 2.088 Ratio | Standard Deviation 1.0472 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Accumulation Ratio (Rac) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Ratio | — |
Secondary
Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
CL/F was calculated as Dose/AUCinf.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Population: PK parameter analysis population used. Overall Number of Participants Analyzed= participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' =number of participants evaluable for specified rows. CL/F could not be calculated either due to either participants had insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined, which affects the ability to calculate CL/F and thus reported 0 as applicable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 100 mg QD | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 200 mg QD | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 300 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Liter per hour (L/hr) | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 33.97 Liter per hour (L/hr) | Standard Deviation 13.627 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 40.48 Liter per hour (L/hr) | Standard Deviation 12.458 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Apparent Oral Clearance (CL/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter per hour (L/hr) | — |
Secondary
Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Population: PK parameter analysis population used. Overall Number of Participants Analyzed= participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' =number of participants evaluable for specified rows. Vz/F could not be calculated either due to either participants had insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined, which affects the ability to calculate Vz/F and thus reported 0 as applicable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter | — |
| Phase 1a: PF-07284890 100 mg QD | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter | — |
| Phase 1a: PF-07284890 200 mg QD | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter | — |
| Phase 1a: PF-07284890 300 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Liter | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Liter | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Liter | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 97.50 Liter | Standard Deviation 7.1757 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Liter | — |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Apparent Volume of Distribution (Vz/F) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 139.3 Liter | Standard Deviation 52.043 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
AUCinf was calculated as AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis. Those outcome measures are either due to either patient(s) has insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Population: PK parameter analysis population used. Overall Number of Participants Analyzed= participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' =number of participants evaluable for specified rows. AUCinf could not be calculated either due to either participants had insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined, which affects the ability to calculate AUCinf and thus reported 0 as applicable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 200 mg QD | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 300 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 450 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 3128 ng*hr/mL | Standard Deviation 3244.1 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1958 ng*hr/mL | Standard Deviation 871.79 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1643 ng*hr/mL | Standard Deviation 631.36 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 15390 ng*hr/mL | Standard Deviation 9558 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1437 ng*hr/mL | Standard Deviation 628.11 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
AUClast was determined using the linear/log trapezoidal method.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Nanogram*hour per milliliter (ng*hr/mL) | — |
| Phase 1a: PF-07284890 100 mg QD | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 14960 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 6415.5 |
| Phase 1a: PF-07284890 200 mg QD | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 16400 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 3404.4 |
| Phase 1a: PF-07284890 200 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 8883 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 6085 |
| Phase 1a: PF-07284890 300 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 13250 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 6943.8 |
| Phase 1a: PF-07284890 450 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 8883 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 8251.1 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 21920 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 15893 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1710 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1362.5 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 9858 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 5391.9 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1639 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 673.91 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Nanogram*hour per milliliter (ng*hr/mL) | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Nanogram*hour per milliliter (ng*hr/mL) | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1289 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 358.45 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 17090 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 7615.8 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 11270 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 5458.1 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve From Time Zero to the Last Time Point of Quantifiable Concentration (AUClast) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 979.4 Nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 227.9 |
Secondary
Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 10260 ng*hr/mL | Standard Deviation 813.65 |
| Phase 1a: PF-07284890 200 mg QD | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 16530 ng*hr/mL | Standard Deviation 1616.6 |
| Phase 1a: PF-07284890 200 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 300 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 30030 ng*hr/mL | Standard Deviation 16644 |
| Phase 1a: PF-07284890 450 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 2740 ng*hr/mL | Standard Deviation 1196.2 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 15370 ng*hr/mL | Standard Deviation 5218.1 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 17450 ng*hr/mL | Standard Deviation 7857.3 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 3150 ng*hr/mL | Standard Deviation 1749.5 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 28550 ng*hr/mL | Standard Deviation 5569.3 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 2458 ng*hr/mL | Standard Deviation 341.89 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 2420 ng*hr/mL | Standard Deviation 1306.5 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Area Under the Plasma Concentration Time Curve Over the Dosing Interval (AUCtau) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 29400 ng*hr/mL | Standard Deviation 9041.5 |
Secondary
AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b
AUClast was determined using the linear/log trapezoidal method.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 50 mg QD | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg QD | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | 932.7 ng*hr/mL | Standard Deviation 208.62 |
| Phase 1a: PF-07284890 100 mg QD | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | 9593 ng*hr/mL | Standard Deviation 1633.7 |
| Phase 1a: PF-07284890 200 mg QD | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 200 mg QD | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 200 mg BID | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | 8033 ng*hr/mL | Standard Deviation 3703.1 |
| Phase 1a: PF-07284890 200 mg BID | AUClast of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | 967.7 ng*hr/mL | Standard Deviation 423.36 |
Secondary
AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 50 mg QD | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 100 mg QD | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 2680 ng*hr/mL | Standard Deviation 408 |
| Phase 1a: PF-07284890 100 mg QD | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 20130 ng*hr/mL | Standard Deviation 7072 |
| Phase 1a: PF-07284890 200 mg QD | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 200 mg QD | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA ng*hr/mL | — |
| Phase 1a: PF-07284890 200 mg BID | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 31740 ng*hr/mL | Standard Deviation 13933 |
| Phase 1a: PF-07284890 200 mg BID | AUCtau of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 3011 ng*hr/mL | Standard Deviation 1469.6 |
Secondary
CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
CL/F was calculated as Dose/AUCinf.
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA L/hr | — |
| Phase 1a: PF-07284890 100 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 9.793 L/hr | Standard Deviation 0.82403 |
| Phase 1a: PF-07284890 200 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 12.20 L/hr | Standard Deviation 1.2767 |
| Phase 1a: PF-07284890 200 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA L/hr | — |
| Phase 1a: PF-07284890 300 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 13.14 L/hr | Standard Deviation 7.2301 |
| Phase 1a: PF-07284890 450 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA L/hr | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 7.147 L/hr | Standard Deviation 2.8564 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 18.27 L/hr | Standard Deviation 6.4034 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 22.42 L/hr | Standard Deviation 20.947 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 6.480 L/hr | Standard Deviation 2.3107 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA L/hr | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA L/hr | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 8.138 L/hr | Standard Deviation 1.7244 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 18.60 L/hr | Standard Deviation 2.5073 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 22.54 L/hr | Standard Deviation 10.178 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 11.18 L/hr | Standard Deviation 4.129 |
Secondary
CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
CL/F was calculated as Dose/AUCinf.
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA L/hr | — |
| Phase 1a: PF-07284890 50 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA L/hr | — |
| Phase 1a: PF-07284890 100 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 17.13 L/hr | Standard Deviation 2.9273 |
| Phase 1a: PF-07284890 100 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 16.03 L/hr | Standard Deviation 4.7983 |
| Phase 1a: PF-07284890 200 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA L/hr | — |
| Phase 1a: PF-07284890 200 mg QD | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA L/hr | — |
| Phase 1a: PF-07284890 200 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 11.02 L/hr | Standard Deviation 4.3338 |
| Phase 1a: PF-07284890 200 mg BID | CL/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 21.19 L/hr | Standard Deviation 16.343 |
Secondary
Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 1102 ng/mL | Standard Deviation 178.49 |
| Phase 1a: PF-07284890 200 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 1830 ng/mL | Standard Deviation 291.03 |
| Phase 1a: PF-07284890 200 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | NA ng/mL | — |
| Phase 1a: PF-07284890 300 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 3489 ng/mL | Standard Deviation 1647.2 |
| Phase 1a: PF-07284890 450 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 518.3 ng/mL | Standard Deviation 243.47 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 1991 ng/mL | Standard Deviation 1325.5 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 633.8 ng/mL | Standard Deviation 370.06 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 2270 ng/mL | Standard Deviation 844.63 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | NA ng/mL | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 674.0 ng/mL | Standard Deviation 276.3 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 3870 ng/mL | Standard Deviation 655.34 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-0728489 | 3613 ng/mL | Standard Deviation 739.91 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 457.3 ng/mL | Standard Deviation 180.5 |
Secondary
Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 50 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 557.5 ng/mL | Standard Deviation 223.36 |
| Phase 1a: PF-07284890 100 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 2897 ng/mL | Standard Deviation 925 |
| Phase 1a: PF-07284890 200 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 200 mg QD | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 200 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 4301 ng/mL | Standard Deviation 1647.6 |
| Phase 1a: PF-07284890 200 mg BID | Cmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 671.4 ng/mL | Standard Deviation 380.67 |
Secondary
Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Population: TThe PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 50 mg QD | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | 3730 ng/mL | Standard Deviation 639.06 |
| Phase 1a: PF-07284890 100 mg QD | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | 400.0 ng/mL | Standard Deviation 120.65 |
| Phase 1a: PF-07284890 200 mg QD | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 200 mg QD | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 200 mg BID | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | 387.2 ng/mL | Standard Deviation 168.62 |
| Phase 1a: PF-07284890 200 mg BID | Cmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | 3406 ng/mL | Standard Deviation 1558.8 |
Secondary
Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 50 mg QD | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 755.7 ng/mL | Standard Deviation 446.61 |
| Phase 1a: PF-07284890 100 mg QD | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 73.98 ng/mL | Standard Deviation 31.319 |
| Phase 1a: PF-07284890 200 mg QD | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 200 mg QD | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 200 mg BID | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 120.4 ng/mL | Standard Deviation 74.848 |
| Phase 1a: PF-07284890 200 mg BID | Cmin of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 1512 ng/mL | Standard Deviation 947.8 |
Secondary
Extracranial Response Rate by RECISTv1.1: Phase 1a
Extracranial response rate was defined as the percentage of participants with a BOR of CR or confirmed PR in extracranial lesions by Investigator assessment per RECIST v1.1. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Population: Extracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable tumor at baseline and at least one post baseline extracranial assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 450 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Extracranial Response Rate by RECISTv1.1: Phase 1a | 0 Percentage of participants |
Secondary
Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b
DCR: percentage of participants with BOR of CR, PR/ SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive disease (PD). PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease.
Time frame: From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days)
Population: Intracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable brain tumor at baseline and at least one post baseline intracranial assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b | 100.0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b | 50.0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Intracranial Disease Control Rate (DCR) Per mRECIST v1.1: Phase1b | 100.0 Percentage of participants |
Secondary
Intracranial Duration of Response (DOR) by mRECIST v1.1: Phase1b
DOR was defined as the time from date of the first radiographic response (CR or PR) to the earliest documented PD or death due to any cause. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non target lesions.
Time frame: From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days)
Population: Intracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable brain tumor at baseline and at least one post baseline intracranial assessment. Here Overall Number of Participants Analyzed as 0 signified participants did not have CR or PR.
Secondary
Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b
PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters recorded since the treatment started . In addition, the sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Analysis was performed using Kaplan-Meier method.
Time frame: From date of first dose of study treatment until first documentation of PD or death due to any cause or censoring date whichever occurred first (maximum treatment exposure: 400 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 100 mg QD | Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg QD | Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg BID | Intracranial Progression Free Survival (PFS) by mRECISTv1.1: Phase1b | NA Months |
Secondary
Intracranial Response Rate by mRECISTv1.1: Phase 1a
Intracranial response rate as assessed using modified mRECIST v 1.1., was defined as the percentage of participants with brain or CNS involvement who achieved a CR or PR. CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Population: Intracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable brain tumor at baseline and at least one post baseline intracranial assessment. Here Overall Number of Participants Analyzed as 0 signifies there was no participant evaluable in specified analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 450 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Intracranial Response Rate by mRECISTv1.1: Phase 1a | 0 Percentage of participants |
Secondary
Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b
Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in the short axis. For non-target lesions: All lymph nodes identified as a site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Population: Intracranial response evaluable set included all participants enrolled and received at least one dose of study treatment and had measurable brain tumor at baseline and at least one post baseline intracranial assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 100 mg QD | Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg QD | Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg BID | Intracranial Time to Response (TTR) by mRECIST v1.1: Phase1b | NA Months |
Secondary
Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 130.2 ng/mL | Standard Deviation 67.258 |
| Phase 1a: PF-07284890 200 mg QD | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 198.0 ng/mL | Standard Deviation 155.75 |
| Phase 1a: PF-07284890 200 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 300 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 1773 ng/mL | Standard Deviation 1344.9 |
| Phase 1a: PF-07284890 450 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 73.57 ng/mL | Standard Deviation 28.576 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 181.7 ng/mL | Standard Deviation 99.887 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 822.3 ng/mL | Standard Deviation 441.12 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 127.1 ng/mL | Standard Deviation 66.662 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA ng/mL | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA ng/mL | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 1223 ng/mL | Standard Deviation 602.84 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 67.13 ng/mL | Standard Deviation 26.085 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 94.72 ng/mL | Standard Deviation 32.053 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 1625 ng/mL | Standard Deviation 612.23 |
Secondary
Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on Cycle 1 Day 1 (C1D1); 24 hours was only for arms where study drug was administered as QD.
Population: The pharmacokinetic (PK) parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment and have sufficient information to estimate at least 1 of the PK parameters of interest.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Nanogram per milliliter (ng/mL) | — |
| Phase 1a: PF-07284890 100 mg QD | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 1692 Nanogram per milliliter (ng/mL) | Standard Deviation 541.62 |
| Phase 1a: PF-07284890 200 mg QD | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 1603 Nanogram per milliliter (ng/mL) | Standard Deviation 308.92 |
| Phase 1a: PF-07284890 200 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 1983 Nanogram per milliliter (ng/mL) | Standard Deviation 789.96 |
| Phase 1a: PF-07284890 300 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 2466 Nanogram per milliliter (ng/mL) | Standard Deviation 1008.9 |
| Phase 1a: PF-07284890 450 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 1771 Nanogram per milliliter (ng/mL) | Standard Deviation 1360.5 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 432.3 Nanogram per milliliter (ng/mL) | Standard Deviation 153.53 |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 1893 Nanogram per milliliter (ng/mL) | Standard Deviation 968.86 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 2009 Nanogram per milliliter (ng/mL) | Standard Deviation 922.45 |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 457.5 Nanogram per milliliter (ng/mL) | Standard Deviation 174.37 |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Nanogram per milliliter (ng/mL) | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Nanogram per milliliter (ng/mL) | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 3286 Nanogram per milliliter (ng/mL) | Standard Deviation 1539.4 |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 396.2 Nanogram per milliliter (ng/mL) | Standard Deviation 208.55 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 287.0 Nanogram per milliliter (ng/mL) | Standard Deviation 127.42 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Maximum Observed Concentration (Cmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 2339 Nanogram per milliliter (ng/mL) | Standard Deviation 1220.8 |
Secondary
Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b
The following chemistry laboratory parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, CPK increased, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia and hyponatremia. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had chemistry laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b | 4 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b | 1 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Chemistry Laboratory Abnormalities: Phase 1b | 11 Participants |
Secondary
Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b
In this outcome measure, dose discontinuations for any drug due to TEAEs were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days])
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b | 2 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Discontinuations Due to TEAEs: Phase 1b | 3 Participants |
Secondary
Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b
Dose interruption was defined as a planned dosing day with 0 mg total dose administered. Dose interruptions were applicable to unexpected dose interruptions. In this outcome measure, dose interruptions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days])
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b | 4 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Interruptions Due to TEAEs: Phase 1b | 8 Participants |
Secondary
Number of Participants With Dose Reduction Due to TEAEs: Phase 1b
A dose reduction was defined as the day when the actual dose was less than the planned dose at enrollment and the actual dose was greater than 0 mg (ie, missed doses were not counted as a reduction). In this outcome measure, dose reductions for any drug were considered.
Time frame: During study treatment (from first dose of study treatment [Day 1] up to last dose of study treatment [maximum treatment exposure: 400 days])
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Dose Reduction Due to TEAEs: Phase 1b | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Dose Reduction Due to TEAEs: Phase 1b | 1 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Dose Reduction Due to TEAEs: Phase 1b | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Dose Reduction Due to TEAEs: Phase 1b | 2 Participants |
Secondary
Number of Participants With Hematology Laboratory Abnormalities: Phase 1b
The following hematology laboratory parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v5.0; grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences and grade 5=death. In this outcome measure, those number of participants are reported who had hematology laboratory abnormality in any parameter of any CTCAE Grades.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With Hematology Laboratory Abnormalities: Phase 1b | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With Hematology Laboratory Abnormalities: Phase 1b | 4 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With Hematology Laboratory Abnormalities: Phase 1b | 1 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With Hematology Laboratory Abnormalities: Phase 1b | 11 Participants |
Secondary
Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b
An AE was any untoward medical occurrence in participant/ clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. TEAEs were defined as any AE that occurs during on-treatment period. The on-treatment period was defined as period that starts with first dose of study treatment and ends at last dose of study treatment +30 days, or start of new anti-cancer therapy \[- 1 day\], whichever occurred first. Serious TEAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity and might caused congenital anomaly/birth defect. Serious treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v 5.0 (grade 3= severe, grade 4= life-threatening and grade 5= death related to AE). AEs included SAEs and all non-SAE.
Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment/start of new anti-cancer therapy (-1 Day) whichever occurred first (maximum treatment exposure: 400 days, maximum follow up: 430 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious TEAEs | 0 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with TEAEs | 1 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious Treatment-Related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 50 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 3 or 4 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 3 or 4 TEAEs | 3 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with TEAEs | 4 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious TEAEs | 3 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious Treatment-Related TEAEs | 1 Participants |
| Phase 1a: PF-07284890 100 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 5 TEAEs | 1 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 5 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious Treatment-Related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 3 or 4 TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with TEAEs | 1 Participants |
| Phase 1a: PF-07284890 200 mg QD | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 3 or 4 TEAEs | 6 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious TEAEs | 3 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Serious Treatment-Related TEAEs | 0 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with TEAEs | 11 Participants |
| Phase 1a: PF-07284890 200 mg BID | Number of Participants With TEAEs, Serious TEAEs, Serious Treatment Related TEAEs, Grade 3 or 4 TEAEs and Grade 5 TEAEs by NCI CTCAE v5.0: Phase 1b | Participants with Grade 5 TEAEs | 1 Participants |
Secondary
ORR by RECISTv1.1: Phase 1a
ORR: percentage of participants with BOR of confirmed CR/PR by investigator assessment in intracranial metastasis (mRECISTv1.1) and extracranial lesions (RECISTv1.1). RECIST v1.1- CR: disappearance of all target and non-target lesions. Any pathological lymph node (non-target) must have reduction in short axis to \<10mm. PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. mRECIST- CR: disappearance of all target and non-target lesion. For target lesion: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesion: All lymph nodes identified as site of disease at baseline must be non-pathological (eg, \<10 mm short axis). PR: at least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Population: The response evaluable population included all participants who received at least one dose of study treatment and had measurable disease at baseline and at least one post baseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 450 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | ORR by RECISTv1.1: Phase 1a | 0 Percentage of participants |
Secondary
Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b
DCR: percentage of participants with BOR of CR, PR or SD, Non-CR/Non-PD by Investigator assessment. CR: disappearance of all target & non-target lesions. For target lesions: Any pathological lymph nodes must be \<10 mm in short axis. For non-target lesions: All lymph nodes identified as site of disease at baseline must be non-pathological. PR: At least 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. In addition, sum must have an absolute increase of at least 5 mm. PD for non-target lesions- unequivocal progression of existing non-target lesions. Non-CR/Non-PD: persistence of 1/ more non-target lesion(s) identified as site of disease.
Time frame: From date of first dose until CR or PR or SD (maximum treatment exposure: 400 days)
Population: The response evaluable population included all participants who received at least one dose of study treatment and had measurable disease at baseline and at least one post baseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b | 100.0 Percentage of participants |
| Phase 1a: PF-07284890 100 mg QD | Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg QD | Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b | 0 Percentage of participants |
| Phase 1a: PF-07284890 200 mg BID | Overall Disease Control Rate (DCR) Per RECIST v1.1: Phase1b | 66.7 Percentage of participants |
Secondary
Overall DOR by RECIST v1.1: Phase1b
DOR: time from date of first radiographic response (CR/PR) to earliest documented PD/ death due to any cause.CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: for target lesions- At least 20% increase in sum of diameters of target lesions, taking as reference smallest sum of diameters recorded since treatment started. PD for non-target lesions- unequivocal progression of existing non-target lesions.
Time frame: From CR or PR until first documented PD or death due to any cause (maximum treatment exposure: 400 days)
Population: The response evaluable population included all participants who received at least one dose of study treatment and had measurable disease at baseline and at least one post baseline disease assessment. Here Overall Number of Participants Analyzed signifies participants who have CR or PR and 0 signified participants did not have CR or PR for respective arms.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Overall DOR by RECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg BID | Overall DOR by RECIST v1.1: Phase1b | NA Months |
Secondary
Overall Progression Free Survival (PFS): Phase1b
PFS was defined as the time from date of the first dose of study treatment to the earliest documented disease progression by Investigator assessment, or death due to any cause, whichever occurred first. PD: for target lesions- at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is smallest on study). In addition to the relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered a sign of progression. PD for non-target lesions- unequivocal progression of existing non-target lesion. If a participant had not had a PFS event at the time of the analysis cutoff or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. Overall PFS included evaluation for brain metastasis and extracranial lesions. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum treatment exposure: 400 days)
Population: The safety analysis set included all enrolled participants who received at least one dose of study intervention.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Overall Progression Free Survival (PFS): Phase1b | NA Months |
| Phase 1a: PF-07284890 100 mg QD | Overall Progression Free Survival (PFS): Phase1b | 1.7 Months |
| Phase 1a: PF-07284890 200 mg QD | Overall Progression Free Survival (PFS): Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg BID | Overall Progression Free Survival (PFS): Phase1b | 4.1 Months |
Secondary
Overall Response Rate as Per RANO for Brain Tumours: Phase 1a
RANO response rate was defined as the percentage of glioblastoma participants who achieved a CR or PR per RANO. CR was defined as complete disappearance of all enhancing measurable and non-measurable disease sustained for \>= 4 weeks; no new lesions; stable or improved non-enhancing (T2/FLAIR) lesions; off steroids and neurological condition stable or improved. PR was defined as \>=50% decrease compared to baseline in the sum of the perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of non-measurable disease; stable or improved non enhancing (T2/FLAIR) lesions on the same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at the time of the baseline scan and neurological condition stable or improved.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 542 days)
Population: The response evaluable population included all participants who received at least one dose of study treatment and had measurable disease at baseline and at least one post baseline disease assessment. The outcome measure was to be evaluated only in glioblastoma participants. Overall Number of Participants Analyzed signifies participants evaluable for this outcome and 0 represents no glioblastoma participants for respective reporting arms.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1a: PF-07284890 300 mg BID | Overall Response Rate as Per RANO for Brain Tumours: Phase 1a | 0 Percentage of participants |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Overall Response Rate as Per RANO for Brain Tumours: Phase 1a | 100.0 Percentage of participants |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Overall Response Rate as Per RANO for Brain Tumours: Phase 1a | 0 Percentage of participants |
Secondary
Overall Survival (OS): Phase1b
Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants who were still alive at the end of the study or lost to follow-up were censored at the last date they were known to be alive. Analysis was performed using Kaplan-Meier method.
Time frame: From start of study treatment until death due to any cause or censoring date (maximum treatment exposure: 400 days)
Population: The full analysis set includes all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Overall Survival (OS): Phase1b | NA Months |
| Phase 1a: PF-07284890 100 mg QD | Overall Survival (OS): Phase1b | 5.3 Months |
| Phase 1a: PF-07284890 200 mg QD | Overall Survival (OS): Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg BID | Overall Survival (OS): Phase1b | 12.1 Months |
Secondary
Overall TTR by RECIST v1.1: Phase1b
Time to response is the time from treatment start to date of first documentation of objective response (PR or CR). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (non-target) must have reduction in short axis to \< 10 mm. PR: at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response evaluable population.
Time frame: From date of first dose until CR or PR (maximum treatment exposure: 400 days)
Population: The response evaluable population included all participants who received at least one dose of study treatment and had measurable disease at baseline and at least one post baseline disease assessment. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Overall TTR by RECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 100 mg QD | Overall TTR by RECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg QD | Overall TTR by RECIST v1.1: Phase1b | NA Months |
| Phase 1a: PF-07284890 200 mg BID | Overall TTR by RECIST v1.1: Phase1b | NA Months |
Secondary
t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. In the determination of the t1/2, steady-state was assumed and the pre-dose value was used for the 24-hour post-dose value, which could have enabled the reporting of the t1/2 value higher than 8 hours.
Time frame: Pre-dose (24 hours post-dose concentration), 1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 100 mg QD | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 200 mg QD | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 7.430 Hours | Standard Deviation 4.1 |
| Phase 1a: PF-07284890 200 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 300 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Hours | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Hours | — |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | t½ of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Hours | — |
Secondary
Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Population: The PK parameter analysis population used. Here Overall Number of Participants Analyzed= participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' =number of participants evaluable for specified rows. T1/2 could not be calculated for all participants due to challenges with determining T1/2 using an 8-hour profile particularly for C1D1 (where the pre-dose sample cannot be used), so the data could not be included and thus reported as 0 as applicable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 100 mg QD | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 200 mg QD | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 300 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Hours | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Hours | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Hours | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 2.153 Hours | Standard Deviation 0.62389 |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours | — |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Terminal Elimination Half Life (t½) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 2.443 Hours | Standard Deviation 0.91318 |
Secondary
Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1; 24 hours was only for arms where study drug was administered as QD.
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 100 mg QD | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 4.94 Hours |
| Phase 1a: PF-07284890 200 mg QD | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 5.93 Hours |
| Phase 1a: PF-07284890 200 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 5.87 Hours |
| Phase 1a: PF-07284890 300 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 3.95 Hours |
| Phase 1a: PF-07284890 450 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 2.00 Hours |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 3.44 Hours |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1.01 Hours |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 4.00 Hours |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1.66 Hours |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | NA Hours |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 3.92 Hours |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1.00 Hours |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | PF-07284890 | 3.12 Hours |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Time for Cmax (Tmax) of PF-07284890 and Binimetinib for Single Dose: Phase 1a | Binimetinib | 1.00 Hours |
Secondary
Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 100 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 4.03 Hours |
| Phase 1a: PF-07284890 200 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 2.15 Hours |
| Phase 1a: PF-07284890 200 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 300 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 3.90 Hours |
| Phase 1a: PF-07284890 450 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 1.93 Hours |
| Phase 1a: PF-07284890 100 mg QD + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 3.95 Hours |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 2.08 Hours |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 0.977 Hours |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Hours |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 2.01 Hours |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 1.01 Hours |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 2.03 Hours |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | 1.04 Hours |
Secondary
Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 50 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA Hours |
| Phase 1a: PF-07284890 100 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 1.92 Hours |
| Phase 1a: PF-07284890 100 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 3.50 Hours |
| Phase 1a: PF-07284890 200 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 200 mg QD | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | NA Hours |
| Phase 1a: PF-07284890 200 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | PF-07284890 | 2.08 Hours |
| Phase 1a: PF-07284890 200 mg BID | Tmax of PF-07284890 and Binimetinib for Multiple Dose: Phase 1b | Binimetinib | 1.50 Hours |
Secondary
Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b
Time frame: Pre-dose,1, 2, 4, 6, 8 and 24 hours post-dose on C1D1
Population: The PK parameter analysis population included all enrolled participants treated who did not have protocol deviations influencing PK parameter assessment, and have sufficient information to estimate at least 1 of the PK parameters of interest. Here Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' signifies number of participants evaluable for the specified rows.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 50 mg QD | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | NA Hours |
| Phase 1a: PF-07284890 100 mg QD | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | 2.25 Hours |
| Phase 1a: PF-07284890 100 mg QD | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | 1.25 Hours |
| Phase 1a: PF-07284890 200 mg QD | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | NA Hours |
| Phase 1a: PF-07284890 200 mg QD | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | NA Hours |
| Phase 1a: PF-07284890 200 mg BID | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | Binimetinib | 1.95 Hours |
| Phase 1a: PF-07284890 200 mg BID | Tmax of PF-07284890 and Binimetinib for Single Dose: Phase 1b | PF-07284890 | 3.88 Hours |
Secondary
Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a
Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Pre-dose,1, 2, 4, 6 and 8 hours post dose on C1D15
Population: PK parameter analysis population used. Overall Number of Participants Analyzed= participants evaluable for this outcome measure and contributed to data; 'Number Analyzed' =number of participants evaluable for specified rows. Vz/F could not be calculated either due to either participants had insufficient sample(s) (e.g., sampling only through Tmax or 1 sample after) for analyses or t1/2 could not be determined, which affects the ability to calculate Vz/F and thus reported 0 as applicable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1a: PF-07284890 50 mg QD | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 100 mg QD | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 200 mg QD | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | 126.4 Litre | Standard Deviation 64.519 |
| Phase 1a: PF-07284890 200 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 300 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 100 mg BID + Binimetinib 45 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 150 mg BID + Binimetinib 45 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Litre | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | PF-07284890 | NA Litre | — |
| Phase 1a: PF-07284890 225 mg BID + Binimetinib 45 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Litre | — |
| Phase 1a: PF-07284890 300 mg BID + Binimetinib 45 mg BID | Vz/F of PF-07284890 and Binimetinib for Multiple Dose: Phase 1a | Binimetinib | NA Litre | — |