| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer. Solid tumours in the escalation phase and colorectal cancer in the expansion groups. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancers, especially bowel cancers. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
In the dose escalation part of the trial the main objective is to find the best doses for the combination of MEK inhibitors PD-0325901 or Binimetinib with cMET inhibitor Crizotinib.
In the second (expansion) part of the trial we want to see how well this combination works in three particular sub-types of bowel cancer. We want to do this by looking at tumour shrinkage, and at the molecular level through a variety of tests on tumour and bloods samples. |
|
| E.2.2 | Secondary objectives of the trial |
| In the both parts of the trial we will also look at the drug effects in skin or tumour (looking at biopsies) and at the level of drugs in blood over time (called pharmacokinetics) to check if there is any interaction between the two drugs. We also hope to identify molecular signatures that tell us who stands to benefit from this approach. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients
• Age ≥ 16 years
• 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 x 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 (combination of PF-02341066 with PD-0325901):
• Patients with any advanced solid tumours
• Patients for whom PF-02341066 with PD‐0325901 is a reasonable option.
Dose escalation phase (combination of PF-02341066 with Binimetinib):
• Patients with any advanced solid tumours
• Patients for whom PF-02341066 with Binimetinib is a reasonable option.
Dose expansion
Patients will be eligible for pre-screening for MErCuRIC 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 a) RASMT (KRAS codon 12, 13, 61,117; NRAS codon 12, 13, 63, 227, 136) mutations or b) RASWT/c-METmutated or amplified CRC 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 RASWT/c-MET over-expressed.
• 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. |
|
| E.4 | Principal exclusion criteria |
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 conditions
• 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
• Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C)
• 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.
• History of other malignancy less than 3 years before the diagnosis of current cancer
• 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose escalation phase:
• Maximal tolerated dose (MTD) of PD-0325901 or Binimetinib with PF-02341066 according to toxicities graded by NCI CTCAE v4.03 in cycle 1 of treatment.
Dose expansion phase:
• Clinical and radiological response to Binimetinib with PF-02341066 as defined by stable, partially or completely responding disease using RECIST version 1.1.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dose escalation phase:
• Throughout the first cycle of treatment (28d).
Dose expansion phase:
• At the end of the second treatment cycle (56d).
|
|
| E.5.2 | Secondary end point(s) |
Dose Escalation phase (PF-02341066 with PD-0325901)
• To define the recommended phase II dose and schedule (RPII), guided by safety, PK and PD data.
• To investigate pharmacokinetics (PK) of drug combination by determining plasma Cmax, Cmin, AUC, oral clearance and t1/2 etc for PF-02341066 and PD‐0325901 and its metabolite.
• To measure pharmacodynamic (PD) biomarkers of drug combination using ELISA for soluble c-MET and HGF in plasma; ERK phosphorylation (pERK) in PBMC; Immunohistochemistry (IHC) for pERK1/2, and c-METY1234/1235 in (mandatory) skin and (optional) tumour biopsies.
• To preliminarily assess the efficacy of RPII dose of drug combination, using objective response from CT scan and modified RECIST version 1.1, and progression free and overall survival.
Dose Escalation Phase (PF-02341066 with Binimetinib)
• To define the recommended phase II dose and schedule (RPII), guided by safety, PK and PD data.
• To investigate pharmacokinetics (PK) of drug combination by determining plasma Cmax, Cmin, AUC, oral clearance and t1/2 etc for PF-02341066 and Binimetinib.
• To measure pharmacodynamic (PD) biomarkers of drug combination using ELISA for soluble c-MET and HGF in plasma; ERK phosphorylation (pERK) in PBMC; Immunohistochemistry (IHC) for pERK1/2, and c-METY1234/1235 in (mandatory) skin and (optional) tumour biopsies.
• To preliminarily assess the efficacy of RPII dose of drug combination, using objective response from CT scan and modified RECIST version 1.1, and progression free and overall survival.
Dose Expansion phase:
• To assess the efficacy of RPII dose of PF-02341066 in combination with Binimetinib in patients with a) RASMT or b)RASWT/c-MET mut/amplified CRC or c)RASWT/c-MET over-expressed CRC , using progression free survival using RECIST version 1.1 and overall survival.
• To further investigate the safety and toxicity profile/tolerability of the drug combination using adverse events according to NCI CTCAE V4.03 across all treatment cycles.
• To investigate pharmacokinetic (PK) biomarkers of the drugs in blood by determining plasma Cmax, Cmin, AUC, oral clearance and t1/2 etc for PF-02341066 and Binimetinib.
• To measure pharmacodynamic (PD) effect of PF-02341066 in combination with Binimetinib using ELISA for soluble c-MET and HGF in plasma; Immunohistochemistry (IHC) for pERK1/2, and c-METY1234/1235 in skin and tumour biopsies.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK will be assessed in detail in the first treatment cycle, as will PD endpoints.
Efficacy will be evaluated every 2 treatment cycles.
In the expansion phase a tumour biopsy at disease progression will inform further translational endpoints. During this phase the number of responders in each cohort will be observed to decide whether or not to continue the trial. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| New combination of two IMPs, with preliminary exploration of therapeutic benefit |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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