Colorectal Carcinoma, Malignant Melanoma
Conditions
Brief summary
The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.
Detailed description
Activating mutations of the BRAF gene have been observed in a variety of cancers, including 55-68% of malignant melanomas. In general, oncogenic mutations of BRAF correlate with a poor outcome. PLX4032 is a compound that selectively inhibits oncogenic B-Raf kinase. Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma.
Interventions
DRUGPLX4032
Oral capsules administered BID
Sponsors
Roche Pharma AG
Plexxikon
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Solid tumors confirmed histologically whose tumors are refractory to standard therapy, or for whom standard or curative therapy does not exist * Patients from whom paired melanoma biopsies are planned must have a V600E+ BRAF mutation confirmed prior to the administration of PLX4032 * Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at least 2 weeks prior to starting PLX4032 therapy, and all associated toxicity must be resolved prior to administration of PLX4032 * Patients in the Extension cohorts (melanoma or adenocarcinoma of the colon or rectum) must have both a V600E+ BRAF mutation and measurable disease (by RECIST V 1.0 criteria) prior to the administration of PLX4032. All patients enrolled must provide archival or fresh melanoma tumor biopsy for confirmation of V600E+ BRAF mutation status by TaqMan assay * ECOG performance status 0 or 1 * Life expectancy ≥ 3 months * Adequate hematologic, hepatic, and renal function
Exclusion criteria
* Brain metastases that are progressing or have been documented to be stable for less than 3 months, or for which systemic corticosteroids are required * Investigational drug use within 28 days of the first dose of PLX4032 * Uncontrolled intercurrent illness * Refractory nausea and vomiting, malabsorption, or significant bowel resection that would preclude adequate absorption
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days) | BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method. |
| Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8 | — |
| Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16 | — |
| AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8 | — |
| Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16 | — |
| Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8 | — |
| Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16 | — |
| Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma | Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days) | BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method. |
| Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC | Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days) | BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method. |
| Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation | Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days) | BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method. |
| Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8 | — |
| Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16 | — |
| Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8 | — |
| Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16 | — |
| AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose | Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1. |
| Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose | Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1. |
| Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8 | — |
| Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Month 1, 3, 4, 6, 9, and Last event (350) days | PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. |
| PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma | Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days) | PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment. |
| Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Screening, BL, until PD, or end of efficacy follow-up, up to 444 days | — |
| Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma | Screening, BL, until PD, or end of efficacy follow-up, up to 444 days | OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used. |
| Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma | Screening, BL, and up to 168 days | Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1. |
| Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose | AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule. |
| Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16 | — |
| Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG) | BL and Day 15 | Tumor uptake of FDG was assessed by means of positron-emission tomography (PET) |
| Cmax of RO5185426 - Food Effect | Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16 | — |
| Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67 | BL and Day 15 | The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining. |
| Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma | Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days) | Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment. |
Countries
Australia, United States
Participant flow
Pre-assignment details
Enrollment to Dose Escalation: Original Formulation was halted based on bioavailability results and the drug was reformulated as microprecipitated bulk powder (MBP) and then the enrollment was resumed in Dose Escalation: MBP Formulation arm
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation: Original Formulation Cohorts of 3 to 6 participants received RO5185426 capsules in original (crystalline) formulation at a starting dose of 200 mg BID for 4 weeks. After Day 15 pharmacokinetic assessment and adequate safety and tolerability was shown, next cohort of 3 to 6 participants received 50 % to 100% increased dose of RO5185426 original formulation for 4 weeks. Dose escalation was continued up to 1600 mg BID dose level. | 26 |
| Dose Escalation: MBP Formulation Cohorts of 3 to 6 participants received RO5185426 capsules/tablets in MBP formulation at a starting dose of 160 mg BID for 4 weeks. After Day 15 pharmacokinetic assessment and adequate safety and tolerability was shown, next cohort of 3 to 6 participants received 50 % to 100% increased dose of RO5185426 MBP formulation for 4 weeks. Dose escalation was continued up to unacceptable toxicity or disease progression occurred. | 30 |
| Extension: BRAFV600E- Positive Melanoma Participants with melanoma tumors that carried the V600E mutation of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg BID until disease progression, death, or withdrawal from the study. | 32 |
| Extension: BRAFV600E- Positive CRC Participants with CRC that carried the V600E mutation of BRAF received RO5185426 capsules/tablets in MBP formulation at a dose of 960 mg BID until disease progression, death, or withdrawal from the study. | 21 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Disease Progression | 22 | 23 | 21 | 17 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Overall Study | Participant not dosed | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 3 | 2 | 0 | 0 |
| Overall Study | Radiation induced necrosis | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Dose Escalation: Original Formulation | Dose Escalation: MBP Formulation | Extension: BRAFV600E- Positive Melanoma | Extension: BRAFV600E- Positive CRC | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 13.75 | 58.0 years STANDARD_DEVIATION 14.77 | 50.4 years STANDARD_DEVIATION 13.54 | 63.6 years STANDARD_DEVIATION 14.86 | 58.6 years STANDARD_DEVIATION 15.24 |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 14 Participants | 10 Participants | 46 Participants |
| Sex: Female, Male Male | 15 Participants | 19 Participants | 18 Participants | 11 Participants | 63 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 3 / 3 | 5 / 5 | 7 / 7 | 6 / 6 | 6 / 6 | 6 / 6 | 10 / 10 | 4 / 4 | 32 / 32 | 21 / 21 |
| serious Total, serious adverse events | 0 / 4 | 2 / 4 | 2 / 3 | 3 / 5 | 1 / 7 | 2 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 4 | 18 / 32 | 9 / 21 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n=6, 3, 3, 4) | 9.37 ug*hr/mL | Standard Deviation 6.18 |
| Dose Escalation: Original Formulation - 200 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 2, 2, 3, 4) | 46.28 ug*hr/mL | Standard Deviation 10.47 |
| Dose Escalation: Original Formulation - 400 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 2, 2, 3, 4) | 105.10 ug*hr/mL | Standard Deviation 65.41 |
| Dose Escalation: Original Formulation - 400 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n=6, 3, 3, 4) | 30.90 ug*hr/mL | Standard Deviation 11.44 |
| Dose Escalation: Original Formulation - 800 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n=6, 3, 3, 4) | 30.58 ug*hr/mL | Standard Deviation 7.08 |
| Dose Escalation: Original Formulation - 800 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 2, 2, 3, 4) | 91.01 ug*hr/mL | Standard Deviation 26.86 |
| Dose Escalation: Original Formulation - 1600 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n=6, 3, 3, 4) | 33.89 ug*hr/mL | Standard Deviation 17.24 |
| Dose Escalation: Original Formulation - 1600 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 2, 2, 3, 4) | 101.13 ug*hr/mL | Standard Deviation 48.4 |
Primary
Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n= 6, 4, 4, 4) | 2.02 ug*hr/mL | Standard Deviation 1.03 |
| Dose Escalation: Original Formulation - 200 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 6, 4, 4, 4) | 8.43 ug*hr/mL | Standard Deviation 4.84 |
| Dose Escalation: Original Formulation - 400 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 6, 4, 4, 4) | 14.86 ug*hr/mL | Standard Deviation 7.89 |
| Dose Escalation: Original Formulation - 400 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n= 6, 4, 4, 4) | 3.28 ug*hr/mL | Standard Deviation 1.66 |
| Dose Escalation: Original Formulation - 800 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n= 6, 4, 4, 4) | 4.47 ug*hr/mL | Standard Deviation 0.61 |
| Dose Escalation: Original Formulation - 800 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 6, 4, 4, 4) | 21.66 ug*hr/mL | Standard Deviation 10.59 |
| Dose Escalation: Original Formulation - 1600 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-8 hour) (n= 6, 4, 4, 4) | 4.23 ug*hr/mL | Standard Deviation 2 |
| Dose Escalation: Original Formulation - 1600 mg | Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | AUC (0-24 hour) (n= 6, 4, 4, 4) | 22.34 ug*hr/mL | Standard Deviation 10.59 |
Primary
AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4) | 33.91 mcg*hr/mL | Standard Deviation 19.14 |
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3) | 87.18 mcg*hr/mL | Standard Deviation 88.78 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4) | 71.64 mcg*hr/mL | Standard Deviation 30.09 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3) | 228.97 mcg*hr/mL | Standard Deviation 81.03 |
| Dose Escalation: Original Formulation - 800 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4) | 114.50 mcg*hr/mL | Standard Deviation 35.33 |
| Dose Escalation: Original Formulation - 800 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3) | 373.94 mcg*hr/mL | Standard Deviation 94.51 |
| Dose Escalation: Original Formulation - 1600 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4) | 212.28 mcg*hr/mL | Standard Deviation 123.24 |
| Dose Escalation: Original Formulation - 1600 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3) | 622.21 mcg*hr/mL | Standard Deviation 406.89 |
| Dose Escalation: MBP Formulation - 960 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4) | 229.96 mcg*hr/mL | Standard Deviation 42.75 |
| Dose Escalation: MBP Formulation - 960 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3) | 649.29 mcg*hr/mL | Standard Deviation 200.95 |
| Dose Escalation: MBP Formulation - 1120 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-8 hour) (n= 4, 4, 4, 4, 3, 4) | 536.47 mcg*hr/mL | Standard Deviation 137.18 |
| Dose Escalation: MBP Formulation - 1120 mg | AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | AUC (0-24 hour) (n= 2, 3, 3, 3, 2, 3) | 1494.27 mcg*hr/mL | Standard Deviation 367.68 |
Primary
AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-8 hour) (n= 14, 13 ) | 289.26 ug*hr/mL | Standard Deviation 105.88 |
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-24 hour) (n= 9, 11) | 924.65 ug*hr/mL | Standard Deviation 317.71 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-8 hour) (n= 14, 13 ) | 262.42 ug*hr/mL | Standard Deviation 101.37 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-24 hour) (n= 9, 11) | 752.64 ug*hr/mL | Standard Deviation 314.47 |
Primary
AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 5.98 ug*hr/mL | Standard Deviation 3.31 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 15.85 ug*hr/mL | Standard Deviation 1.53 |
| Dose Escalation: Original Formulation - 800 mg | AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 14.95 ug*hr/mL | Standard Deviation 4.99 |
| Dose Escalation: Original Formulation - 1600 mg | AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 39.09 ug*hr/mL | Standard Deviation 35.82 |
| Dose Escalation: MBP Formulation - 960 mg | AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 39.48 ug*hr/mL | Standard Deviation 19.58 |
| Dose Escalation: MBP Formulation - 1120 mg | AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 44.94 ug*hr/mL | Standard Deviation 20.88 |
Primary
AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-8 hour) (n= 29, 21) | 31.35 mcg*hr/mL | Standard Deviation 15.51 |
| Dose Escalation: Original Formulation - 200 mg | AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-24 hour) (n= 5, 0) | 108.52 mcg*hr/mL | Standard Deviation 42.36 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-8 hour) (n= 29, 21) | 31.53 mcg*hr/mL | Standard Deviation 15.1 |
| Dose Escalation: Original Formulation - 400 mg | AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | AUC (0-24 hour) (n= 5, 0) | NA mcg*hr/mL | — |
Primary
Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 5.16 micrograms per milliliter | Standard Deviation 2.72 |
| Dose Escalation: Original Formulation - 400 mg | Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 11.64 micrograms per milliliter | Standard Deviation 4.55 |
| Dose Escalation: Original Formulation - 800 mg | Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 17.90 micrograms per milliliter | Standard Deviation 8.01 |
| Dose Escalation: Original Formulation - 1600 mg | Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 31.15 micrograms per milliliter | Standard Deviation 15.56 |
| Dose Escalation: MBP Formulation - 960 mg | Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 34.10 micrograms per milliliter | Standard Deviation 5.47 |
| Dose Escalation: MBP Formulation - 1120 mg | Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 84.30 micrograms per milliliter | Standard Deviation 23.51 |
Primary
Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16
Population: Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | 44.31 microgram/milliliter | Standard Deviation 16.38 |
| Dose Escalation: Original Formulation - 400 mg | Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | 38.55 microgram/milliliter | Standard Deviation 15.92 |
Primary
Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 1.14 micrograms per milliliter | Standard Deviation 0.48 |
| Dose Escalation: Original Formulation - 400 mg | Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 2.93 micrograms per milliliter | Standard Deviation 0.39 |
| Dose Escalation: Original Formulation - 800 mg | Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 2.72 micrograms per milliliter | Standard Deviation 0.94 |
| Dose Escalation: Original Formulation - 1600 mg | Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 7.2 micrograms per milliliter | Standard Deviation 6.06 |
| Dose Escalation: MBP Formulation - 960 mg | Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 7.12 micrograms per milliliter | Standard Deviation 3.71 |
| Dose Escalation: MBP Formulation - 1120 mg | Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 7.73 micrograms per milliliter | Standard Deviation 3.54 |
Primary
Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Population: Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | 5.84 microgram/milliliter | Standard Deviation 2.61 |
| Dose Escalation: Original Formulation - 400 mg | Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | 5.53 microgram/milliliter | Standard Deviation 2.27 |
Primary
Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation
Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Time frame: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | 4.75 ratio | Standard Deviation 3.14 |
| Dose Escalation: Original Formulation - 400 mg | Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | 4.47 ratio | Standard Deviation 1.57 |
| Dose Escalation: Original Formulation - 800 mg | Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | 8.66 ratio | Standard Deviation 5.37 |
| Dose Escalation: Original Formulation - 1600 mg | Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | 8.89 ratio | Standard Deviation 6.03 |
| Dose Escalation: MBP Formulation - 960 mg | Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | 10.11 ratio | Standard Deviation 3.09 |
| Dose Escalation: MBP Formulation - 1120 mg | Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation | 13.86 ratio | Standard Deviation 4.68 |
Primary
Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC
Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.
Time frame: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | 11.61 ratio | Standard Deviation 4.59 |
| Dose Escalation: Original Formulation - 400 mg | Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC | 9.31 ratio | Standard Deviation 3.9 |
Primary
Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16
Population: PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 1.34 Micrograms per milliliter | Standard Deviation 0.81 |
| Dose Escalation: Original Formulation - 400 mg | Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 4.57 Micrograms per milliliter | Standard Deviation 2.07 |
| Dose Escalation: Original Formulation - 800 mg | Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 5.41 Micrograms per milliliter | Standard Deviation 2.26 |
| Dose Escalation: Original Formulation - 1600 mg | Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 5.34 Micrograms per milliliter | Standard Deviation 3.04 |
Primary
Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Population: PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 0.37 Micrograms per milliliter | Standard Deviation 0.2 |
| Dose Escalation: Original Formulation - 400 mg | Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 0.58 Micrograms per milliliter | Standard Deviation 0.27 |
| Dose Escalation: Original Formulation - 800 mg | Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 0.85 Micrograms per milliliter | Standard Deviation 0.06 |
| Dose Escalation: Original Formulation - 1600 mg | Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 0.73 Micrograms per milliliter | Standard Deviation 0.38 |
Primary
Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma
BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Population: Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma | Confirmed BOR | 56.3 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma | Unconfirmed BOR | 81.3 percentage of participants |
Primary
Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation
BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Population: Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | 0 percentage of participants |
| Dose Escalation: Original Formulation - 400 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | 25.0 percentage of participants |
| Dose Escalation: Original Formulation - 800 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | 33.3 percentage of participants |
| Dose Escalation: Original Formulation - 1600 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | 40.0 percentage of participants |
| Dose Escalation: MBP Formulation - 960 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | 28.6 percentage of participants |
| Dose Escalation: MBP Formulation - 1120 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation | 50.0 percentage of participants |
Primary
Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation
BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Population: Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation | 0 percentage of participants |
| Dose Escalation: Original Formulation - 400 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation | 0 percentage of participants |
| Dose Escalation: Original Formulation - 800 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation | 10.0 percentage of participants |
| Dose Escalation: Original Formulation - 1600 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation | 0 percentage of participants |
Primary
Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC
BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Population: Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered evaluable for efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC | 5.0 percentage of participants |
Primary
Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16
Population: PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 0.02 hours |
| Dose Escalation: Original Formulation - 400 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 0.5 hours |
| Dose Escalation: Original Formulation - 800 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 0 hours |
| Dose Escalation: Original Formulation - 1600 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation | 3 hours |
Primary
Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Population: PK Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 9.98 hours |
| Dose Escalation: Original Formulation - 400 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 4 hours |
| Dose Escalation: Original Formulation - 800 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 3.01 hours |
| Dose Escalation: Original Formulation - 1600 mg | Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation | 4 hours |
Primary
Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 1.5 hours |
| Dose Escalation: Original Formulation - 400 mg | Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 2.0 hours |
| Dose Escalation: Original Formulation - 800 mg | Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 4.10 hours |
| Dose Escalation: Original Formulation - 1600 mg | Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 4.07 hours |
| Dose Escalation: MBP Formulation - 960 mg | Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 4.33 hours |
| Dose Escalation: MBP Formulation - 1120 mg | Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation | 0.41 hours |
Primary
Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16
Population: Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC | 1.01 hours |
| Dose Escalation: Original Formulation - 400 mg | Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC | 2.0 hours |
Primary
Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Population: Pharmacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 2 hours |
| Dose Escalation: Original Formulation - 400 mg | Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 3 hours |
| Dose Escalation: Original Formulation - 800 mg | Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 3.21 hours |
| Dose Escalation: Original Formulation - 1600 mg | Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 6.29 hours |
| Dose Escalation: MBP Formulation - 960 mg | Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 3.29 hours |
| Dose Escalation: MBP Formulation - 1120 mg | Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation | 4.33 hours |
Primary
Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8
Population: Phamacokinetic (PK) Population: Participants who received all RO5185426 doses without dose reduction up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC | 4 hours |
| Dose Escalation: Original Formulation - 400 mg | Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC | 4 hours |
Secondary
Cmax of RO5185426 - Food Effect
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16
Secondary
Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)
Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)
Time frame: BL and Day 15
Secondary
Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma
Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)
Population: Modified ITT population: Participants with confirmed CR or PR with a measurable disease at BL, and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Seven participants were censored for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma | 227 days |
Secondary
Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma
AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.
Time frame: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose
Population: The analysis was planned only for those participants who received 80 or 120 mg dose of RO5185426 up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome; n=participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | AUC (0-8hour) (n= 10, 19) | 0.179 ug*hr/mL | Standard Deviation 0.081 |
| Dose Escalation: Original Formulation - 200 mg | Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | AUC (0-24 hour) (n= 7, 9) | 0.524 ug*hr/mL | Standard Deviation 0.233 |
| Dose Escalation: Original Formulation - 400 mg | Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | AUC (0-8hour) (n= 10, 19) | 0.197 ug*hr/mL | Standard Deviation 0.091 |
| Dose Escalation: Original Formulation - 400 mg | Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | AUC (0-24 hour) (n= 7, 9) | 0.482 ug*hr/mL | Standard Deviation 0.165 |
Secondary
Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma
Time frame: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16
Population: PK Population: The analysis was planned only for those participants who received 80 or 120 mg dose of RO5185426 up to and including Day 15 and provided at least PK assessments up to and including 8 to 10 hours after first dose on Day 15. Number of participants analyzed=participants evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | 0.028 ug/mL | Standard Deviation 0.012 |
| Dose Escalation: Original Formulation - 400 mg | Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma | 0.030 ug/mL | Standard Deviation 0.013 |
Secondary
Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma
OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
Population: Modified ITT Population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Twenty participants were censored for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma | NA days |
Secondary
Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days
Population: Modified ITT Population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Month 1 | 0 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Month 3 | 3.1 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Month 4 | 6.2 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Month 6 | 12.7 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Month 9 | 29.4 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma | Month 12 | 43.2 percentage of participants |
Secondary
Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort
PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.
Time frame: Month 1, 3, 4, 6, 9, and Last event (350) days
Population: Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Eight participants were censored for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Month 1 | 96.9 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Month 3 | 87.5 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Month 4 | 75.0 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Month 6 | 59.4 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Month 9 | 43.3 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | 1 Year | 16.9 percentage of participants |
| Dose Escalation: Original Formulation - 200 mg | Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort | Last Event (350 Days) | 16.9 percentage of participants |
Secondary
PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma
PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.
Time frame: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)
Population: Modified ITT population: All participants with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered. Eight participants were censored for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma | 233 days |
Secondary
Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma
Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.
Time frame: Screening, BL, and up to 168 days
Population: Modified ITT population: Participants with a confirmed CR or PR with a measurable disease at BL and completed at least one post-baseline radiographic assessment or discontinued study medication early due to disease progression were considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation: Original Formulation - 200 mg | Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma | 56.5 days |
Secondary
Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67
The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.
Time frame: BL and Day 15