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MEK and MET Inhibition in Colorectal Cancer (MErCuRIC1)

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ClinicalTrials.gov Identifier: NCT02510001
Recruitment Status : Recruiting
First Posted : July 28, 2015
Last Update Posted : November 17, 2017
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
University of Oxford

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
Solid Tumor Colorectal Cancer Drug: PF-02341066 Drug: PD-0325901 Drug: Binimetinib Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 92 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 : November 2014
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : April 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Crizotinib

Arm Intervention/treatment
Experimental: Dose Escalation Phase Dose 1.
Crizotinib 250mg OD Days 1-28 continuously PD-0325901 2mg BD Run in Day -7 to Cycle 1 Day1, then Day 1-21 every 28 day cycle
Drug: PF-02341066
PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Other Name: 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 Name: No other Intervention name for this drug

Experimental: Dose Escalation Phase 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 Name: 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 Name: No other Intervention name for this drug

Experimental: Dose Escalation Phase 3.
Crizotinib 250mg OD Days 1-28 continuously PD-0325901 4mg 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 Name: 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 Name: No other Intervention name for this drug

Experimental: Diose Escalation Phase 4.
Crizotinib 200mg BD Days 1-28 continuously PD-0325901 4mg 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 Name: 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 Name: No other Intervention name for this drug

Experimental: Dose Escalation Phase 5.
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 Name: 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 Name: No other Intervention name for this drug

Experimental: Dose Escalation Phase 6.
Crizotinib 200mg OD 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 Name: 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 Name: No other Intervention name for this drug

Experimental: Dose Escalation Phase 7
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 Name: Crizotinib

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

Experimental: Dose Escalation Phase 8
Binimetinib 45mg 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 Name: Crizotinib

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

Experimental: Dose Escalation Phase 9
Binimetinib 45mg BD continuous administration or days 1-21 every 28 days. PF-02341066 250mg BD continuous administration
Drug: PF-02341066
PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Other Name: Crizotinib

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

Experimental: Dose Escalation Phase 10
Binimetinib 30mg BD continuous administration or 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 Name: Crizotinib

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

Experimental: Dose Escalation Phase 11
Binimetinib 45mg BD continuous administration or 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 Name: Crizotinib

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

Experimental: Dose Expansion Phase
PF-02341066 (Crizotinib) 200mg OD/ 200mg BD Days 1-28 continuously Binimetinib 30mg/45mg Dosage to be determined once the recommended Phase II dose has been identified in the dose escalation phase.
Drug: PF-02341066
PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously
Other Name: Crizotinib

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




Primary Outcome Measures :
  1. Maximal tolerated dose (MTD) of PD-0325901 /PF-02341066 or Binimetinib with PF-02341066 [ Time Frame: Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD0325901/PF-02341066 combination) ]
    Determine maximum tolerated dose (MTD) of PD-0325901 or Binimetinib 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 [ Time Frame: 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 using RECIST version 1.1.

  3. Radiological response to Binimetinib with PF-02341066 [ Time Frame: Dose Expansion phase: change from baseline and up to 12 months. ]
    Objective tumour response to treatment with RPII dose will be measured according to RECIST (Version 1.1) from measurable lesions at baseline until disease progression in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC.


Secondary Outcome Measures :
  1. Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to safety blood samples for haematology, biochemistry and coagulation data. [ Time Frame: Dose Escalation Phase: at baseline; Cycle 1 Days 1 and 15 (PD-0325901/PF-02341066 combination additional assessments on Cycle 1 Days-7 and 28) and then on Day 1 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066 by assessing the adverse event grading and number of the haematological toxicities.

  2. Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to ECOG data. [ Time Frame: Dose Escalation Phase: scheduled at baseline and every cycle on Days 1; 8; 15; 21 (PD-0325901/PF-02341066 combination additional assessments on Cycle 1 Days-7 and 28) up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066 by assessing the adverse event grading related to ECOG performance.

  3. Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to vital signs of temperature, blood pressure and heart rate data. [ Time Frame: Dose Escalation Phase: scheduled at baseline and every cycle 1 on Days 1; 8;15;21(PD-0325901/PF-02341066 combination additional assessments on Cycle 1 Days-7 and 28) up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066 by assessing the adverse event grading related to vital signs performance.

  4. Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to ECG measurements. [ Time Frame: Dose Escalation Phase: at baseline; Cycle 1 Days 1 and 15 (PD-0325901/PF-02341066 combination additional assessments on Cycle 1 Days-7 and 28) and then on Day 1 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066 by assessing the adverse event grading related to ECG measurements.

  5. Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to weight measurements. [ Time Frame: Dose Escalation Phase: scheduled at baseline; Cycle 1 Days 1; 8; 15; 21 (PD-0325901/PF-02341066 combination additional assessments on Cycle 1 Days-7 and 28)and then on Day1 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066 by assessing the adverse event grading related to weight measurements.

  6. Recommended phase II (RPII) dose and schedule guided by the number of participants with adverse events related to ophthalmic measurements. [ Time Frame: Dose Escalation Phase: change from baseline in visual health on Day 21 at Cycles 2, 4, 6 and then every third cycles. ]
    To define the RPII dose and schedule of Binimetinib in combination with PF-023241066 by assessing the adverse event grading determined on ophthalmic examination and through optical coherence tomography and fluorescin angiography.

  7. Recommended phase II (RPII) dose and schedule guided by PK data. [ Time Frame: Dose Escalation: Up to 12 months. PK assessments: Cycle 1 PK profile - PD-0325901/PF-02341066 on Day -7/-6; 21/22 and 28/29; Binimetinib/PF-02341066 on Day 21/22. Cycle1 PD profile at baseline, Day1/2 and Day15/16 (plus Day-7/-6 PD-901/PF-02341066). ]
    To define the recommended phase II (RPII) dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066

  8. Recommended phase II (RPII) dose and schedule guided by PD data. [ Time Frame: Dose Escalation Phase: Cycle 1 PD profile at baseline, Day 1/2 and Day15/16 plus Day-7/-6 for PD-0325901/PF-02341066 combination. ]
    to define the recommended phase II (RPII) dose and schedule of PD-0325901 or Binimetinib in combination with PF-023241066

  9. Pharmacokinetic peak plasma concentration (Cmax) for PF-02341066 and PD-0325901 or Binimetinib. [ Time Frame: Dose Escalation:Up to 12 months. PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22 (PD-0325901/PF-02341066 combination plus C1 Day -7/6; 28/29);PK trough samples on Day 21 pre-dose and 2 hrs post dose at cycle 2,4,6,8,10,12. ]
    To investigate the pharmacokinetics (PK) plasma Cmax of PD-0325901 (and its metabolite) or Binimetinib with PF-023241066 when administered in combination.

  10. Pharmacokinetic minimum plasma trough concentration (Cmin) for PF-02341066 and PD-0325901 or Binimetinib. [ Time Frame: Dose Escalation:Up to 12 mths. Cycle 1 PK profile at pre-dose,1,2,4,6,8,10,24hrs post dose on Day21/22 (PD-0325901/PF-02341066 combination plus C1 Day-7/6; 28/29), and PK trough samples on Day 21 pre-dose and 2 hrs post dose at cycle 2, 4, 6, 8, 10, 12. ]
    To investigate the pharmacokinetics (PK) plasma Cmin of PD-0325901 (and its metabolite) or Binimetinib with PF-023241066 when administered in combination.

  11. Pharmacokinetic area under the plasma concentration versus time curve (AUC) for PF-02341066 and PD‐0325901(and its metabolite) or Binimetinib. [ Time Frame: Dose Escalation:Up to12 months. Cycle1 PK profile at pre-dose,1,2,4,6,8,10,24hrs post dose on Day21/22 (PD-0325901/PF-02341066 combination plus C1 Day -7/6; 28/29), and PK trough samples on Day 21 pre-dose and 2 hrs post dose at cycle 2, 4, 6, 8, 10, 12. ]
    To investigate the pharmacokinetics (PK) plasma AUC of PD-0325901 (and its metabolite) or Binimetinib with PF-023241066 when administered in combination.

  12. Pharmacokinetic plasma oral clearance and t1/2 etc for PF-02341066 and PD-0325901 or Binimetinib. [ Time Frame: Dose Escalation:Up to12 months.PK profile at pre-dose,1,2,4,6,8,10,24 hrs post dose on Days 21/22 ,(PD-0325901/PF-02341066 combination plus C1 Day -7/6; 28/29) and PK trough samples on Day 21 pre-dose and 2 hrs post dose at cycle 2, 4, 6, 8,10,12. ]
    To investigate the pharmacokinetics (PK) plasma oral clearance and half life of PD-0325901 (and its metabolite) Binimetinib with PF-023241066 when administered in combination.

  13. Pharmacodynamic (PD) biomarkers of PD-0325901 or Binimetinib and PF-02341066 in paired skin biopsies, tumour biopsies (where possible), in serum and PBMCs. [ Time Frame: Dose Escalation:12 months.c-MET/HGF samples at baseline, pre-dose and 6hrs at Cycle 1 & 2, D1 and D15, then D1, Cycles 3,4,5,6. PD pERK samples - D-7; C1,D1;C1, D15, at predose,1,2,4,8,24 hrs. Biopsies at baseline and Cycle1 D15. ]
    To investigate the pharmacodynamics (PD) biomarkers of PD-0325901 or Binimetinib with PF-023241066 in paired skin biopsies, tumour biopsies (where possible), in serum and PBMCs.

  14. Tumour assessment using CT scan and modified RECIST version 1.1 and progression free and overall survival. [ Time Frame: Dose Escalation Phase: Baseline and Day1 at cycles 3, 5, 7, 9, 11. Scan also within 30 days of end of study treatment. ]
    Objective response to preliminarily assess the efficacy of RPII dose of PF-02341066 in combination with PD-0325901 or Binimetinib.

  15. Carinoembryonic antigen blood level assessments. [ Time Frame: Dose Escalation Phase: Baseline Day -7 and cycle1 Day 21; Day 1 at cycles 3, 5, 7, 9, 11. ]
    Objective response to preliminarily assess the efficacy of RPII dose of PF-02341066 in combination with PD-0325901.

  16. Tumour Marker blood level assessments. [ Time Frame: Dose Escalation Phase: Baseline and Day 1 at cycles 3, 5, 7, 9, 11. ]
    Objective response to preliminarily assess the efficacy of RPII dose of PF-02341066 in combination with Binimetinib.

  17. Tumour assessment using CT scan and modified RECIST version 1.1, and progression free and overall survival. [ Time Frame: Dose Expansion Phase: Baseline; Day1 cycles 3, 5, 7, 9, 11. Scan also within 30 days of end of study treatment. ]
    Objective response to assess the efficacy of RPII dose of PF-023441066 in combination with Binimetinib in patients with RASMT and RASWT/c-MET+CRC.

  18. Tumour Marker blood level assessment. [ Time Frame: Dose Expansion Phase: Baseline and Day 1 at Cycles 3, 5, 7, 9 and 11. ]
    Objective response to assess the efficacy of RPII dose of PF-023441066 in combination with Binimetinib in patients with RASMT and RASWT/c-MET+CRC.

  19. Adverse events according to NCI CTCAE v4.03 across all treatment cycles. [ Time Frame: Dose Escalation and Expansion Phase: Up to12 months. Quantity of Grade 3 and 4 events noted at every trial visit. ]
    to further investigate the safety and toxicity profile/tolerability of PD-0325901/PF-02341066 or Binimetinib/PF-02341066 combination.

  20. Pharmacokinetic peak plasma concentration (Cmax) for PF-02341066 and Binimetinib. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Cycle 1 Days 21/22, and PK trough samples on Day 21 pre-dose and 2 hrs post dose at Cycle 2, 4, 6, 8, 10, 12. ]
    To investigate pharmacokinetic (PK) Cmax of PF-02341066 and Binimetinib in blood.

  21. Pharmacokinetic minimum plasma trough concentration (Cmin) for PF-02341066 and Binimetinib. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Cycle 1 Days 21/22, and PK trough samples on Day 21 pre-dose and 2 hrs post dose at Cycle 2, 4, 6, 8, 10, 12. ]
    to investigate pharmacokinetic (PK) Cmin of PF-02341066 and Binimetinib in blood.

  22. Pharmacokinetic area under the plasma concentration versus time curve (AUC) for PF-02341066 and Binimetinib. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Cycle 1 Days 21/22, and PK trough samples on Day 21 pre-dose and 2 hrs post dose at cycle 2, 4, 6, 8, 10, 12. ]
    to investigate pharmacokinetic (PK) AUC of PF-02341066 and Binimetinib in blood.

  23. Pharmacokinetic oral clearance and plasma t1/2 for PF-02341066 and Binimetinib. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Cycle 1 Days 21/22, and PK trough samples on Day 21 pre-dose and 2 hrs post dose at cycle 2, 4, 6, 8, 10, 12. ]
    To investigate pharmacokinetic (PK) oral clearance and t1/2 of PF-02341066 and Binimetinib in blood.

  24. Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 or Binimetinib in paired skin biopsies. [ Time Frame: Dose Escalation and Expansion: at baseline and Cycle1, D15. ]
    For measurement of c-METY1234/1235 in skin biopsies to determine objective response to treatment.

  25. Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 or Binimetinib in paired tumour biopsies (where possible). [ Time Frame: Dose Escalation: Biopsies at baseline and Cycle1 D15 - both optional. ]
    For measurement of c-METY1234/1235 in tumour biopsies to determine objective response to treatment.

  26. Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with Binimetinib in paired tumour biopsies (where possible). [ Time Frame: Dose Expansion: Biopsies at baseline and Cycle1 D15. Optional metastic tumour biopsy within 28 days following radiological confirmation of disease progression. ]
    For measurement of c-METY1234/1235 in tumour biopsies to determine objective response to treatment.

  27. Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 or Binimetinib in plasma blood samples. [ Time Frame: Dose Escalation and Expansion: samples at baseline, pre-dose and 6hrs at Cycle 1 & 2, Days 1 and 15, then Day1 at cycles 3,4,5,6. ]
    To investigate the pharmacodynamics (PD) biomarkers of ELISA for soluble c-MET and HGF in plasma.

  28. Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 or Binimetinib in plasma PBMC blood samples. [ Time Frame: Dose Escalation and Expansion: PD pERK samples at baseline (Day -7: PD901/PF02341066 combination); Cycle1, Day1 and D15 at predose then 1,2,4,8,24 hrs post dose. ]
    To investigate pharmacodynamics (PD) biomarkers of ERK phosphorylation (pERK) in PBMC and immunohistochemistry (IHC) for pERK1/2.


Other Outcome Measures:
  1. Whole exome sequencing and miRNA profiling on tumour biopsies [ Time Frame: Tertiary and Exploratory: At baseline and up to 12 months. ]
    to identify molecular signatures of response and resistance to combined PF-02341066 and PD-0325901 or Binimetinib treatment.

  2. Gene sequencing outputs from ctDNA in serially collected plasma samples from mCRC patients [ Time Frame: Tertiary and Exploratory: Up to 12 months. Samples taken at baseline; Day 1 Pre-dose at Cycles1,2,3,4,5,6,7,8,9,10,11,12 and within 30 days of end of study treatment. ]
    Develop a liquid biopsy platform for routine assessment of therapeutic efficacy.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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, 62, 227, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02510001


Contacts
Contact: Jennifer Houlden +44 (0)1865 227194 jennifer.houlden@oncology.ox.ac.uk
Contact: Usharani D Wahengbam +44(0) 1865 227197 Usharani.Wahengbam@oncology.ox.ac.uk

Locations
United Kingdom
Oxford University Hospital NHS Trust Recruiting
Oxford, United Kingdom, OX3 7LE
Contact: Mark Middleton    01865 235315    mark.middleton@oncology.ox.ac.uk   
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)

Documents provided by University of Oxford:
Study Protocol  [PDF] September 11, 2017
Statistical Analysis Plan  [PDF] June 9, 2016
Informed Consent Form  [PDF] May 11, 2017


Additional Information:
Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT02510001     History of Changes
Other Study ID Numbers: OCTO-049
First Posted: July 28, 2015    Key Record Dates
Last Update Posted: November 17, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
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
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Crizotinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action