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MErCuRIC1: MEK and MET Inhibition in Colorectal Cancer

Sponsor
University of Oxford (Other)
Overall Status
Completed
CT.gov ID
NCT02510001
Collaborator
Queen's University, Belfast (Other), Oxford University Hospitals NHS Trust (Other), Velindre NHS Trust (Other), University Hospital, Antwerp (Other), Hospital Vall d'Hebron (Other), Saint Antoine University Hospital (Other), European Georges Pompidou Hospital (Other), Pfizer (Industry), University of Turin, Italy (Other), Belfast Health and Social Care Trust (Other), Beaumont Hospital (Other), European Commission (Other), Array BioPharma (Industry), University of Paris 5 - Rene Descartes (Other)
82
Enrollment
1
Location
8
Arms
49.1
Actual Duration (Months)
1.7
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
82 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Sequential Phase I Study of MEK1/2 Inhibitors PD-0325901 or Binimetinib Combined With cMET Inhibitor PF-02341066 in Patients With RAS Mutant and RAS Wild Type (With Aberrant c-MET) Colorectal Cancer
Actual Study Start Date :
Nov 1, 2014
Actual Primary Completion Date :
Dec 3, 2018
Actual Study Completion Date :
Dec 3, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose Escalation Phase Cohort 1 Dose level 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

Drug: PF-02341066
PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Other Names:
  • Crizotinib

    • Drug: 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.
    Other Names:
  • No other Intervention name for this drug

    		•
    Experimental: Dose Escalation Phase Cohort 2 Dose level 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

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: 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.
    Other Names:
  • No other Intervention name for this drug

    		•
    Experimental: Dose Escalation Phase Cohort 3 Dose level 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

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: 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.
    Other Names:
  • No other Intervention name for this drug

    		•
    Experimental: Dose Escalation Phase Cohort 4 Dose level 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

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: 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.
    Other Names:
  • No other Intervention name for this drug

    		•
    Experimental: Dose Escalation Phase Cohort 7 Dose level 5

    Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. PF-02341066 200mg BD continuous administration

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: 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.
    Other Names:
  • No other Intervention name for this drug

    • Drug: Binimetinib
    Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
    Other Names:
  • MEK162

    		•
    Experimental: Dose Escalation Phase Cohort 13 Dose level 5a

    Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. PF-02341066 250mg OD continuous administration

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: Binimetinib
    Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
    Other Names:
  • MEK162

    		•
    Experimental: 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.

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: Binimetinib
    Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
    Other Names:
  • MEK162

    		•
    Experimental: Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)

    Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. PF-02341066 200mg BD continuous administration

    Drug: PF-02341066
    PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
    Other Names:
  • Crizotinib

    • Drug: Binimetinib
    Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
    Other Names:
  • MEK162

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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

    3. 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 Outcome Measures

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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.

    6. 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).

    7. 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.

    8. 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.

    9. 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.

    10. 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.

    11. 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.

    12. 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.

    13. 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.

    14. 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.

    15. 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).

    16. 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.

    17. 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.

    18. Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib. [Dose Escalation :Up to 12 months. PK profile pre-dose and up to 10 hrs post dose on Day 21 of Cycle 1]

      To investigate the pharmacokinetic (PK) area under the plasma concentration versus time curve (AUC) of PF-02341066 and Binimetinib in blood.

    19. 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.

    20. 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.

    21. 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.

    22. 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.

    23. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    16 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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 (Exclusion criteria for the completed initial dose escalation phase using PF-02341066/PD-0325901 are listed in Appendix 7.) All patients

    • Unstable ischaemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment.

    • Uncontrolled arterial hypertension despite medical treatment.

    • Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled atrial fibrillation.

    • History of extensive disseminated/bilateral or known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease (ILD), obliterative bronchiolitis, and pulmonary fibrosis. A history of prior radiation pneumonitis is allowed.

    • Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions) and/or leptomeningeal metastases. However, patients treated with stereotactic radiotherapy or surgery are eligible if the patient remained without evidence of CNS disease progression ≥ 3 months. Patients must be off corticosteroid therapy for ≥ 3 weeks.

    • Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);

    • Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on Binimetinib treatment

    • Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.

    • Carcinomatous meningitis or leptomeningeal disease.

    • History of hypoalbuminaemia, or patients with peritoneal disease or pleural disease, where there is a requirement for ascitic or pleural taps.

    • History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at risk of retinal vein thrombosis (e.g. history of hyperviscosity or hypercoagulability syndromes).

    • History of retinal degenerative disease.

    • History of Gilbert's syndrome.

    • Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe immunologic defect, compromised bone marrow function.

    • Other severe acute or chronic medical (including severe gastro-intestinal disorders e.g. partial bowel obstruction, malabsorption, active inflammatory bowel disease) or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results.

    • Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure.

    • Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 substrates with narrow therapeutic indices (see Appendix 5).

    • Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C) and four weeks for investigational medicinal products before treatment. Patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens.

    • Resting ECG with QTc > 480msec at 2 or more time points within a 24h period (using Fredericia correction).

    • Requirement for medication known to prolong QT interval (Appendix 5).

    • History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free

    • Women with the ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum pregnancy test before enrolment and agree to use one highly effective form of contraception (oral, injected or implanted hormonal contraception or intra-uterine device) in addition to condom plus spermicide for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.

    • Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception including oral, injected or implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

    • Prior exposure to any of a HGF, cMET or a MEK inhibitor.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Oxford University Hospital NHS Trust Oxford United Kingdom OX3 7LE

    Sponsors and Collaborators

    • University of Oxford
    • 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

    Investigators

    • Principal Investigator: Mark R Middleton, Oxford University Hospital NHS Trust

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    University of Oxford
    ClinicalTrials.gov Identifier:
    NCT02510001
    Other Study ID Numbers:
    • OCTO-049
    First Posted:
    Jul 28, 2015
    Last Update Posted:
    Jul 13, 2021
    Last Verified:
    Jan 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by University of Oxford
    RASMT CRC
    RASWT/c-MET CRC
    Dose Escalation
    Histologically or cytologically confirmed
    Dose Expansion
    Additional relevant MeSH terms:
    Colorectal Neoplasms
    Crizotinib

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 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.
    Arm/Group Title Dose Escalation Phase Dose 1. 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 Escalation Phase Dose 5 (Interval Dosing) Dose Expansion Phase
    Arm/Group Description Crizotinib (PF-02341066) 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Crizotinib (PF-02341066) 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 Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. Crizotinib (PF-02341066) 200mg BD continuous administration Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. Crizotinib (PF-02341066) 250mg OD continuous administration Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. Crizotinib (PF-02341066) 200mg BD continuous administration 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
    Period Title: Overall Study
    STARTED 6 5 6 8 8 7 5 37
    COMPLETED 6 5 6 6 4 5 3 30
    NOT COMPLETED 0 0 0 2 4 2 2 7

    Baseline Characteristics

    Arm/Group Title Dose Escalation Phase Dose 1. 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 5 (Interval Dosing) Total
    Arm/Group Description 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. 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. 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. 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. 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 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 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 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 Total of all reporting groups
    Overall Participants 6 5 6 8 8 7 37 5 82
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    4
    66.7%
    3
    60%
    5
    83.3%
    5
    62.5%
    6
    75%
    5
    71.4%
    24
    64.9%
    4
    80%
    56
    68.3%
    >=65 years
    2
    33.3%
    2
    40%
    1
    16.7%
    3
    37.5%
    2
    25%
    2
    28.6%
    13
    35.1%
    1
    20%
    26
    31.7%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    65.8
    64.8
    58.4
    61.2
    51.0
    60.0
    62.0
    55.0
    60.4
    Sex: Female, Male (Count of Participants)
    Female
    4
    66.7%
    3
    60%
    3
    50%
    2
    25%
    3
    37.5%
    0
    0%
    18
    48.6%
    3
    60%
    36
    43.9%
    Male
    2
    33.3%
    2
    40%
    3
    50%
    6
    75%
    5
    62.5%
    7
    100%
    19
    51.4%
    2
    40%
    46
    56.1%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%

    Outcome Measures

    1. Primary Outcome
    Title Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Cohort 1 Dose Level 1 Dose Escalation Phase Cohort 2 Dose Level 2 Dose Escalation Phase Cohort 3 Dose Level 3 Dose Escalation Phase Cohort 4 Dose Level 4
    Arm/Group Description Crizotinib (PF-02341066) 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Crizotinib (PF-02341066) 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 Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle
    Measure Participants 6 5 4 6
    Number [Dose Limiting Toxicities (DLTs)]
    0
    0
    0
    1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose Escalation Phase Cohort 1 Dose Level 1, Dose Escalation Phase Cohort 2 Dose Level 2, Dose Escalation Phase Cohort 3 Dose Level 3, Dose Escalation Phase Cohort 4 Dose Level 4
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Other Statistical Analysis The primary dose escalation analysis was to find the MTD, which was defined as the dose of PF-02341066 in combination with PD-0325901 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 PD-0325901. The MTD for the PD 0325901/PF-02341066 combination was 8mg BD(days1-21) and 200mg BD continuously in a 28 day cycle (Dose Level 4).
    2. Primary Outcome
    Title Clinical Response to Binimetinib Combined With PF-02341066
    Description 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.

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 30
    Stable Disease
    7
    116.7%
    Progressive Disease
    22
    366.7%
    Early death from malignant disease
    1
    16.7%
    3. Primary Outcome
    Title Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Cohort 7 Dose Level 5 Dose Escalation Phase Cohort 12 Dose Level 5 (Interval Dosing) Dose Escalation Phase Cohort 13 Dose Level 5a
    Arm/Group Description 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 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 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
    Measure Participants 6 5 6
    Number [Dose Limiting Toxicities (DLTs)]
    2
    2
    1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dose Escalation Phase Cohort 1 Dose Level 1, Dose Escalation Phase Cohort 2 Dose Level 2, Dose Escalation Phase Cohort 3 Dose Level 3
    Comments 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.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Other Statistical Analysis Binimetinib 30mg BD on days 1 - 21 every 28 days with Crizotinib 250 mg OD continuously is the MTD, the recommended dose and schedule for further evaluation in our and other trials. This was as only one DLT was experienced in 6 evaluable patients at this final dose escalation level.
    4. Secondary Outcome
    Title Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and PD-0325901.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Dose Escalation Phase Dose 1. Dose Escalation Phase Dose 2. Dose Escalation Phase Dose 3. Dose Escalation Phase Dose 4.
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 6 4 3 4
    Summary PD-0325901 PK Day -1
    77.8
    (41.9)
    129
    (50.5)
    226
    (66.1)
    484
    (84.1)
    Summary PD-0325901 PK Day 21
    70.3
    (43.1)
    62.3
    (34.7)
    135
    (36.2)
    219
    (93.6)
    Summary PD-0315209 PK Day -1
    53.1
    (30.7)
    59.4
    (35.3)
    117
    (44.3)
    195
    (55.6)
    Summary PD-0315209 PK Day 21
    52.0
    (24.8)
    46.7
    (29.5)
    103
    (40.5)
    117
    (57.6)
    Summary PF-02341066 PK Day 21
    170
    (81.3)
    300
    (53.9)
    235
    (35.3)
    269
    (157)
    Summary PF-02341066 PK Day 28
    164
    (59.8)
    281
    (118)
    341
    (133)
    275
    (105)
    5. Secondary Outcome
    Title Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and PD-0325901
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 1. Dose Escalation Phase Dose 2. Dose Escalation Phase Dose 3. Dose Escalation Phase Dose 4.
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 6 4 3 4
    Summary PD-0325901 PK Day -1
    23.6
    (9.3)
    18.7
    (5.83)
    37.9
    (5.89)
    89.2
    (24.3)
    Summary PD-0325901 PK Day 21
    26.0
    (16.1)
    17.6
    (3.12)
    35.8
    (13.3)
    45.4
    (13.0)
    Summary PD-0315209 PK Day -1
    44.0
    (29.6)
    40.4
    (26.3)
    80.6
    (22.1)
    147
    (47.7)
    Summary PD-0315209 PK Day 21
    41.3
    (23.3)
    37.3
    (25.4)
    66.6
    (18.8)
    73.1
    (31.7)
    Summary PF-02341066 PK Day 21
    115
    (64.4)
    186
    (55.8)
    172
    (43.6)
    203
    (121)
    Summary PF-02341066 PK Day 28
    119
    (44.4)
    183
    (66.3)
    259
    (96.0)
    211
    (78.6)
    6. Secondary Outcome
    Title Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and PD-0325901(and Its Metabolite)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 1. Dose Escalation Phase Dose 2. Dose Escalation Phase Dose 3. Dose Escalation Phase Dose 4.
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 6 4 3 4
    Summary PD-0325901 PK Day -1
    400
    (117)
    432
    (129)
    796
    (120)
    1907
    (254)
    Summary PD-0325901 PK Day 21
    400
    (160)
    301
    (106)
    683
    (51.7)
    1162
    (190)
    Summary PD-0315209 PK Day -1
    498
    (304)
    508
    (318)
    954
    (301)
    1726
    (501)
    Summary PD-0315209 PK Day 21
    487
    (226)
    413
    (273)
    831
    (246)
    1092
    (228)
    Summary PF-02341066 PK Day 21
    1341
    (688)
    2115
    (448)
    2034
    (397)
    2336
    (1414)
    Summary PF-02341066 PK Day 28
    1378
    (567)
    2358
    (905)
    2919
    (1207)
    2402
    (873)
    7. Secondary Outcome
    Title Pharmacokinetic Plasma Oral Clearance for PF-02341066 and PD-0325901
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Dose Escalation Phase Dose 1. Dose Escalation Phase Dose 2. Dose Escalation Phase Dose 3. Dose Escalation Phase Dose 4.
    Arm/Group Description Crizotinib (PF-02341066) 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle Crizotinib (PF-02341066) 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 Crizotinib (PF-02341066) 200mg BD Days 1-28 continuously PD-0325901 8mg BD Run in Day -7 to Cycle 1 Day -1, then Day 1-21 every 28 day cycle
    Measure Participants 0 0 0 0
    8. Secondary Outcome
    Title Progression Free Survival (Dose Expansion)
    Description 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)).

    Outcome Measure Data

    Analysis Population Description
    All 37 registered patients are included in this analysis.
    Arm/Group Title Dose Expansion Phase
    Arm/Group Description All of the patients registered for this expansion phase are included in this survival analysis, to preliminarily assess the efficacy of the drug combination.
    Measure Participants 37
    Median (95% Confidence Interval) [months]
    1.81
    9. Secondary Outcome
    Title Overall Survival (Dose Expansion)
    Description 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).

    Outcome Measure Data

    Analysis Population Description
    All 37 registered patients are included in this analysis.
    Arm/Group Title Dose Expansion Phase
    Arm/Group Description All of the patients registered for this expansion phase are included in this survival analysis, to preliminarily assess the efficacy of the drug combination.
    Measure Participants 37
    Median (95% Confidence Interval) [months]
    5.42
    10. Secondary Outcome
    Title Pharmacokinetic (PK) Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Data not available for 2 patients in PF-02341066 outcome measure and 8 patients each in binimetinib and AR00426032 outcome measures
    Arm/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 26
    Summary PF-02341066 PK Cycle 1 D21 up to 10h
    197
    (112)
    Summary binimetinib PK Cycle 1 D21 up to 10h
    357
    (171)
    Summary AR00426032 PK Cycle 1 D21
    22.7
    (16.0)
    11. Secondary Outcome
    Title Pharmacokinetic Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.
    Description 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 .

    Outcome Measure Data

    Analysis Population Description
    No data available for 8 patients for binimetinib outcome and for 16 patients in AR00426032 outcome measure.
    Arm/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 26
    Summary PF-02341066 PK Cycle 1 D21 up to 10h
    149
    (85.3)
    Summary binimetinib PK Cycle 1 D21 up to 10h
    103
    (58.5)
    Summary AR00426032 PK Cycle 1 D21
    12.1
    (4.80)
    12. Secondary Outcome
    Title Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    No data available for 2 patients in PF-02341066 outcome measure, 8 for binimetinib outcome measure and 13 for AR00426032 outcome measure
    Arm/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 26
    Summary PF-02341066 PK Cycle 1 D21 up to 10h
    3478
    (2083)
    Summary binimetinib PK Cycle 1 D21 up to 10h
    2129
    (1152)
    Summary AR00426032 PK Cycle 1 D21
    194
    (85.2)
    13. Secondary Outcome
    Title Pharmacokinetic Oral Clearance for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Dose Escalation Phase 5. Dose Escalation Phase Dose 5a Dose Escalation Phase Dose 5 (Interval Dosing)
    Arm/Group Description Binimetinib 30mg BD continuous administration or Days 1-21 every 28 days. Crizotinib (PF-02341066) 200mg BD continuous administration Binimetinib 30mg BD interval dose administration Days 1-21 every 28 days. Crizotinib (PF-02341066) 250mg OD continuous administration Binimetinib 30mg BD interval dose administration days 1-21 every 28 days. Crizotinib (PF-02341066) 200mg BD continuous administration
    Measure Participants 0 0 0
    14. Secondary Outcome
    Title Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoMEK1/2.
    Description 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.

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 1. 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 Escalation Phase Dose 5 (Interval Dosing) Dose Expansion Phase
    Arm/Group Description 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. 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. 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. 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. Binimetinib 30mg BD continuous administration. PF-02341066 200mg BD continuous administration 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 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 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
    Measure Participants 6 5 5 5 5 5 3 13
    Mean (Standard Deviation) [ratio]
    3.74
    (2.366)
    1.89
    (1.425)
    6.52
    (5.982)
    5.74
    (3.067)
    1.93
    (0.844)
    1.03
    (0.28)
    0.93
    (0.418)
    1.11
    (0.697)
    15. Secondary Outcome
    Title Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Tumour Biopsies (Where Possible).
    Description 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.

    Outcome Measure Data

    Analysis Population Description
    Biopsies optional for this phase and only consented to by 2 patients for the combination of PF-02341066 with Binimetinib.
    Arm/Group Title Dose Escalation Phase
    Arm/Group Description 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
    Measure Participants 2
    Mean (Standard Deviation) [ratio]
    0.35
    (0.2687)
    16. Secondary Outcome
    Title Pharmacodynamic (PD) Effect of PF-02341066 in Combination With Binimetinib in Paired Tumour Biopsies (Where Possible).
    Description 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.

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 2
    Mean (Standard Deviation) [ratio]
    0.155
    (0.0212)
    17. Secondary Outcome
    Title Progression Free Survival (Dose Escalation Binimetinib/PF-02341066).
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Binimetinib/PF-02341066
    Arm/Group Description All of the patients registered for this escalation phase are included in this progression free analysis, to preliminarily assess the efficacy of the drug combination.
    Measure Participants 20
    Median (95% Confidence Interval) [months]
    2.3
    18. Secondary Outcome
    Title Overall Survival (Dose Escalation Binimetinib/PF-02341066)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Binimetinib/PF-02341066
    Arm/Group Description All of the patients registered for this escalation phase are included in this survival analysis, to preliminarily assess the efficacy of the drug combination.
    Measure Participants 20
    Median (95% Confidence Interval) [months]
    8.78
    19. Secondary Outcome
    Title Pharmacokinetic Peak Plasma Concentration (Cmax) for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 5 Dose Escalation Phase Dose 5 (Interval Dosing) Dose Escalation Phase Dose 5a
    Arm/Group Description 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 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 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
    Measure Participants 5 4 6
    Summary PF-02341066 PK Cycle 1 D21 up to 10h
    273
    (118)
    250
    (145)
    186
    (36.8)
    Summary binimetinib PK Cycle 1 D21 up to 10h
    265
    (83.4)
    386
    (189)
    320
    (136)
    Summary AR00426032 PK Cycle 1 D21
    25.1
    (15.1)
    29.5
    (8.62)
    23.4
    (8.04)
    20. Secondary Outcome
    Title Pharmacokinetic (PK) Minimum Plasma Trough Concentration (Cmin) for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 5 Dose Escalation Phase Dose 5 (Interval Dosing) Dose Escalation Phase Dose 5a
    Arm/Group Description 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 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 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
    Measure Participants 3 3 5
    Summary PF-02341066 PK Cycle 1 D21 up to 10h
    205
    (78.0)
    181
    (136)
    114
    (43.1)
    Summary binimetinib PK Cycle 1 D21 up to 10h
    77.1
    (40.3)
    85.8
    (51.9)
    64.0
    (28.9)
    Summary AR00426032 PK Cycle 1 D21
    10.4
    (2.66)
    10.2
    (2.47)
    6.95
    (1.60)
    21. Secondary Outcome
    Title Pharmacokinetic Area Under the Plasma Concentration Versus Time Curve (AUC) for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    No data available for dose level 5 for 3 patients and for 2 patients in dose level 5 (interval dosing)
    Arm/Group Title Dose Escalation Phase Dose 5 Dose Escalation Phase Dose 5 (Interval Dosing) Dose Escalation Phase Dose 5a
    Arm/Group Description 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 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 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
    Measure Participants 4 3 6
    Summary PF-02341066 PK Cycle 1 D21 up to 10h
    2481
    (980)
    2119
    (1341)
    1467
    (410)
    Summary binimetinib PK Cycle 1 D21 up to 10h
    1604
    (554)
    1780
    (706)
    1402
    (666)
    Summary AR00426032 PK Cycle 1 D21
    203
    (112)
    183
    (24.8)
    121
    (28.9)
    22. Secondary Outcome
    Title Pharmacokinetic Plasma Oral Clearance for PF-02341066 and Binimetinib
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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.
    Arm/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 0
    23. Secondary Outcome
    Title Pharmacodynamic (PD) Effect of PF-02341066 in Combination With PD-0325901 or Binimetinib in Paired Skin Biopsies - Measurement of phosphoERK1/2.
    Description 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.

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 1. 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 Escalation Phase Dose 5 (Interval Dosing) Dose Expansion Phase
    Arm/Group Description 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. 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. 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. 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. Binimetinib 30mg BD continuous administration. PF-02341066 200mg BD continuous administration 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 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 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
    Measure Participants 6 5 5 5 5 5 3 13
    Mean (Standard Deviation) [ratio]
    0.47
    (0.277)
    0.35
    (0.356)
    0.49
    (0.727)
    0.34
    (0.218)
    0.38
    (0.238)
    0.69
    (0.147)
    0.23
    (0.166)
    0.44
    (0.309)
    24. Secondary Outcome
    Title Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and PD-0325901
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase Dose 1. Dose Escalation Phase Dose 2. Dose Escalation Phase Dose 3. Dose Escalation Phase Dose 4.
    Arm/Group Description 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. 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. 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. 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.
    Measure Participants 6 4 3 4
    Summary Half Life of PD-0325901 PK Day -1
    7.9
    (4.1)
    16.8
    (13.9)
    9.9
    (3.2)
    15.1
    (12.5)
    Summary Half Life of PD-0325901 PK Day 21
    4.5
    (0.7)
    9.7
    (2.8)
    6.3
    (3.2)
    24.8
    (27.9)
    Summary Half Life of PD-0315209 PK Day -1
    18.0
    (5.66)
    11.3
    (1.2)
    16.0
    (6.2)
    15.0
    (2.0)
    Summary Half Life of PD-0315209 PK Day 21
    10.6
    (4.88)
    19.3
    (3.8)
    11.0
    (1.4)
    6.6
    (0.6)
    Summary Half Life of PF-02341066 PK Day 21
    31.5
    (22.4)
    10.0
    (3.0)
    20.0
    (12.3)
    16.0
    (10.0)
    Summary Half Life of PF-02341066 PK Day 28
    31.2
    (16.3)
    12.0
    (3.3)
    18.5
    (12.0)
    22.0
    (13.4)
    25. Secondary Outcome
    Title Pharmacokinetic Plasma t1/2 for PF-02341066 and Binimetinib.
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Escalation Phase 5. Dose Escalation Phase Dose 5 (Interval Dosing) Dose Escalation Phase Dose 5a
    Arm/Group Description 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 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 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
    Measure Participants 4 3 5
    Summary Half Life for Binimetinib for PK Day 21 up to 10h
    4.3
    (1.7)
    5.5
    (2.9)
    4.7
    (1.0)
    Summary Half Life for AR00426032 (binimetinib metabolite) for PK Day 21 up to 10h
    4.3
    (1.9)
    5.3
    (2.2)
    5.4
    (1.8)
    26. Secondary Outcome
    Title Pharmacokinetic Plasma t1/2 Etc for PF-02341066 and Binimetinib
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Dose Expansion Phase
    Arm/Group Description 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
    Measure Participants 26
    Summary t1/2 life for PF-02341066 PK Cycle 1 D21 up to 24 h
    21
    (11)
    Summary t1/2 life for binimetinib PK Cycle 1 D21 up to 10h
    6.32
    (8.06)
    Summary t1/2 life for AR00426032 PK Cycle 1 D21 up to 10 hr
    4.70
    (1.39)

    Adverse Events

    Time Frame Adverse event monitoring starts from the time the time of consent until study completion, an average of 6 months.
    Adverse Event Reporting Description The Investigator will monitor each patient for clinical and laboratory evidence of adverse events on a routine basis throughout the study. The numbers for this outcome are presented by phase of study rather than dose level for a comparative review across both escalation and expansion phases as Adverse Events numbers at each dose level are very low, especially when separated by AE term. These events were collected irrespective of dose levels and cannot be separated into individual dose levels.
    Arm/Group Title Dose Escalation Phase 1 PF-02341066 and PD-0325901 Dose Escalation Phase 2 PF-0341066 and Binimetinib Dose Expansion Phase
    Arm/Group Description Dose Escalation Phase 1 - Crizotinib and PD-0325901 Dose Escalation Phase 2 - Binimetinib and PF-02341066 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.
    All Cause Mortality
    Dose Escalation Phase 1 PF-02341066 and PD-0325901 Dose Escalation Phase 2 PF-0341066 and Binimetinib Dose Expansion Phase
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 18/25 (72%) 15/20 (75%) 27/36 (75%)
    Serious Adverse Events
    Dose Escalation Phase 1 PF-02341066 and PD-0325901 Dose Escalation Phase 2 PF-0341066 and Binimetinib Dose Expansion Phase
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/25 (36%) 12/20 (60%) 18/36 (50%)
    Cardiac disorders
    Caridac Failure 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pericarditis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Eye disorders
    Central Serous Retinopathy (Bilateral) 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Gastrointestinal disorders
    Abdominal Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Ascitis 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Bowel Obstruction 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Colonic Obstruction 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Constipation 0/25 (0%) 0 1/20 (5%) 1 2/36 (5.6%) 2
    Diarrhoea 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Lower Gastrointestinal Hemorrhage 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    General disorders
    Edema Face 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Fever 2/25 (8%) 2 0/20 (0%) 0 1/36 (2.8%) 1
    Mucositis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pain 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Hepatobiliary disorders
    Hypertransaminasemia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Infections and infestations
    Abdominal Infection 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Lung Infection 0/25 (0%) 0 3/20 (15%) 3 1/36 (2.8%) 1
    Skin Infection 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Wound Infection 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Injury, poisoning and procedural complications
    Postoperative Hemorrhage 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Investigations
    Ejection Fraction Decreased 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Metabolism and nutrition disorders
    Cytolysis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Dehydration 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Hyperglycemia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Hypoalbuminemia 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis Of Jaw 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Worsening Back Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain Metastases 0/25 (0%) 0 1/20 (5%) 1 1/36 (2.8%) 1
    Nervous system disorders
    Tingling In Lower Limbs 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Vertigo 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 1/25 (4%) 1 1/20 (5%) 1 2/36 (5.6%) 2
    Lower Respiratory Infection 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pleural Effusion 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pneumonitis 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Vascular disorders
    Postural hypotension 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Pulmonary Embolism 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Thromboembolic Event 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Other (Not Including Serious) Adverse Events
    Dose Escalation Phase 1 PF-02341066 and PD-0325901 Dose Escalation Phase 2 PF-0341066 and Binimetinib Dose Expansion Phase
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 25/25 (100%) 20/20 (100%) 36/36 (100%)
    Blood and lymphatic system disorders
    Anaemia 7/25 (28%) 9 1/20 (5%) 1 9/36 (25%) 16
    Neutropenia 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Thrombocytopenia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Cardiac disorders
    Bradycardia 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Cardiac Failure 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Extrasystoles 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Pericardial Effusion 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Sinus Bradycardia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Ear and labyrinth disorders
    Ear Disorder 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Vertigo 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Eye disorders
    Blepharitis 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Chorioretinopathy 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Conjunctival Haemorrhage 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Corneal Opacity 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Dry Eye 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Eye disorder 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Eyelid Function Disorder 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Periorbital Oedema 0/25 (0%) 0 3/20 (15%) 3 1/36 (2.8%) 1
    Photophobia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Retinal Detachment 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Retinal Hemorrhage 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Subconjunctival Haemorrhage 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Vision Abnormal 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Visual Disturbance 3/25 (12%) 3 0/20 (0%) 0 0/36 (0%) 0
    Gastrointestinal disorders
    Abdominal Distension 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Abdominal Pain 3/25 (12%) 3 1/20 (5%) 3 5/36 (13.9%) 7
    Abdominal Pain Lower 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Ascites 1/25 (4%) 1 1/20 (5%) 6 0/36 (0%) 0
    Constipation 12/25 (48%) 20 4/20 (20%) 5 9/36 (25%) 12
    Diarrhoea 10/25 (40%) 15 14/20 (70%) 28 18/36 (50%) 29
    Dry Mouth 2/25 (8%) 2 1/20 (5%) 1 1/36 (2.8%) 1
    Dyspepsia 2/25 (8%) 2 1/20 (5%) 2 1/36 (2.8%) 1
    Epigastric Pain 1/25 (4%) 1 1/20 (5%) 1 0/36 (0%) 0
    Frequent Bowel Movements 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Gastritis 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Gastrooesophageal Reflux 2/25 (8%) 2 1/20 (5%) 1 0/36 (0%) 0
    Haemorrhoids 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Heartburn 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Intestinal Obstruction 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Loose Stools 1/25 (4%) 3 0/20 (0%) 0 0/36 (0%) 0
    Nausea 11/25 (44%) 20 11/20 (55%) 16 20/36 (55.6%) 29
    Nausea And Vomiting 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Oesophagitis 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Postprandial Emesis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Rectal Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Right Upper Quadrant Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Sore Gums 2/25 (8%) 2 0/20 (0%) 0 0/36 (0%) 0
    Stomach Cramps 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Stomach Pain 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Stomatitis 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Vomiting 10/25 (40%) 20 6/20 (30%) 9 19/36 (52.8%) 37
    General disorders
    Asthenia 2/25 (8%) 2 6/20 (30%) 10 9/36 (25%) 12
    Chest Pain 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Chills 2/25 (8%) 2 1/20 (5%) 1 0/36 (0%) 0
    Edema 1/25 (4%) 1 0/20 (0%) 0 1/36 (2.8%) 1
    Edema extremities 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Edema Face 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Edema Limbs 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Edema Lower Limb 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Edema of legs 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Fatigue 10/25 (40%) 18 10/20 (50%) 16 14/36 (38.9%) 30
    Fever 2/25 (8%) 2 1/20 (5%) 1 4/36 (11.1%) 5
    Flu like symptoms 1/25 (4%) 1 1/20 (5%) 1 0/36 (0%) 0
    Foot Oedema 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Generalised Oedema 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Hand Swelling 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Headache 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Leg Oedema 2/25 (8%) 2 2/20 (10%) 3 0/36 (0%) 0
    Malaise 1/25 (4%) 1 1/20 (5%) 1 0/36 (0%) 0
    Mucositis 2/25 (8%) 2 1/20 (5%) 1 1/36 (2.8%) 2
    Oedema 1/25 (4%) 4 2/20 (10%) 4 1/36 (2.8%) 1
    Oedema Abdomen 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Oedema Arms 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Oedema Extremities 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Oedema Legs 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Oedema Limbs 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Oedema Of Lower Extremities 1/25 (4%) 1 1/20 (5%) 1 1/36 (2.8%) 1
    Orofacial Oedema 1/25 (4%) 1 0/20 (0%) 0 1/36 (2.8%) 1
    Pain 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Peripheral Oedema 0/25 (0%) 0 2/20 (10%) 4 0/36 (0%) 0
    Retrosternal Chest Pain 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Rigors 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Serous Discharge 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Swelling Of Hands 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Swelling Of Legs 1/25 (4%) 1 1/20 (5%) 1 0/36 (0%) 0
    Teeth Chattering 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Hepatobiliary disorders
    Hepatic Haemorrhage 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Hyperbilirubinaemia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Hypertransaminasaemia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Liver Pain 0/25 (0%) 0 2/20 (10%) 2 1/36 (2.8%) 1
    Immune system disorders
    Hypersensitivity 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Infections and infestations
    Abdominal abscess 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Candida Infection 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Device Related Infection 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Ear infection 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Folliculitis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Furunculosis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Herpes Lesion Intra-Oral 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Intra-Abdominal Abscess 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Lower Respiratory Tract Infection 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 3
    Oral Candida 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Paronychia 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Parotiditis 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Periorbital Infection 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Pneumonia 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Pustular Rash 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Upper Respiratory Tract Infection 2/25 (8%) 2 1/20 (5%) 1 1/36 (2.8%) 1
    Urinary Tract Infection 1/25 (4%) 1 0/20 (0%) 0 2/36 (5.6%) 3
    Wound Infection 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Injury, poisoning and procedural complications
    Fall 2/25 (8%) 2 0/20 (0%) 0 1/36 (2.8%) 1
    Intestinal Stoma Complication 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Prolapse Of Intestinal Stoma 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Scar 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Stoma Site Bleeding 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Vascular Access Complication 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Wound Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Investigations
    Alanine Aminotransferase Increased 3/25 (12%) 5 3/20 (15%) 4 8/36 (22.2%) 17
    Aspartate Aminotransferase Increased 3/25 (12%) 4 3/20 (15%) 5 9/36 (25%) 13
    Blood Albumin Decreased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Blood Alkaline Phosphatase Increased 5/25 (20%) 7 0/20 (0%) 0 6/36 (16.7%) 9
    Blood Creatine Phosphokinase Increased 0/25 (0%) 0 7/20 (35%) 19 11/36 (30.6%) 25
    Blood Creatinine Increased 1/25 (4%) 1 0/20 (0%) 0 1/36 (2.8%) 1
    Blood Lactate Dehydrogenase Increased 1/25 (4%) 1 0/20 (0%) 0 1/36 (2.8%) 1
    Blood Glucose Increased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Blood Potassium Decreased 0/25 (0%) 0 2/20 (10%) 2 0/36 (0%) 0
    Blood Pressure Increased 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Blood Sodium Decreased 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Body Temperature Increased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    C-Reactive Protein Increased 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Ejection Fraction Decreased 0/25 (0%) 0 1/20 (5%) 1 2/36 (5.6%) 2
    Electrocardiogram Qtc Interval Prolonged 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Gamma-Glutamyltransferase Increased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Ggt Increased 1/25 (4%) 1 0/20 (0%) 0 2/36 (5.6%) 2
    Glucose Increased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    K+ Decreased 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Ldh Increased 1/25 (4%) 1 0/20 (0%) 0 1/36 (2.8%) 1
    Left Ventricular Ejection Fraction Decreased 0/25 (0%) 0 1/20 (5%) 1 1/36 (2.8%) 1
    Platelet Count Decreased 1/25 (4%) 1 1/20 (5%) 1 2/36 (5.6%) 2
    Qt Prolonged 4/25 (16%) 4 0/20 (0%) 0 0/36 (0%) 0
    Sodium Decreased 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Transaminases Increased 1/25 (4%) 1 1/20 (5%) 4 0/36 (0%) 0
    Transaminitis 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 0
    Troponin Increased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Weight Gain 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Weight Loss 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Metabolism and nutrition disorders
    Anorexia 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Decreased Appetite 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Dehydration 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Gout 0/25 (0%) 0 1/20 (5%) 1 1/36 (2.8%) 1
    Hyperglycaemia 0/25 (0%) 0 1/20 (5%) 1 1/36 (2.8%) 1
    Hypoalbuminaemia 7/25 (28%) 10 3/20 (15%) 4 3/36 (8.3%) 5
    Hypoglycaemia 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/25 (0%) 0 1/20 (5%) 5 3/36 (8.3%) 4
    Back pain 2/25 (8%) 2 0/20 (0%) 0 2/36 (5.6%) 4
    Finger cramps 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Flank pain 1/25 (4%) 2 1/20 (5%) 1 0/36 (0%) 0
    Hypokalaemia 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Intercostal Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Joint Instability 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Low Back Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Muscle Ache 1/25 (4%) 1 0/20 (0%) 0 1/36 (2.8%) 1
    Muscle Weakness 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Musculoskeletal Pain 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Myalgia 0/25 (0%) 0 3/20 (15%) 3 1/36 (2.8%) 1
    Myalgia Of Lower Extremities 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Neck Pain 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Osteoarticular Pain 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Osteonecrosis Of Jaw 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Pain In Hip 0/25 (0%) 0 1/20 (5%) 3 0/36 (0%) 0
    Pain In Thigh 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pain Jaw 1/25 (4%) 3 0/20 (0%) 0 0/36 (0%) 0
    Painful Hips 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Shoulder Pain 2/25 (8%) 2 0/20 (0%) 0 0/36 (0%) 0
    Nervous system disorders
    Amnesia 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Aphasia 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Dizziness 1/25 (4%) 1 4/20 (20%) 5 2/36 (5.6%) 3
    Dizziness Postural 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Dysgeusia 1/25 (4%) 1 0/20 (0%) 0 2/36 (5.6%) 2
    Expressive Dysphasia 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Localised Numbness 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Neuropathic Pain 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Neuropathy 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Neuropathy Peripheral 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Neurotoxicity 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Paraesthesia 2/25 (8%) 3 1/20 (5%) 1 0/36 (0%) 0
    Paraesthesia Lower Limb 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Peripheral Sensory Neuropathy 0/25 (0%) 0 3/20 (15%) 3 0/36 (0%) 0
    Presyncope 0/25 (0%) 0 1/20 (5%) 1 2/36 (5.6%) 4
    Tremor 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Vasovagal Attack 2/25 (8%) 2 0/20 (0%) 0 0/36 (0%) 0
    Visual Field Defect 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Weakness Left Or Right Side 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Psychiatric disorders
    Anxiety 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Cognitive Disorder Cognitive Disorder 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Confusional State 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Depressed Mood 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Insomnia 1/25 (4%) 2 0/20 (0%) 0 1/36 (2.8%) 1
    Libido Decreased 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Low Mood 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Renal and urinary disorders
    Haematuria 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Renal Impairment 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Urinary Frequency 1/25 (4%) 2 0/20 (0%) 0 0/36 (0%) 0
    Urine Incontinence 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 3/25 (12%) 4 6/20 (30%) 9 1/36 (2.8%) 4
    Dysphonia 1/25 (4%) 2 1/20 (5%) 1 5/36 (13.9%) 8
    Epistaxis 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Exertional Dyspnoea 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Hoarseness 0/25 (0%) 0 1/20 (5%) 2 0/36 (0%) 0
    Nasal Congestion 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Nose Bleeds 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pleural Effusion 0/25 (0%) 0 2/20 (10%) 3 0/36 (0%) 0
    Pleurisy 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pneumothorax 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Productive Cough 0/25 (0%) 0 2/20 (10%) 2 0/36 (0%) 0
    Pulmonary Embolism 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Respiratory Distress 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Rib Pain 1/25 (4%) 2 0/20 (0%) 0 1/36 (2.8%) 1
    Runny Nose 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Shortness Of Breath 1/25 (4%) 1 0/20 (0%) 0 2/36 (5.6%) 2
    Sore Throat 2/25 (8%) 2 2/20 (10%) 2 0/36 (0%) 0
    Wheeze 0/25 (0%) 0 1/20 (5%) 1 1/36 (2.8%) 1
    Skin and subcutaneous tissue disorders
    Alopecia 1/25 (4%) 1 2/20 (10%) 2 0/36 (0%) 0
    Dermatitis Acneiform 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Dry Skin 2/25 (8%) 2 1/20 (5%) 1 3/36 (8.3%) 3
    Facial rash 3/25 (12%) 3 0/20 (0%) 0 0/36 (0%) 0
    Genital Itching Nos 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Itchy Scalp 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Macular Rash 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Maculopapular Rash 2/25 (8%) 2 1/20 (5%) 1 0/36 (0%) 0
    Neck rash 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Night Sweats 1/25 (4%) 1 0/20 (0%) 0 3/36 (8.3%) 3
    Papular Rash 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Pruritis 0/25 (0%) 0 0/20 (0%) 0 5/36 (13.9%) 6
    Purpura 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Rash 7/25 (28%) 8 7/20 (35%) 12 11/36 (30.6%) 21
    Rash Acneiform 9/25 (36%) 12 8/20 (40%) 12 13/36 (36.1%) 19
    Rash Face 2/25 (8%) 2 2/20 (10%) 2 1/36 (2.8%) 1
    Rash On Legs & Arms 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Rosacea 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Seborrhoeic Dermatitis 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Skin Lesion 1/25 (4%) 1 0/20 (0%) 0 0/36 (0%) 0
    Skin Oedema 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Skin Peeling 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Skin Rash 0/25 (0%) 0 3/20 (15%) 5 0/36 (0%) 0
    Skin Toxicity 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 4
    Surgical and medical procedures
    Cataract Operation 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Vascular disorders
    Haematoma 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0
    Hot Flushes 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 1
    Hypertension 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Hypotension 0/25 (0%) 0 0/20 (0%) 0 2/36 (5.6%) 2
    Lymphoedema 1/25 (4%) 5 0/20 (0%) 0 0/36 (0%) 0
    Postural Hypotension 0/25 (0%) 0 0/20 (0%) 0 1/36 (2.8%) 2
    Thrombosis 0/25 (0%) 0 1/20 (5%) 1 0/36 (0%) 0

    Limitations/Caveats

    Few patients stayed on treatment beyond cycle 2 so long term tolerability has not been evaluated in depth.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Heather House
    Organization University of Oxford Clinical Trials and Research Governance (CTRG)
    Phone 01865 572245
    Email heather.house@admin.ox.ac.uk
    Responsible Party:
    University of Oxford
    ClinicalTrials.gov Identifier:
    NCT02510001
    Other Study ID Numbers:
    • OCTO-049
    First Posted:
    Jul 28, 2015
    Last Update Posted:
    Jul 13, 2021
    Last Verified:
    Jan 1, 2021