Condition category
Cancer
Date applied
04/02/2015
Date assigned
04/02/2015
Last edited
19/09/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Mrs Jennifer Houlden

ORCID ID

Contact details

University of Oxford
Department of Oncology
Oncology Clinical Trials Office (OCTO)
Old Road Campus Research Buliding
Roosevelt Drive
Oxford
OX3 7DQ
United Kingdom

Additional identifiers

EudraCT number

2014-000463-40

ClinicalTrials.gov number

NCT02510001

Protocol/serial number

17363

Study information

Scientific title

A Sequential Phase I study of MEK1/2 inhibitors PD0325901 or Binimetinib combined with cMET inhibitor PF02341066 in KRAS Mutant and RAS Wild Type (with aberrant cMET) Colorectal Cancer

Acronym

MErCuRIC1

Study hypothesis

Combined MEK/MET inhibitor treatment is well tolerated and results in superior survival of patients with RASMT CRC and RASWT CRC with aberrant c-MET signalling (overexpression, amplification or mutation; RASWT/c-MET+) compared to standard chemotherapy treatment. (added 07/09/2016)

There are two phases of the study:
1. Dose escalation phase in patients with solid tumours to discover the maximum tolerated drug doses
2. Dose expansion phase in two particular patient groups who have advanced colorectal cancer to study the treatment responses in each of those groups.
Both drugs have shown beneficial activity in studies treating patients with advanced cancer and it is believed that using this combination will inhibit the chemical pathways that are involved in colorectal cancer.

Ethics approval

14/SC/1010; First MREC approval date 06/08/2014

Study design

Non-randomised; Interventional; Design type: Treatment

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a patient information sheet

Condition

Topic: Cancer; Subtopic: Colorectal Cancer; Disease: Colon

Intervention

1. PD-0325901: This is a highly specific non-ATP competitive inhibitor of MEK1 and MEK2. Dose start will be at 4mg BD up to maximum levels of 8mg BD which is known to inhibit the target of MEK1 and MEK2.
2. Binimetinib is a selective and potent mitogen-activated protein (MAP) kinase (MEK) 1 and MEK 2 inhibitor. Dose start will be at 30mg BD up to maximum level of 45mg BD.(added 07/09/2016)
3. PF-02341066 (Crizotinib): A selective ATP-competitive small molecule oral inhibitor of ALK, cMet/hepatocyte growth factor receptor(HGFR), RON and ROS RTKs and their oncogenic variants. PF-02341066 has a long half life, takes 15 days to reach steady state and is excreted by the fecal route. It is both a CYP3A substrate and inhibitor. The extent and duration of inhibition of c-MET activity is directly linked to its anti-tumour efficacy.

Intervention type

Drug

Phase

Phase I

Drug names

PD-0325901
Binimetinib
PF-02341066 (Crizotinib)

Primary outcome measures

As of 07/09/2016:
Dose Expansion phase; Time point(s): Clinical & radiological response to PD-0325901 or Binimetinib with PF-02341066 using RECIST v1.1

Initial:
Dose Expansion phase; Timepoint(s): Clinical & radiological response to PD-0325901 with PF-02341066 using RECIST v1.1

Secondary outcome measures

As of 07/09/2016:Dose Escalation Phase; Time point(s): Maximal tolerated dose of PD-0325901 or Binimetinib with PF-02341066 according to toxicities in cycle 1.

Initial:
Dose Escalation Phase; Timepoint(s): Maximal tolerated dose of PD-0325901 with PF-02341066 according to toxicities in cycle 1.

Overall trial start date

14/11/2014

Overall trial end date

31/12/2018

Reason abandoned

Eligibility

Participant inclusion criteria

As of 07/09/2016:
1. Age at least 16 years
2. ECOG performance status 0-1
3. Adequate respiratory and cardiac function on clinical assessment
4. Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram.
5. Able to give informed consent prior to any screening procedures being performed and be capable of complying with the protocol and its requirements
6. Haematological and biochemical indices within the ranges shown below:
6.1. Haemoglobin (Hb) =9g/dl (transfusion to achieve this allowed),
6.2. Neutrophils= 1,500/μl,
6.3. Platelet count = 100,000/μl,
6.4. AST or ALT = <2.5 x ULN, patient with liver metastases <5 x ULN, alkaline phosphatase = <2 x ULN,
6.5. Serum Bilirubin = 1.5 x ULN,
6.6. Creatinine Clearance = 50ml/min
7. Able to swallow oral medication
8. Life expectancy of at least 3 months

Dose escalation phase
1. Patients with any advanced solid tumours
2. Patients for whom the combination of PF-02341066 with Binimetinib is a reasonable option.

Dose expansion
Patients will be eligible for pre-screening for MErCuRIC provided that:
1. They have given informed consent to screening
2. They are willing to undergo a biopsy for assessment of tumour KRAS mutation status and c-MET assessment
3. 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 pr-e-screening, requires:
1. Histologically confirmed colon adenocarcinoma that is RASMT (KRAS codon 12, 13, 61, 117, 146; NRAS codon 12, 13, 61, 117, 146)) or RASWT/c-MET+, with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy and/or targeted therapies for metastatic disease.
2. No evidence for a mutation in BRAF at codon600
3. Metastases accessible for biopsy on at least 2-3 occasions
4. At least one other measurable lesion (according to RECIST v1.1).
5. Unsuitable for potential curative resection

Initial:
All patients
1. Age at least16 years
2. ECOG performance status 0-1
3. Adequate respiratory and cardiac function
4. Able to give informed consent to co-operate with the protocol
5. Haematological and biochemical indices within the ranges shown below:
5.1. Haemoglobin (Hb) =9g/dl (transfusion to achieve this allowed),
5.2. Neutrophils= 1,500/µl,
5.3. Platelet count = 100,000/µl,
5.4. AST or ALT = 3 x ULN, alkaline phosphatase = 2 x ULN,
5.5 Serum Bilirubin = 1.5 x ULN,
5.6. Creatinine Clearance = 30ml/min
6. Able to swallow oral medication
7. Only well-controlled

CNS metastatic disease
1. Life expectancy of at least 3 months

Dose escalation phase
1. Patients with any advanced solid tumours
2. Patients for whom PF-02341066
with PD_0325901 is a reasonable option.

Dose expansion
Patients will be eligible for prescreening for MErCuRIC provided that:
1. They have given informed consent to screening.
2. They are willing to undergo a biopsy for assessment of tumour KRAS mutation status and c-MET assessment.
3. The Investigator anticipates that they are likely to satisfy the eligibility criteria for the trial. Formal screening should not be performed until the tumour prescreening result is known.

Eligibility for the trial, in patients passing pr-escreening, requires:
1. Histologically confirmed colon adenocarcinoma KRASMT (codon 12, 13, 61 mutations) or KRASWT/c-MET+, with progressive disease on or within 6 months of completion of adjuvant therapy or after chemotherapy and/or targeted therapies for metastatic disease.
2. Metastases accessible for biopsy
3. At least one other measurable lesion (according to RECIST v1.1).
4. Unsuitable for potential curative resection.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 78 (changed from 48 on 07/08/2016); UK Sample Size: Unknown; Description: Actual UK sample size expected to be less as the study is also recruiting from 4 European sites.

Participant exclusion criteria

As of 07/09/2016:
1. Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment.
2. Uncontrolled arterial hypertension despite medical treatment.
3. Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade =>2 or uncontrolled atrial fibrillation.
4. 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.
5. 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.
6. Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
7. 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
8. Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function
9. Carcinomatous meningitis or leptomeningeal disease
10. History of hypoalbuminaemia, or patients with peritoneal disease or pleural disease, where there is a requirement for ascitic or pleural taps.
11. History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at risk of retinal vein thrombosis.
12. History of retinal degenerative disease.
13. History of Gilbert’s syndrome.
14. Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe immunologic defect, compromised bone marrow function
15. Other severe acute or chronic medical conditions
16. Patients who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
17. Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 substrates with narrow therapeutic indices
18. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C)
19. Resting ECG with QTc >480msec at 2 or more time points within a 24h period.
20. Requirement for medication known to prolong QT interval.
21. History of other malignancy less than 3 years before the diagnosis of current cancer
22. Women with the ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have a intrauterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
23. Male patients with partners of childbearing potential (unless they agree to take measures not to father children by using two forms of highly effective contraception [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 (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate
24. Prior exposure to a HGF or cMET inhibitor and/or a MEK inhibitor

Initial:
All patients
1. Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment.
2. Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade =2 or uncontrolled atrial fibrillation.
3. 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.
4. Spinal cord compression unless treated with the patient attaining good pain control and stable or recovered neurologic function.
5. Carcinomatous meningitis or leptomeningeal disease.
6. History of retinal vein occlusion, intraocular pressure > 21 mmHg or patient considered at risk of retinal vein thrombosis.
7. Active infections (including chronic hepatitis type B or C and HIV infection if status known), severe immunologic defect, compromised bone marrow function
8. Other severe acute or chronic medical conditions
9. Use of drugs or foods that are known potent CYP3A4 inhibitors or inhibitors or are CYP3A4 substrates with narrow therapeutic indices
10. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C)
11. Resting ECG with QTc >480msec at 2 or more time points within a 24h period.
12. Requirement for medication known to prolong QT interval.
13. History of other malignancy less than 5 years before the diagnosis of current cancer
14. Women with the ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have a intrauterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
15. Male patients with partners of childbearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [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 (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
16. Prior exposure to a HGF or cMET inhibitor and/or a MEK inhibitor.

Recruitment start date

14/11/2014

Recruitment end date

30/09/2017

Locations

Countries of recruitment

Belgium, France, Ireland, Spain, United Kingdom

Trial participating centre

Churchill Hospital
Old Rd Headington
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Belfast Health and Social Care Trust
Knockbracken Healthcare Saintfield Rd
Belfast
BT8 8BH
United Kingdom

Trial participating centre

Velindre Cancer Centre
Velindre Rd
Cardiff
CF14 2TL
United Kingdom

Trial participating centre

University Hospital Antwerp
Wilrijkstraat 10
Edegem
2650
Belgium

Trial participating centre

Vall d'Hebron University Hospital
Passeig de la Vall d'Hebron, 119-129
Barcelona
08035
Spain

Trial participating centre

Beaumont Hospital
Beaumont Rd
Dublin 9
-
Ireland

Trial participating centre

St Antoine Hospital
184 Rue du Faubourg Saint-Antoine
Paris
75012
France

Trial participating centre

European Hospital Georges Pompidou
20 Rue Leblanc
Paris
75015
France

Trial participating centre

University of Oxford
Department of Oncology Oncology Clinical Trials Office (OCTO) Old Road Campus Research Builiding Roosevelt Drive
Oxford
OX3 7DQ
United Kingdom

Sponsor information

Organisation

University of Oxford

Sponsor details

Joint Research Office
Block 60
Churchill Hospital
Oxford
OX3 7LE
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

European Commission

Alternative name(s)

EC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

Belgium

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

19/09/2016: Internal review 07/09/2016: Scientific title changed from "A Phase I study of MEK1/2 inhibitor PD0325901 with cMET, inhibitor PF02341066 in KRASMT and KRASWT(with aberrant cMET) Colorectal Cancer Patients". Drug name and phase of trial added. Amendments made to study hypothesis, interventions, outcome measures, inclusion/exclusion criteria and number of participants - all date stamped in appropriate field. Extra trial participating centres added (in addition to University of Oxford). Overall end date changed from 26/06/2016 to 31/12/2018. Recruitment end date changed from 26/06/2016 to 30/09/2017. Sponsor address changed. 09/08/2016: Internal review