| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Microsatellite-stable (MSS) Metastatic Colorectal Cancer with RAS Mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase 1b:
Determine the MTD and RP2D of binimetinib administered in combination
with nivolumab
Determine the MTD and RP2D of binimetinib administered in combination
with nivolumab plus ipilimumab
Phase 2:
Assess the preliminary antitumor activity of the treatment combinations
based on Response Evaluation Criteria in Solid Tumors (RECIST) version
1.1 |
|
| E.2.2 | Secondary objectives of the trial |
Both Phases:
Further assess the preliminary antitumor activity of the treatment
combinations based on RECIST version 1.1
Characterize the safety profile of the treatment combinations
Characterize the PK of binimetinib in both treatment combinations |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Prescreening Inclusion Criteria:
1. Provide a signed and dated Prescreening ICF.
2. Male or female ≥ 18 years of age at the time of signing the Screening ICF.
3. Measurable, histologically/cytologically confirmed mCRC.
4. Have willingness and ability to participate in the study.
5. Able to provide a sufficient amount (tumor block or minimum of 6 slides) of representative tumor specimen (primary or metastatic, archival or newly obtained) for central laboratory testing of RAS mutation status and MSS.
a. If a fresh tissue sample is provided, a blood sample is required.
6. Have received no more than 2 prior lines of therapy (maintenance therapy given in the metastatic setting will not be considered a separate regimen). Generally, treatments that are separated by an event of progression are considered different regimens.
7. Have received prior systemic treatment as recommended by National Comprehensive Cancer Network (NCCN) or European Society for Medical Oncology (ESMO) guidelines, including fluoropyrimidines, oxaliplatin, irinotecan or bevacizumab in the metastatic setting or similar treatments, as per local guidelines.
8. No known contraindications to study treatment.
Screening Inclusion Criteria:
1. Patients must meet all Prescreening inclusion criteria.
2. Provide a personally signed and dated Screening ICF.
3. mCRC categorized as MSS by polymerase chain reaction (PCR) per local assay at any time prior to Screening or by the central laboratory.
4. RAS mutation per local assay at any time prior to Screening or by the central laboratory.
5. Have received at least 1 prior line of systematic therapy in the
metastatic setting as recommended by National Comprehensive Cancer
Network (NCCN) or European Society for Medical Oncology (ESMO)
guidelines, including fluoropyrimidines, oxaliplatin, irinotecan or
bevacizumab, or similar treatments, as per local guidelines, and meets at
least one of the following criteria:
a. were unable to tolerate the prior first-line regimen
b. experienced disease progression during or after prior first-line regimen for metastatic disease
c. progressed during or within 3 months of completing adjuvant chemotherapy
Note: Generally, treatments that are separated by an event of progression are considered different regimens.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
7. Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks; if a female patient is of childbearing potential, she must agree to follow instructions for acceptable or highly effective method(s) of contraception for the duration of study treatment and for 5 months after the last dose of study treatment with nivolumab (i.e., 30 days [duration of ovulatory cycle] plus the time required for the investigational drug to undergo approximately 5 half-lives)
8. Non-sterile male patients who are sexually active with female partners of childbearing potential must agree to follow instructions for acceptable or highly effective method(s) of contraception for the duration of study treatment and for 7 months after the last dose of study treatment with nivolumab (i.e., 90 days [duration of sperm turnover] plus the time required for the investigational drug to undergo approximately 5 half-lives) (Section 5.3).
9. Adequate renal and bone marrow function as measured by the following Screening laboratory values:
a. White blood cells (WBC) ≥ 2000/μL
b. Neutrophils ≥ 1500/μL
c. Platelets ≥ 100 ×103/μL
d. Hemoglobin ≥ 9.0 g/dL
e. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance > 50 mL/min (using the Cockcroft Gault formula)
10. Adequate hepatic function characterized by the following Screening laboratory values:
a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL Note: Patients who have a total bilirubin level > 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN.
b. ALT and/or AST ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases
11. Adequate cardiac function as follows:
a. LVEF ≥ 50% or above institutional normal value as determined by a MUGA scan or ECHO
b. QTcF interval ≤ 480 msec (preferably the mean from triplicate electrocardiograms (ECGs)
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures including computed tomography (CT)/magnetic resonance imaging (MRI) scans. |
|
| E.4 | Principal exclusion criteria |
Prescreening Exclusion Criteria:
1. Prior treatment with any MEK inhibitor.
2. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
3. Any untreated central nervous system (CNS) lesion. However, patients are eligible if: a) all known CNS lesions have been treated with radiotherapy or surgery, and b) patients remained without evidence of CNS disease progression ≥ 4weeks after treatment, and c) patients must be off corticosteroid therapy for ≥ 3 weeks.
4. Patients with an active, known or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
5. Partial or complete bowel obstruction.
6. Impaired gastrointestinal function or disease that may significantly alter the absorption of binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) or baseline diarrhea ≥ Grade 1.
7. Known history of RVO.
8. Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy
9. Known history of Gilbert’s syndrome.
10. Severe uncontrolled medical illness.
11. Psychiatric illness inhibiting informed consent or protocol compliance.
12. Pregnant or breastfeeding females.
13. History of severe hypersensitivity reactions to mAbs.
14. History of allergy or intolerance (unacceptable AEs) to study drug components or polysorbate-80-containing infusions.
Screening Exclusion Criteria:
1. Patients must not meet any of the Prescreening exclusion criteria.
2. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to first day of study treatment:
a. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) and topical steroids are allowed. Patients who have received acute and/or low-dose systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or chronic use of ≤ 10 mg/day of prednisone or dose-equivalent corticosteroid) may be enrolled in the study after discussion with and approval by the Sponsor’s Medical Monitor.
3. Impaired gastrointestinal function or disease that may significantly alter the absorption of binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) or baseline diarrhea ≥ Grade 1.
4. History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
5. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
6. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
7. History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
8. Clinically significant cardiac disease, including, but not limited to, any of the following:
a. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2).
b. Clinically significant and uncontrolled atrial fibrillation.
c. History of acute coronary syndromes including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting < 6 months prior to screening.
d. Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening except controlled atrial fibrillation and paroxysmal supraventricular tachycardia.
9. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
10. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
11. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
Incidence of dose-limiting toxicities (DLTs) resulting from binimetinib in combination with nivolumab
Incidence of DLTs resulting from binimetinib in combination with nivolumab plus ipilimumab
Phase 2:
ORR per RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b:
At each dose level after the first 3 evaluable patients have completed Cycle 1, the Sponsor’s Medical Monitor and the Investigators will meet to clinically assess the available data from the dose cohort. An End-of-Cohort meeting between the Sponsor’s Medical Monitor and the Investigators will occur after the last patient in each cohort has completed at least 1 treatment cycle (28 days) for careful assessment of AEs before escalating to the next dose.
Phase 2:
In addition to end-of-study evaluations, safety meetings between the Sponsor’s Medical Monitor and the Investigators will be scheduled periodically during Phase 2 of the study to review safety data for ongoing patients and patients who are being monitored during the follow-up period. |
|
| E.5.2 | Secondary end point(s) |
Phase 1b only:
ORR per RECIST v1.1
Both Phases:
DOR per RECIST v1.1
Rate of CR per RECIST v1.1
Incidence and severity of AEs graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03, and changes in clinical laboratory parameters
Sparse plasma concentrations for binimetinib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| In addition to end-of study evaluations, safety meetings between the Sponsor’s Medical Monitor and the Investigators will be scheduled periodically during Phase 2 of the study to review safety data for ongoing patients and patients who are being monitored during the follow-up period. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 |
| Determination of maximum tolerated dose and recommended phase 2 dose |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| France |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| End of study will be defined as the point when all patients have the opportunity to be followed for at least 1 year after the randomization date of the last patient enrolled. The Sponsor will notify all applicable regulatory agencies in accordance with local requirements when the study has ended. After the end of the study, access to study drugs will be provided only in accordance with local regulations and requirements. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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