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MEK and MET Inhibition in Colorectal Cancer (MErCuRIC1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02510001
Recruitment Status : Active, not recruiting
First Posted : July 28, 2015
Last Update Posted : November 27, 2018
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

Tracking Information
First Submitted Date  ICMJE June 18, 2015
First Posted Date  ICMJE July 28, 2015
Last Update Posted Date November 27, 2018
Actual Study Start Date  ICMJE November 2014
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 14, 2017)
  • 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.
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 27, 2015)
  • Maximal tolerated dose (MTD) of PD-0325901 with PF-02341066 [ Time Frame: Dose Escalation Phase: treatment Cycle1 (28 days plus 7 day run-in) ]
    Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours.
  • Clinical response to PD-0325901combined 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 PD-0325901 with Crizotinib (PF-02341066), in patients with RASMT and RASWT/cMET + CRC, as defined by stable, partially or completely responding disease using RECIST version 1.1.
  • Radiological response to PD-0325901 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 RASMT and RASWT/cMET + CRC.
Change History Complete list of historical versions of study NCT02510001 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 14, 2017)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 27, 2015)
  • 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 -7; 1;15; 28 and then on Day 1 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 in combination with PF-023241066 by assessing the adverse event grading and number of the haematological toxicities.
  • 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; Cycle 1 Days -7; 1; 8; 15; 21; 28 and then on Days 1; 8; 15; 21 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 in combination with PF-023241066 by assessing the adverse event grading related to ECOG performance.
  • 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; Cycle 1 Days -7; 1; 8; 15; 21; 28 and then on Days 1; 8;15;21 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 in combination with PF-023241066 by assessing the adverse event grading related to vital signs performance.
  • 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 -7; 1;15; 28 and then on Day 1 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 in combination with PF-023241066 by assessing the adverse event grading related to ECG measurements.
  • 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 -7; 1; 8; 15; 21; 28 and then on Day1 for every cycle up to 12 months. ]
    To define the RPII dose and schedule of PD-0325901 in combination with PF-023241066 by assessing the adverse event grading related to weight measurements.
  • 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 at Cycle 1 Day 21. ]
    To define the RPII dose and schedule of PD-0325901 in combination with PF-023241066 by assessing the adverse event grading determined on ophthalmic examination and through optical coherence tomography and fluorescin angiography.
  • Recommended phase II (RPII) dose and schedule guided by PK data. [ Time Frame: Dose Escalation Phase: Up to 12 months. PK assessments throughout the trial. Cycle 1 PK profile on Days -1/1, 21/22 and 28/29. Cycle 1 PD profile at baseline Day-7/6, Day 1/2 and Day15/16. ]
    to define the recommended phase II (RPII) dose and schedule of PD-0325901 in combination with PF-023241066
  • Recommended phase II (RPII) dose and schedule guided by PD data. [ Time Frame: Dose Escalation Phase: Cycle 1 PD profile at baseline Day-7/6, Day 1/2 and Day15/16. ]
    to define the recommended phase II (RPII) dose and schedule of PD-0325901 in combination with PF-023241066
  • Pharmacokinetic peak plasma concentration (Cmax) for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Escalation: Up to12 months. PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 Cmax of PD-0325901 with PF-023241066 when administered in combination.
  • Pharmacokinetic minimum plasma trough concentration (Cmin) for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Escalation: Up to12 months. PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 with PF-023241066 when administered in combination.
  • Pharmacokinetic area under the plasma concentration versus time curve (AUC) for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Escalation: Up to12 months. PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 with PF-023241066 when administered in combination.
  • Pharmacokinetic plasma oral clearance and t1/2 etc for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Escalation: Up to12 months. PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 lfe of PD-0325901 with PF-023241066 when administered in combination.
  • Pharmacodynamic (PD) biomarkers of PD-0325901 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 at 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 with PF-023241066 in paired skin biopsies, tumour biopsies (where possible), in serum and PBMCs.
  • 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.
  • 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.
  • Tumour assessment using CT scan and modified RECIST version 1.1, and progression free and overall survival. [ Time Frame: Dose Expansion Phase: Baseline Day -7 and 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 PD-0325901 in patients with RASMT and RASWT/c-MET+CRC.
  • Carcinoembryonic antigen blood level assessment. [ Time Frame: Dose Expansion Phase: Baseline and Day -7 and Cycle 1, Day 28 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 PD-0325901 in patients with RASMT and RASWT/c-MET+CRC.
  • 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 combination.
  • Pharmacokinetic peak plasma concentration (Cmax) for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 PD-0325901 in blood.
  • Pharmacokinetic minimum plasma trough concentration (Cmin) for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 PD-0325901 in blood.
  • Pharmacokinetic area under the plasma concentration versus time curve (AUC) for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 PD-0325901 in blood.
  • Pharmacokinetic oral clearance and plasma t1/2 for PF-02341066 and PD‐0325901and its metabolite. [ Time Frame: Dose Expansion: PK profile at pre-dose and 1,2,4,6,8,10 and 24 hrs post dose on Days 21/22; 28/29 (PF02341066) and Days -1/1; 21/22 (PD-0325901) , 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 PD-0325901 in blood.
  • Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 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.
  • Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 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.
  • Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 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.
  • Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 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.
  • Measurement of pharmacodynamic (PD) effect of PF-02341066 in combination with PD‐0325901 in plasma PBMC blood samples. [ Time Frame: Dose Escalation and Expansion: PD pERK samples at baseline Day -7; 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.
Current Other Pre-specified Outcome Measures
 (submitted: August 31, 2016)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: July 27, 2015)
  • 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 treatment.
  • 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.
 
Descriptive Information
Brief Title  ICMJE MEK and MET Inhibition in Colorectal Cancer
Official Title  ICMJE 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
Brief Summary This trial is designed to try two new cancer drugs together for the first time. The investigators think that they might be effective in some types of bowel cancer. The first part of the trial will see what doses of the two drugs can safely be given together. Once the investigators have identified a suitable dose combination they will look at how effective treatment is in bowel cancers where either the RAS gene is mutated, or MET is over-active. In the trial the investigators will look at samples of blood, skin and tumour to check the drugs are working in the way expected. The trial will take place in three sites in the UK and 5 sites in Europe. The trial is funded as part of the European commission's FP7 program.
Detailed Description

This is a two stage study. Firstly a dose escalation step is used to define the best dose for the drug combination, using the rolling 6 design where up to 6 patients are recruited at each dose level, and increasing the dose of one or other agent according to the side effects of treatment. An initial dose escalation phase was completed where 25 patients were enrolled, using the study treatment combination of PD-0325901 with PF-02341066. Following discontinuation of the MEKi (inihibitor), PD-0325901, the study was updated to include a further dose escalation phase using the new combination study treatment, MEKi, Binimetinib with METi, PF-02341066. The effects of this drug combination will be assessed to define the recommended dose level for the dose expansion phase of the study.

Second the new drug combination is observed in 42-98 patients with bowel cancer for its efficacy and tolerability. Patients who give consent will have their archival tumour samples tested for RAS and c-MET status.

Potential participants will, after giving consent, undergo screening tests to ensure that it is safe for them to take part. These involve a detailed medical history, physical exam, blood tests, ophthalmology exam, ECG and ultrasound and skin biopsies. The size and extent of tumours is also assessed by CT and/or MRI scan.

For the initial dose escalation phase, on assurance that the test results are satisfactory, patients start on PD-0325901 first for one week. On Day -7 a physical exam, ECG and blood test is performed, with a repeat blood test on Day -6. End of first week PD samples of blood are taken to observe the level of PD-0325901. Day 1 PF-02341066 is introduced after further clinical safety assessments. There are further blood samples taken over 24 hours to measure levels of PD-0325901 and PF-02341066 on days 21 and 28 of the first cycle.

For the further dose escalation phase, again assuming that the screening test results are satisfactory, patients start on Day 1 with the combined treatment of PF-02341066 with Binimetinib. A physical exam, ECG and blood test is performed, with a repeat blood test on Day 2. There are further blood samples taken over 24 hours to measure levels of Binimetinib and PF-02341066 on day 21of the first cycle.

Patients have weekly visits when side effects are reviewed and a physical examination is performed. On Day 15 a second skin biopsy is taken along with blood tests to assess liver and renal function. At the end of the first 4 weeks cycle, for the initial dose escalation phase, and at end of 8 weeks for the new combination therapy dose escalation phase, an ophthalmology exam is compared with the baseline assessment.

For subsequent cycles in both the initial dose escalation and further dose escalation phases, visits remain weekly and include safety assessments as per Day 1. Blood levels of PD-0325901 or Binimetinib and PF-02341066 are measured on day 21 of even numbered cycles. In addition the tumour size is checked every second cycle, and the study treatment stopped if the tumour continues to grow.

When patients stop taking the study treatment they will be reviewed after 4 weeks for any side effects and have a physical examination and other safety tests performed.

For patients entering the expansion phase of the trial the procedures are similar, except that there is a pre-screening stage where tumour biopsies are required. Patients will have a sample of their tumour assessed, following consent, to determine their RAS and cMET status. This may involve a fresh biopsy. If suitable, the patient will be entered into the screening for the dose expansion phase and a fresh tumour biopsy may be taken if not already done so. The study schedule is the same as for the escalation phase using Binimetinib with PF-02341066. At the end of treatment a further, optional, tumour biopsy may be taken.

After trial participation patients will be offered further care with the trial team or their referring oncology team as appropriate.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumor
  • Colorectal Cancer
Intervention  ICMJE
  • 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
  • Drug: Binimetinib
    Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days
    Other Name: MEK162
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: PF-02341066
    • Drug: PD-0325901
  • 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
    Interventions:
    • Drug: PF-02341066
    • Drug: PD-0325901
  • 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
    Interventions:
    • Drug: PF-02341066
    • Drug: PD-0325901
  • 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
    Interventions:
    • Drug: PF-02341066
    • Drug: PD-0325901
  • 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
    Interventions:
    • Drug: PF-02341066
    • Drug: PD-0325901
  • 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
    Interventions:
    • Drug: PF-02341066
    • Drug: PD-0325901
  • Experimental: Dose Escalation Phase 7
    Binimetinib 30mg BD continuous administration or days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
    Interventions:
    • Drug: PF-02341066
    • Drug: Binimetinib
  • Experimental: Dose Escalation Phase 8
    Binimetinib 45mg BD continuous administration or days 1-21 every 28 days. PF-02341066 200mg BD continuous administration
    Interventions:
    • Drug: PF-02341066
    • Drug: Binimetinib
  • Experimental: Dose Escalation Phase 9
    Binimetinib 45mg BD continuous administration or days 1-21 every 28 days. PF-02341066 250mg BD continuous administration
    Interventions:
    • Drug: PF-02341066
    • Drug: Binimetinib
  • Experimental: Dose Escalation Phase 10
    Binimetinib 30mg BD continuous administration or days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
    Interventions:
    • Drug: PF-02341066
    • Drug: Binimetinib
  • Experimental: Dose Escalation Phase 11
    Binimetinib 45mg BD continuous administration or days 1-21 every 28 days. PF-02341066 250mg OD continuous administration
    Interventions:
    • Drug: PF-02341066
    • Drug: Binimetinib
  • 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.
    Interventions:
    • Drug: PF-02341066
    • Drug: Binimetinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 22, 2018)
82
Original Estimated Enrollment  ICMJE
 (submitted: July 27, 2015)
48
Estimated Study Completion Date  ICMJE September 2019
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02510001
Other Study ID Numbers  ICMJE OCTO-049
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: Mark R Middleton Oxford University Hospital NHS Trust
PRS Account University of Oxford
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP