MEK and MET Inhibition in Colorectal Cancer

NCT02510001 | Completed Phase 1 Results DMC

• 1 other identifier: OCTO-049
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 1

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.

Conditions

Solid Tumor; Colorectal Cancer

Keywords

RASMT CRC; RASWT/c-MET CRC; Dose Escalation; Histologically or cytologically confirmed; Dose Expansion

Outcome Measures

Primary Outcomes (3)

• Maximal Tolerated Dose (MTD) of PD-0325901 and PF-02341066 /PF-02341066 or Binimetinib With PF-02341066

  Determine maximum tolerated dose (MTD) of PD-0325901 with Crizotinib (PF-02341066) according to toxicities graded by NCI CTCAE v4.03, in patients with advanced solid tumours.

  Dose Escalation Phase: treatment Cycle 1 28 days (plus 7 day run-in for PD-0325901/PF-02341066 combination)

• Clinical Response to Binimetinib Combined With PF-02341066

  To investigate response to treatment with RPII dose of Binimetinib with Crizotinib (PF-02341066), in patients with a) RASMT CRC or b) RASWT/cMET mut amplified CRC or c) RASWT/c-MET over-expressed CRC, as defined by stable, partially or completely responding disease, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase (\>=20%) to qualify for Progressive Disease; Overall Response (OR) = CR + PR + SD

  Dose Expansion phase: change from baseline and up to 12 months.

• Maximal Tolerated Dose (MTD) of Binimetinib and PF-02341066

  To determine the maximal tolerated dose (MTD) of Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE V4.03 in cycle 1 of treatment.

  Dose Escalation Phase: treatment Cycle 1 28 days

Secondary Outcomes (23)

• 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

• 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

• 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

• 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

• 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)).

Study Arms (8)

Dose Escalation Phase Cohort 1 Dose level 1

EXPERIMENTAL

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; Drug: PD-0325901

Dose Escalation Phase Cohort 2 Dose level 2

EXPERIMENTAL

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; Drug: PD-0325901

Dose Escalation Phase Cohort 3 Dose level 3

EXPERIMENTAL

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; Drug: PD-0325901

Dose Escalation Phase Cohort 4 Dose level 4

EXPERIMENTAL

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; Drug: PD-0325901

Dose Escalation Phase Cohort 7 Dose level 5

EXPERIMENTAL

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

Drug: PF-02341066; Drug: PD-0325901; Drug: Binimetinib

Dose Escalation Phase Cohort 13 Dose level 5a

EXPERIMENTAL

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

Drug: PF-02341066; Drug: Binimetinib

Dose Expansion Phase

EXPERIMENTAL

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; Drug: Binimetinib

Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing)

EXPERIMENTAL

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

Drug: PF-02341066; Drug: Binimetinib

Interventions

PF-02341066 DRUG

PF-02341066 (Crizotinib) 250mg OD or 200mg BD or 250mg BD Days 1-28 continuously

Also known as: Crizotinib

Dose Escalation Phase Cohort 1 Dose level 1; Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing); Dose Escalation Phase Cohort 13 Dose level 5a; Dose Escalation Phase Cohort 2 Dose level 2; Dose Escalation Phase Cohort 3 Dose level 3; Dose Escalation Phase Cohort 4 Dose level 4; Dose Escalation Phase Cohort 7 Dose level 5; Dose Expansion Phase

PD-0325901 DRUG

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.

Also known as: No other Intervention name for this drug

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; Dose Escalation Phase Cohort 7 Dose level 5

Binimetinib DRUG

Binimetinib 30mg or 45 mg BD either continuously or Days 1-21 every 28 days

Also known as: MEK162

Dose Escalation Phase Cohort 12 Dose level 5 (Interval dosing); Dose Escalation Phase Cohort 13 Dose level 5a; Dose Escalation Phase Cohort 7 Dose level 5; Dose Expansion Phase

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Oxford: lead
• Queen's University, Belfast: collaborator
• Oxford University Hospitals NHS Trust: collaborator
• Velindre NHS Trust: collaborator
• University Hospital, Antwerp: collaborator
• Hospital Vall d'Hebron: collaborator
• Saint Antoine University Hospital: collaborator
• European Georges Pompidou Hospital: collaborator
• Pfizer: collaborator
• University of Turin, Italy: collaborator
• Belfast Health and Social Care Trust: collaborator
• Beaumont Hospital: collaborator
• European Commission: collaborator
• Array BioPharma: collaborator
• University of Paris 5 - Rene Descartes: collaborator

Study Sites (1)

Oxford University Hospital NHS Trust

Oxford, OX3 7LE, United Kingdom

Location

Related Links

• Information about the trial on the Oncology Clinical Trials Office (OCTO) website.

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Crizotinib; mirdametinib; binimetinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopyridines; Pyridines

Limitations and Caveats

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

Results Point of Contact

• Title: Heather House
• Organization: University of Oxford Clinical Trials and Research Governance (CTRG)

heather.house@admin.ox.ac.uk

01865 572245

Study Officials

• Mark R Middleton

  Oxford University Hospital NHS Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 18, 2015
• First Posted: July 28, 2015
• Study Start: November 1, 2014
• Primary Completion: December 3, 2018
• Study Completion: December 3, 2018
• Last Updated: July 13, 2021
• Results First Posted: April 26, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)