Colorectal Cancer, Solid Tumor
Conditions
Keywords
RASMT CRC, RASWT/c-MET CRC, Dose Escalation, Histologically or cytologically confirmed, Dose Expansion
Brief summary
This trial is designed to try two new cancer drugs together for the first time. The investigators think that they might be effective in some types of bowel cancer. The first part of the trial will see what doses of the two drugs can safely be given together. Once the investigators have identified a suitable dose combination they will look at how effective treatment is in bowel cancers where either the RAS gene is mutated, or MET is over-active. In the trial the investigators will look at samples of blood, skin and tumour to check the drugs are working in the way expected. The trial will take place in three sites in the UK and 5 sites in Europe. The trial is funded as part of the European commission's FP7 program.
Detailed description
This is a two stage study. Firstly a dose escalation step is used to define the best dose for the drug combination, using the rolling 6 design where up to 6 patients are recruited at each dose level, and increasing the dose of one or other agent according to the side effects of treatment. An initial dose escalation phase was completed where 25 patients were enrolled, using the study treatment combination of PD-0325901 with PF-02341066. Following discontinuation of the MEKi (inihibitor), PD-0325901, the study was updated to include a further dose escalation phase using the new combination study treatment, MEKi, Binimetinib with METi, PF-02341066. The effects of this drug combination will be assessed to define the recommended dose level for the dose expansion phase of the study. Second the new drug combination is observed in 42-98 patients with bowel cancer for its efficacy and tolerability. Patients who give consent will have their archival tumour samples tested for RAS and c-MET status. Potential participants will, after giving consent, undergo screening tests to ensure that it is safe for them to take part. These involve a detailed medical history, physical exam, blood tests, ophthalmology exam, ECG and ultrasound and skin biopsies. The size and extent of tumours is also assessed by CT and/or MRI scan. For the initial dose escalation phase, on assurance that the test results are satisfactory, patients start on PD-0325901 first for one week. On Day -7 a physical exam, ECG and blood test is performed, with a repeat blood test on Day -6. End of first week PD samples of blood are taken to observe the level of PD-0325901. Day 1 PF-02341066 is introduced after further clinical safety assessments. There are further blood samples taken over 24 hours to measure levels of PD-0325901 and PF-02341066 on days 21 and 28 of the first cycle. For the further dose escalation phase, again assuming that the screening test results are satisfactory, patients start on Day 1 with the combined treatment of PF-02341066 with Binimetinib. A physical exam, ECG and blood test is performed, with a repeat blood test on Day 2. There are further blood samples taken over 24 hours to measure levels of Binimetinib and PF-02341066 on day 21of the first cycle. Patients have weekly visits when side effects are reviewed and a physical examination is performed. On Day 15 a second skin biopsy is taken along with blood tests to assess liver and renal function. At the end of the first 4 weeks cycle, for the initial dose escalation phase, and at end of 8 weeks for the new combination therapy dose escalation phase, an ophthalmology exam is compared with the baseline assessment. For subsequent cycles in both the initial dose escalation and further dose escalation phases, visits remain weekly and include safety assessments as per Day 1. Blood levels of PD-0325901 or Binimetinib and PF-02341066 are measured on day 21 of even numbered cycles. In addition the tumour size is checked every second cycle, and the study treatment stopped if the tumour continues to grow. When patients stop taking the study treatment they will be reviewed after 4 weeks for any side effects and have a physical examination and other safety tests performed. For patients entering the expansion phase of the trial the procedures are similar, except that there is a pre-screening stage where tumour biopsies are required. Patients will have a sample of their tumour assessed, following consent, to determine their RAS and cMET status. This may involve a fresh biopsy. If suitable, the patient will be entered into the screening for the dose expansion phase and a fresh tumour biopsy may be taken if not already done so. The study schedule is the same as for the escalation phase using Binimetinib with PF-02341066. At the end of treatment a further, optional, tumour biopsy may be taken. After trial participation patients will be offered further care with the trial team or their referring oncology team as appropriate.
Interventions
DRUGPF-02341066
PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
DRUGPD-0325901
PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle.
DRUGBinimetinib
Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
Sponsors
Queen's University, Belfast
Oxford University Hospitals NHS Trust
Velindre NHS Trust
University Hospital, Antwerp
Hospital Vall d'Hebron
Saint Antoine University Hospital
European Georges Pompidou Hospital
Pfizer
University of Turin, Italy
Belfast Health and Social Care Trust
Beaumont Hospital
European Commission
Array BioPharma
University of Paris 5 - Rene Descartes
University of Oxford
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
(Inclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 are listed in Appendix 7.) All patients * Age ≥ 16 years (\>18 years in France) * ECOG performance status 0-1 (Appendix 1) * Adequate respiratory function on clinical assessment * Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram┼ * Able to give informed consent prior to any screening procedures being performed and be capable of complying with the protocol and its requirements * Haematological and biochemical indices within the ranges shown below: * Haemoglobin (Hb) ≥ 9g/dl (transfusion to achieve this allowed ), * Neutrophils ≥ 1,500/μl, * Platelet count ≥ 100,000/μl, * AST or ALT ≤ 2.5 x ULN, patient with liver metastases ≤ 5 × ULN, * Alkaline phosphatase ≤ 5 x ULN, * Serum Bilirubin ≤ 1.5 x ULN, * Creatinine Clearance ≥ 50ml/min (Calculated by Cockcroft Gault equation, or by EDTA) (Appendix 2) * Able to swallow oral medication * Life expectancy of at least 3 months. Dose escalation phase: * Patients with any advanced solid tumours * Patients for whom the combination of PF-02341066 with Binimetinib is a reasonable option. Dose expansion phase: Patients will be eligible for pre-screening for this phase provided that: * They have given informed consent to screening. * They are willing to undergo a biopsy for assessment of tumour RAS mutation status and c-MET assessment. * The Investigator anticipates that they are likely to satisfy the eligibility criteria for the trial. Formal screening should not be performed until the tumour pre-screening result is known. Eligibility for the trial, in patients passing pre-screening, requires: * Histologically confirmed colorectal adenocarcinoma that is either a) RASMT (KRAS codon 12, 13, 61, 117, 146; NRAS codon 12, 13, 61, 117, 146) or b) RASWT/c-MET mutated/amplified or c) RASWT/c-MET over-expressed with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy and/or targeted therapies for metastatic disease. * Prior treatment with an EGFR targeted monoclonal antibody for patients with RASWT/c-MET mutated or amplified CRC or c) RASWT/c-MET over-expressed CRC. * No evidence for a mutation in BRAF at codon600 * Metastases accessible for biopsy on 2-3 occasions * At least one other measurable lesion (according to RECIST v1.1). * Unsuitable for potential curative resection. ┼For non-UK territories: if echocardiogram (ECHO) cannot be performed, a MUGA scan may be performed in compliance with local policy, applicable national legislation and relevant approvals. Cardiac ejection fraction must be determined as measured by ECHO in the UK.
Exclusion criteria
(
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066 | Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination) | Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours. |
| Clinical Response to Binimetinib Combined With PF-02341066 | Dose Expansion phase: change from baseline and up to 12 months. | To investigate response to treatment with RPII dose of Binimetinib with Crizotinib (PF-02341066), in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC, as defined by stable, partially or completely responding disease, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase (\>=20%) to qualify for Progressive Disease; Overall Response (OR) = CR + PR + SD |
| Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066 | Dose Escalation Phase: treatment Cycle 1 28 days | To determine the maximal tolerated dose (MTD) of Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE V4.03 in cycle 1 of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Plasma Oral Clearance for PF-02341066 and PD-0325901 | Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28 | To investigate the pharmacokinetics (PK) plasma oral clearance of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination. |
| Progression Free Survival (Dose Expansion) | From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months (dose expansion)). | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>=20% increase in the sum of diameters of target lesions (also demonstrating an absolute increase of at least 5mm) or the appearance of new lesions. |
| Overall Survival (Dose Expansion) | From date of study entry until the date of death, assessed up to study completion, an average of 6 months (dose escalation). | Overall survival (dose expansion). |
| Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Dose Expansion: PK profile up to 10 hrs at Cycle 1 Day 21 | To investigate the pharmacokinetic (PK) peak plasma concentration (Cmax) of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood. |
| Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs . | To investigate pharmacokinetic plasma trough concentration Cmin of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood. |
| Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs | To investigate pharmacokinetic area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood. |
| Pharmacokinetic Oral Clearance for PF-02341066 and Binimetinib. | Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21 | To investigate pharmacokinetic (PK) oral clearance of PF-02341066 and Binimetinib in blood. |
| Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | Dose Escalation and Expansion: at baseline and Cycle1, D15. | Measurement of phosphoMEK1/2 in skin biopsies to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired skin biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum. |
| Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Tumour Biopsies (Where Possible). | Dose Escalation: Biopsies at baseline and Cycle1 D15 - both optional. | Measurement of pSTAT3Y705 to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired tumour biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum. |
| Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day - 1, Day 21 and Day 28 of Cycle 1 | To investigate the pharmacokinetics (PK) plasma Cmax of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination. |
| Progression Free Survival (Dose Escalation Binimetinib/PF-02341066). | From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>=20% increase in the sum of diameters of target lesions (also demonstrating an absolute increase of at least 5mm) or the appearance of new lesions. |
| Overall Survival (Dose Escalation Binimetinib/PF-02341066) | From date of study entry until the date of death, assessed up to study completion, an average of 6 months | Overall survival (Dose escalation Binimetinib/PF-02341066). |
| Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1 | To investigate the pharmacokinetics (PK) plasma Cmax of Binimetinib (and its metabolite AR00426032) with PF-023241066 when administered in combination. |
| Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Dose Escalation phase :Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1 | To investigate the pharmacokinetic (PK) minimum plasma trough concentration (Cmin) of PF-02341066 and binimetinib in blood. |
| Pharmacokinetic Plasma Oral Clearance for PF-02341066 and Binimetinib | Dose Expansion phase at Cycle 1 Day 21 up to 10 hours binimetinib and its metabolite, AR00426032, and up to 24 hours for PF-02341066 | To investigate the pharmacokinetics (PK) plasma oral clearance of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination. |
| Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | Dose Escalation and Expansion: at baseline and Cycle1, D15. | Measurement of phosphoERK1/2 to investigte the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired skin biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum. |
| Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28 | To investigate the pharmacokinetics (PK) plasma half life of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination. |
| Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21 | To investigate pharmacokinetic (PK) t1/2 of PF-02341066 and Binimetinib in blood. |
| Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib | Dose Expansion phase at Cycle 1 Day 21 up to 10 hours binimetinib and its metabolite, AR00426032, and up to 24 hours for PF-02341066 | To investigate the pharmacokinetics (PK) plasma half life of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination. |
| Pharmacodynamic (PD) Effect of PF-02341066 in Combination With Binimetinib in Paired Tumour Biopsies (Where Possible). | Dose Expansion: Biopsies at baseline and Cycle1 D15. Optional metastic tumour biopsy within 28 days following radiological confirmation of disease progression. | Measurement of phosphoERK1/2 to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with Binimetinib in paired tumour biopsies (where possible) to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum. |
| Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Dose Escalation:Up to 12 mths. Cycle 1 PK profile up to 10 hrs post dose on Day -1, 21 and 28 | To investigate the pharmacokinetics (PK) plasma Cmin of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination. |
| Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Dose Escalation:Up to12 months. Cycle 1 PK profile up to 10 hrs on Day -1, 21 and 28 | To investigate the pharmacokinetics (PK) plasma AUC of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination. |
Countries
United Kingdom
Participant flow
Pre-assignment details
1 patient in escalation phase dose 5 was registered to the trial on 28Sep2016 but withdrew before dose administration due to unexpected and fast disease progression.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Phase Dose 1. Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
PD-0325901: PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle. | 6 |
| Dose Escalation Phase Dose 2. Crizotinib 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
PD-0325901: PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle. | 5 |
| Dose Escalation Phase Dose 3. Crizotinib 200mg BD Days 1-28 continuously PD-0325901 4mg BD Run in Day -7 to Cycle 1 Day 1, then Day 1-21 every 28 day cycle
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
PD-0325901: PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle. | 6 |
| Dose Escalation Phase Dose 4. Crizotinib 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
PD-0325901: PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle. | 8 |
| Dose Escalation Phase 5. Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
PD-0325901: PD-0325901 2mg - 8mg BD with Run in Day -7 to Day-1 on Cycle 1 Day1, then Day 1-21 every 28 day cycle.
Binimetinib: Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days | 8 |
| Dose Escalation Phase Dose 5a Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Binimetinib: Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days | 7 |
| Dose Expansion Phase Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days PF-02341066 (Crizotinib) 250mg OD Days 1-28 continuously Dosage determined following the recommended Phase II dose identification in the dose escalation phase.
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Binimetinib: Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days | 37 |
| Dose Escalation Phase Dose 5 (Interval Dosing) Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
PF-02341066: PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Binimetinib: Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days | 5 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 2 | 1 | 2 | 5 |
| Overall Study | Early disease progression | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Dose Escalation Phase Dose 2. | Dose Escalation Phase Dose 3. | Dose Escalation Phase Dose 4. | Dose Escalation Phase 5. | Dose Escalation Phase Dose 5a | Dose Expansion Phase | Dose Escalation Phase Dose 1. | Dose Escalation Phase Dose 5 (Interval Dosing) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 13 Participants | 2 Participants | 1 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 5 Participants | 6 Participants | 5 Participants | 24 Participants | 4 Participants | 4 Participants | 56 Participants |
| Age, Continuous | 64.8 years | 58.4 years | 61.2 years | 51.0 years | 60.0 years | 62.0 years | 65.8 years | 55.0 years | 60.4 years |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 18 Participants | 4 Participants | 3 Participants | 36 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 6 Participants | 5 Participants | 7 Participants | 19 Participants | 2 Participants | 2 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 18 / 25 | 15 / 20 | 27 / 36 |
| other Total, other adverse events | 25 / 25 | 20 / 20 | 36 / 36 |
| serious Total, serious adverse events | 9 / 25 | 12 / 20 | 18 / 36 |
Outcome results
Primary
Clinical Response to Binimetinib Combined With PF-02341066
To investigate response to treatment with RPII dose of Binimetinib with Crizotinib (PF-02341066), in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC, as defined by stable, partially or completely responding disease, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase (\>=20%) to qualify for Progressive Disease; Overall Response (OR) = CR + PR + SD
Time frame: Dose Expansion phase: change from baseline and up to 12 months.
Population: Evaluable patients for the primary outcome are those patients who complete a response assessment after cycle 1 of treatment, or who progress early on treatment. 30 of the 36 recruited patients had a response assessment after cycle 1 or progressed early on treatment, and hence these 30 patients are evaluable for the primary analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Clinical Response to Binimetinib Combined With PF-02341066 | Stable Disease | 7 Participants |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Clinical Response to Binimetinib Combined With PF-02341066 | Progressive Disease | 22 Participants |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Clinical Response to Binimetinib Combined With PF-02341066 | Early death from malignant disease | 1 Participants |
Primary
Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066
To determine the maximal tolerated dose (MTD) of Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE V4.03 in cycle 1 of treatment.
Time frame: Dose Escalation Phase: treatment Cycle 1 28 days
Population: Evaluable patients are those patients who completed cycle 1 or who withdraw early for experiencing a DLT. Three patients withdrew early from the study not for DLTs, consequently 17 of the 20 recruited patients are evaluable for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066 | 2 Dose Limiting Toxicities (DLTs) |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066 | 2 Dose Limiting Toxicities (DLTs) |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066 | 1 Dose Limiting Toxicities (DLTs) |
Comparison: The primary dose escalation analysis was to find the MTD, which was defined as the dose of PF-02341066 in combination with Binimetinib at which no more than one out of six patients experience a DLT (dose limiting toxicity). The DLT was based on observed toxicity in cycle 1, and was defined as an almost certainly or probably drug-related adverse event to PF-02341066 and/or Binimetinib.
Primary
Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066
Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours.
Time frame: Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination)
Population: Evaluable patients are those patients who completed cycle 1 or withdrew early for experiencing a DLT. Four patients withdrew early from the study not for DLTs, consequently 21 patients remained for the dose escalation primary analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066 | 0 Dose Limiting Toxicities (DLTs) |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066 | 0 Dose Limiting Toxicities (DLTs) |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066 | 0 Dose Limiting Toxicities (DLTs) |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066 | 1 Dose Limiting Toxicities (DLTs) |
Secondary
Overall Survival (Dose Escalation Binimetinib/PF-02341066)
Overall survival (Dose escalation Binimetinib/PF-02341066).
Time frame: From date of study entry until the date of death, assessed up to study completion, an average of 6 months
Population: All patients registered for this escalation phase are included in this Intention to Treat analysis, as the number of patients in each arm are separately too small for survival analysis, and it is only to preliminarily assess efficacy of the drug. The data is present as pre-specified in the Statistical Analysis Plan Version 1.0\_09June2016.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Overall Survival (Dose Escalation Binimetinib/PF-02341066) | 8.78 months |
Secondary
Overall Survival (Dose Expansion)
Overall survival (dose expansion).
Time frame: From date of study entry until the date of death, assessed up to study completion, an average of 6 months (dose escalation).
Population: All 37 registered patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Overall Survival (Dose Expansion) | 5.42 months |
Secondary
Pharmacodynamic (PD) Effect of PF-02341066 in Combination With Binimetinib in Paired Tumour Biopsies (Where Possible).
Measurement of phosphoERK1/2 to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with Binimetinib in paired tumour biopsies (where possible) to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
Time frame: Dose Expansion: Biopsies at baseline and Cycle1 D15. Optional metastic tumour biopsy within 28 days following radiological confirmation of disease progression.
Population: Most patients in expansion phase did not have biopsy collection at Day 15 despite consenting to this procedure prior to commencement of the trial mainly for ethical reasons or inability to access suitable tumour biopsy site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With Binimetinib in Paired Tumour Biopsies (Where Possible). | 0.155 ratio | Standard Deviation 0.0212 |
Secondary
Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2.
Measurement of phosphoERK1/2 to investigte the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired skin biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
Time frame: Dose Escalation and Expansion: at baseline and Cycle1, D15.
Population: For the Dose Escalation phases of the study the paired skin biopsies were collected and analysed for eligible patients (achieving end of Cycle 1) where available. Samples for Collection of paired skin biopsies were mandatory for first 10 patients registered to the expansion phase of the study only. An additional 3 samples were collected and analysed in the Expansion phase due to multiple screening performed over several participating sites.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.47 ratio | Standard Deviation 0.277 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.35 ratio | Standard Deviation 0.356 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.49 ratio | Standard Deviation 0.727 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.34 ratio | Standard Deviation 0.218 |
| Dose Escalation Phase 5. | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.38 ratio | Standard Deviation 0.238 |
| Dose Escalation Phase Dose 5a | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.69 ratio | Standard Deviation 0.147 |
| Dose Escalation Phase Dose 5 (Interval Dosing) | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.23 ratio | Standard Deviation 0.166 |
| Dose Expansion Phase | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2. | 0.44 ratio | Standard Deviation 0.309 |
Secondary
Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2.
Measurement of phosphoMEK1/2 in skin biopsies to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired skin biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
Time frame: Dose Escalation and Expansion: at baseline and Cycle1, D15.
Population: For the Dose Escalation phases of the study the paired skin biopsies were collected and analysed for eligible patients (achieving end of Cycle 1) where available. Samples for Collection of paired skin biopsies were mandatory for first 10 patients registered to the expansion phase of the study only. An additional 3 samples were collected and analysed in the Expansion phase due to multiple screening performed over several participating sites.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 3.74 ratio | Standard Deviation 2.366 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 1.89 ratio | Standard Deviation 1.425 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 6.52 ratio | Standard Deviation 5.982 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 5.74 ratio | Standard Deviation 3.067 |
| Dose Escalation Phase 5. | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 1.93 ratio | Standard Deviation 0.844 |
| Dose Escalation Phase Dose 5a | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 1.03 ratio | Standard Deviation 0.28 |
| Dose Escalation Phase Dose 5 (Interval Dosing) | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 0.93 ratio | Standard Deviation 0.418 |
| Dose Expansion Phase | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2. | 1.11 ratio | Standard Deviation 0.697 |
Secondary
Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Tumour Biopsies (Where Possible).
Measurement of pSTAT3Y705 to investigate the pharmacodynamic (PD) effect of PF-02341066 in combination with PD-0325901 or Binimetinib in paired tumour biopsies to determine objective response to treatment. Western blots are used to measure levels of expression and images are taken of the gels. Image J is used to measure pixels. The minimum is 0 and there is no maximum.
Time frame: Dose Escalation: Biopsies at baseline and Cycle1 D15 - both optional.
Population: Biopsies optional for this phase and only consented to by 2 patients for the combination of PF-02341066 with Binimetinib.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Tumour Biopsies (Where Possible). | 0.35 ratio | Standard Deviation 0.2687 |
Secondary
Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.
To investigate the pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood.
Time frame: Dose Escalation :Up to 12 months. PK profile pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1
Population: No data available for dose level 5 for 3 patients and for 2 patients in dose level 5 (interval dosing)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 1604 ng.h/ml (0-10h ) | Standard Deviation 554 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 2481 ng.h/ml (0-10h ) | Standard Deviation 980 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 203 ng.h/ml (0-10h ) | Standard Deviation 112 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 1780 ng.h/ml (0-10h ) | Standard Deviation 706 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 2119 ng.h/ml (0-10h ) | Standard Deviation 1341 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 183 ng.h/ml (0-10h ) | Standard Deviation 24.8 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 1467 ng.h/ml (0-10h ) | Standard Deviation 410 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 121 ng.h/ml (0-10h ) | Standard Deviation 28.9 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 1402 ng.h/ml (0-10h ) | Standard Deviation 666 |
Secondary
Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.
To investigate pharmacokinetic area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood.
Time frame: Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs
Population: No data available for 2 patients in PF-02341066 outcome measure, 8 for binimetinib outcome measure and 13 for AR00426032 outcome measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 3478 ng.h/ml (0-10h ) | Standard Deviation 2083 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 2129 ng.h/ml (0-10h ) | Standard Deviation 1152 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 194 ng.h/ml (0-10h ) | Standard Deviation 85.2 |
Secondary
Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite)
To investigate the pharmacokinetics (PK) plasma AUC of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
Time frame: Dose Escalation:Up to12 months. Cycle 1 PK profile up to 10 hrs on Day -1, 21 and 28
Population: PK analysis performed on Cycle 1 Day -1 and Day 21 only for PD-0325901 and PD-0315209 and on Cycle 1 Day 21 and Day 28 only for PF-02341066 according to dosing schedule Day -7 to Day 21 for PD-0325901 and Day 1 to Day 28 for PF-02341066.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day -1 | 400 ng*hr/mL | Standard Deviation 117 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day 21 | 400 ng*hr/mL | Standard Deviation 160 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day -1 | 498 ng*hr/mL | Standard Deviation 304 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day 21 | 487 ng*hr/mL | Standard Deviation 226 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 21 | 1341 ng*hr/mL | Standard Deviation 688 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 28 | 1378 ng*hr/mL | Standard Deviation 567 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 28 | 2358 ng*hr/mL | Standard Deviation 905 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day 21 | 413 ng*hr/mL | Standard Deviation 273 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day -1 | 432 ng*hr/mL | Standard Deviation 129 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day -1 | 508 ng*hr/mL | Standard Deviation 318 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day 21 | 301 ng*hr/mL | Standard Deviation 106 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 21 | 2115 ng*hr/mL | Standard Deviation 448 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day 21 | 683 ng*hr/mL | Standard Deviation 51.7 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day -1 | 954 ng*hr/mL | Standard Deviation 301 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day 21 | 831 ng*hr/mL | Standard Deviation 246 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 28 | 2919 ng*hr/mL | Standard Deviation 1207 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 21 | 2034 ng*hr/mL | Standard Deviation 397 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day -1 | 796 ng*hr/mL | Standard Deviation 120 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 21 | 2336 ng*hr/mL | Standard Deviation 1414 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PF-02341066 PK Day 28 | 2402 ng*hr/mL | Standard Deviation 873 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day 21 | 1162 ng*hr/mL | Standard Deviation 190 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day 21 | 1092 ng*hr/mL | Standard Deviation 228 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0325901 PK Day -1 | 1907 ng*hr/mL | Standard Deviation 254 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite) | Summary PD-0315209 PK Day -1 | 1726 ng*hr/mL | Standard Deviation 501 |
Secondary
Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.
To investigate pharmacokinetic plasma trough concentration Cmin of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood.
Time frame: Dose Expansion: PK profile on Cycle 1 Day 21 up to 10 hrs .
Population: No data available for 8 patients for binimetinib outcome and for 16 patients in AR00426032 outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 149 Cmin (ng/ml) | Standard Deviation 85.3 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 103 Cmin (ng/ml) | Standard Deviation 58.5 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 12.1 Cmin (ng/ml) | Standard Deviation 4.8 |
Secondary
Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901
To investigate the pharmacokinetics (PK) plasma Cmin of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
Time frame: Dose Escalation:Up to 12 mths. Cycle 1 PK profile up to 10 hrs post dose on Day -1, 21 and 28
Population: PK analysis performed on Cycle 1 Day -1 and Day 21 only for PD-0325901 and PD-0315209 and on Cycle 1 Day 21 and Day 28 only for PF-02341066 according to dosing schedule Day -7 to Day 21 for PD-0325901 and Day 1 to Day 28 for PF-02341066.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day -1 | 23.6 ng/ml | Standard Deviation 9.3 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day 21 | 26.0 ng/ml | Standard Deviation 16.1 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day -1 | 44.0 ng/ml | Standard Deviation 29.6 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day 21 | 41.3 ng/ml | Standard Deviation 23.3 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 21 | 115 ng/ml | Standard Deviation 64.4 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 28 | 119 ng/ml | Standard Deviation 44.4 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 28 | 183 ng/ml | Standard Deviation 66.3 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day 21 | 37.3 ng/ml | Standard Deviation 25.4 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day -1 | 18.7 ng/ml | Standard Deviation 5.83 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day -1 | 40.4 ng/ml | Standard Deviation 26.3 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day 21 | 17.6 ng/ml | Standard Deviation 3.12 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 21 | 186 ng/ml | Standard Deviation 55.8 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day 21 | 35.8 ng/ml | Standard Deviation 13.3 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day -1 | 80.6 ng/ml | Standard Deviation 22.1 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day 21 | 66.6 ng/ml | Standard Deviation 18.8 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 28 | 259 ng/ml | Standard Deviation 96 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 21 | 172 ng/ml | Standard Deviation 43.6 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day -1 | 37.9 ng/ml | Standard Deviation 5.89 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 21 | 203 ng/ml | Standard Deviation 121 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PF-02341066 PK Day 28 | 211 ng/ml | Standard Deviation 78.6 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day 21 | 45.4 ng/ml | Standard Deviation 13 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day 21 | 73.1 ng/ml | Standard Deviation 31.7 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0325901 PK Day -1 | 89.2 ng/ml | Standard Deviation 24.3 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901 | Summary PD-0315209 PK Day -1 | 147 ng/ml | Standard Deviation 47.7 |
Secondary
Pharmacokinetic Oral Clearance for PF-02341066 and Binimetinib.
To investigate pharmacokinetic (PK) oral clearance of PF-02341066 and Binimetinib in blood.
Time frame: Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21
Population: Oral clearance could not be calculated, as pre-specified, as bioavailability and full Area Under the Curve (AUC) data, specifically 0 to ∞ (infinity), was not available. Even though AUC data is available on Day 21 for 0-10 hours, residual drug at time of next twice daily dose administration meant oral clearance could not be determined for most patients.
Secondary
Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.
To investigate the pharmacokinetics (PK) plasma Cmax of Binimetinib (and its metabolite AR00426032) with PF-023241066 when administered in combination.
Time frame: Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1
Population: Dose Escalation phase using binimetinib with PF-02341066. Sample data not available in each outcome measure for 2 patients in Dose level 5 and 1 in Dose level 5 (interval dosing) .
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 265 ng/ml | Standard Deviation 83.4 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 273 ng/ml | Standard Deviation 118 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 25.1 ng/ml | Standard Deviation 15.1 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 386 ng/ml | Standard Deviation 189 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 250 ng/ml | Standard Deviation 145 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 29.5 ng/ml | Standard Deviation 8.62 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 186 ng/ml | Standard Deviation 36.8 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 23.4 ng/ml | Standard Deviation 8.04 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 320 ng/ml | Standard Deviation 136 |
Secondary
Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901.
To investigate the pharmacokinetics (PK) plasma Cmax of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
Time frame: Dose Escalation:Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day - 1, Day 21 and Day 28 of Cycle 1
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day -1 | 77.8 ng/ml | Standard Deviation 41.9 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day 21 | 70.3 ng/ml | Standard Deviation 43.1 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day -1 | 53.1 ng/ml | Standard Deviation 30.7 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day 21 | 52.0 ng/ml | Standard Deviation 24.8 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 21 | 170 ng/ml | Standard Deviation 81.3 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 28 | 164 ng/ml | Standard Deviation 59.8 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 28 | 281 ng/ml | Standard Deviation 118 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day 21 | 46.7 ng/ml | Standard Deviation 29.5 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day -1 | 129 ng/ml | Standard Deviation 50.5 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day -1 | 59.4 ng/ml | Standard Deviation 35.3 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day 21 | 62.3 ng/ml | Standard Deviation 34.7 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 21 | 300 ng/ml | Standard Deviation 53.9 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day 21 | 135 ng/ml | Standard Deviation 36.2 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day -1 | 117 ng/ml | Standard Deviation 44.3 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day 21 | 103 ng/ml | Standard Deviation 40.5 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 28 | 341 ng/ml | Standard Deviation 133 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 21 | 235 ng/ml | Standard Deviation 35.3 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day -1 | 226 ng/ml | Standard Deviation 66.1 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 21 | 269 ng/ml | Standard Deviation 157 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PF-02341066 PK Day 28 | 275 ng/ml | Standard Deviation 105 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day 21 | 219 ng/ml | Standard Deviation 93.6 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day 21 | 117 ng/ml | Standard Deviation 57.6 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0325901 PK Day -1 | 484 ng/ml | Standard Deviation 84.1 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901. | Summary PD-0315209 PK Day -1 | 195 ng/ml | Standard Deviation 55.6 |
Secondary
Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.
To investigate the pharmacokinetic (PK) minimum plasma trough concentration (Cmin) of PF-02341066 and binimetinib in blood.
Time frame: Dose Escalation phase :Up to 12 months. PK profile at pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1
Population: No data available for 4 patients in dose level 5, for 2 patients in dose level 5 (interval dosing) and for 1 patient in dose level 5a
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 77.1 ng/ml | Standard Deviation 40.3 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 205 ng/ml | Standard Deviation 78 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 10.4 ng/ml | Standard Deviation 2.66 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 85.8 ng/ml | Standard Deviation 51.9 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 181 ng/ml | Standard Deviation 136 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 10.2 ng/ml | Standard Deviation 2.47 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 114 ng/ml | Standard Deviation 43.1 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 6.95 ng/ml | Standard Deviation 1.6 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 64.0 ng/ml | Standard Deviation 28.9 |
Secondary
Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.
To investigate the pharmacokinetic (PK) peak plasma concentration (Cmax) of PF-02341066 and Binimetinib and its metabolite, AR00426032, in blood.
Time frame: Dose Expansion: PK profile up to 10 hrs at Cycle 1 Day 21
Population: Data not available for 2 patients in PF-02341066 outcome measure and 8 patients each in binimetinib and AR00426032 outcome measures
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary PF-02341066 PK Cycle 1 D21 up to 10h | 197 ng/ml | Standard Deviation 112 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary binimetinib PK Cycle 1 D21 up to 10h | 357 ng/ml | Standard Deviation 171 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib. | Summary AR00426032 PK Cycle 1 D21 | 22.7 ng/ml | Standard Deviation 16 |
Secondary
Pharmacokinetic Plasma Oral Clearance for PF-02341066 and Binimetinib
To investigate the pharmacokinetics (PK) plasma oral clearance of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination.
Time frame: Dose Expansion phase at Cycle 1 Day 21 up to 10 hours binimetinib and its metabolite, AR00426032, and up to 24 hours for PF-02341066
Population: Oral clearance could not be calculated, as pre-specified, as bioavailability and full Area Under the Curve (AUC) data, specifically 0 to ∞ (infinity), was not available. Even though AUC data is available on Day 21 for 0-10 hours, residual drug at time of next twice daily dose administration meant oral clearance could not be determined for most patients.
Secondary
Pharmacokinetic Plasma Oral Clearance for PF-02341066 and PD-0325901
To investigate the pharmacokinetics (PK) plasma oral clearance of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
Time frame: Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28
Population: Oral clearance could not be calculated, as pre-specified, as bioavailability and full Area Under the Curve (AUC) data, specifically 0 to ∞ (infinity), was not available. Even though AUC data is available on Days -1, 21 and 28 for 0-10 hours, residual drug at time of next twice daily dose administration meant oral clearance could not be determined for most patients.
Secondary
Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib
To investigate the pharmacokinetics (PK) plasma half life of binimetinib (and its metabolite,AR00426032 ) with PF-023241066 when administered in combination.
Time frame: Dose Expansion phase at Cycle 1 Day 21 up to 10 hours binimetinib and its metabolite, AR00426032, and up to 24 hours for PF-02341066
Population: Data not available for 8 patients in PF-02341066 outcome measure, 11 patients in binimetinib outcome measure and 16 patients in AR00426032 outcome measure.~Data for PF-02341066 taken at 24 hour time point due to once daily dosing.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib | Summary t1/2 life for PF-02341066 PK Cycle 1 D21 up to 24 h | 21 h | Standard Deviation 11 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib | Summary t1/2 life for binimetinib PK Cycle 1 D21 up to 10h | 6.32 h | Standard Deviation 8.06 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib | Summary t1/2 life for AR00426032 PK Cycle 1 D21 up to 10 hr | 4.70 h | Standard Deviation 1.39 |
Secondary
Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901
To investigate the pharmacokinetics (PK) plasma half life of PD-0325901 (and its metabolite, PD-0315209) with PF-023241066 when administered in combination.
Time frame: Dose Escalation:Up to12 months.PK profile at Cycle 1 up to 10 hrs post dose on Days -1, 21 and 28
Population: PK analysis performed on Cycle 1 Day -1 and Day 21 only for PD-0325901 and PD-0315209 and on Cycle 1 Day 21 and Day 28 only for PF-02341066 according to dosing schedule Day -7 to Day 21 for PD-0325901 and Day 1 to Day 28 for PF-02341066.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day 21 | 4.5 h | Standard Deviation 0.7 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day 21 | 10.6 h | Standard Deviation 4.88 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day -1 | 7.9 h | Standard Deviation 4.1 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 28 | 31.2 h | Standard Deviation 16.3 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day -1 | 18.0 h | Standard Deviation 5.66 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 21 | 31.5 h | Standard Deviation 22.4 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day -1 | 11.3 h | Standard Deviation 1.2 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 21 | 10.0 h | Standard Deviation 3 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day -1 | 16.8 h | Standard Deviation 13.9 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 28 | 12.0 h | Standard Deviation 3.3 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day 21 | 9.7 h | Standard Deviation 2.8 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day 21 | 19.3 h | Standard Deviation 3.8 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day -1 | 16.0 h | Standard Deviation 6.2 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day 21 | 11.0 h | Standard Deviation 1.4 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day -1 | 9.9 h | Standard Deviation 3.2 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day 21 | 6.3 h | Standard Deviation 3.2 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 21 | 20.0 h | Standard Deviation 12.3 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 28 | 18.5 h | Standard Deviation 12 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 28 | 22.0 h | Standard Deviation 13.4 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PF-02341066 PK Day 21 | 16.0 h | Standard Deviation 10 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day 21 | 24.8 h | Standard Deviation 27.9 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0325901 PK Day -1 | 15.1 h | Standard Deviation 12.5 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day 21 | 6.6 h | Standard Deviation 0.6 |
| Dose Escalation Phase Cohort 4 Dose Level 4 | Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901 | Summary Half Life of PD-0315209 PK Day -1 | 15.0 h | Standard Deviation 2 |
Secondary
Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib.
To investigate pharmacokinetic (PK) t1/2 of PF-02341066 and Binimetinib in blood.
Time frame: Dose Escalation: PK profile at up to 10 hrs post dose on Cycle 1 Day 21
Population: No data available for Half Life for Dose Escalation phase outcome measure for PF-02341066 due to limitations of limited time-points available and missing samples, minimal clearance over the 10hr.~No data available for 3 patients in dose level 5 and 2 in dose level 5 (interval dosing) and 1 in dose level 5a.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Summary Half Life for Binimetinib for PK Day 21 up to 10h | 4.3 h | Standard Deviation 1.7 |
| Dose Escalation Phase Cohort 1 Dose Level 1 | Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Summary Half Life for AR00426032 (binimetinib metabolite) for PK Day 21 up to 10h | 4.3 h | Standard Deviation 1.9 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Summary Half Life for Binimetinib for PK Day 21 up to 10h | 5.5 h | Standard Deviation 2.9 |
| Dose Escalation Phase Cohort 2 Dose Level 2 | Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Summary Half Life for AR00426032 (binimetinib metabolite) for PK Day 21 up to 10h | 5.3 h | Standard Deviation 2.2 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Summary Half Life for Binimetinib for PK Day 21 up to 10h | 4.7 h | Standard Deviation 1 |
| Dose Escalation Phase Cohort 3 Dose Level 3 | Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib. | Summary Half Life for AR00426032 (binimetinib metabolite) for PK Day 21 up to 10h | 5.4 h | Standard Deviation 1.8 |
Secondary
Progression Free Survival (Dose Escalation Binimetinib/PF-02341066).
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>=20% increase in the sum of diameters of target lesions (also demonstrating an absolute increase of at least 5mm) or the appearance of new lesions.
Time frame: From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months
Population: All patients registered for this escalation phase are included in this Intention to Treat analysis, as the number of patients in each arm are separately too small for survival analysis, and it is only to preliminarily assess efficacy of the drug. The data is presented as pre-specified in the Statistical Analysis Plan Version 1.0\_09Jun2016.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Progression Free Survival (Dose Escalation Binimetinib/PF-02341066). | 2.3 months |
Secondary
Progression Free Survival (Dose Expansion)
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>=20% increase in the sum of diameters of target lesions (also demonstrating an absolute increase of at least 5mm) or the appearance of new lesions.
Time frame: From date of study entry until the date of progression or date of death, assessed up to study completion, an average of 6 months (dose expansion)).
Population: All 37 registered patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase Cohort 1 Dose Level 1 | Progression Free Survival (Dose Expansion) | 1.81 months |