An Open-label Phase 1b/2 Study of Binimetinib Administered in Combination with Nivolumab or Nivolumab Plus Ipilimumab in Patients with Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer with RAS Mutation.
- Conditions
- Colorectal Cancer10017991
- Registration Number
- NL-OMON50266
- Lead Sponsor
- Array Biopharma, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 9
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 per RECIST v1.1.
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 systematic therapy in the
metastatic setting (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.
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 immunohistochemistry (IHC) or
polymerase chain reaction (PCR)-based 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 6 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 ti
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, with the
following exceptions:
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 diast
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>* Phase 1b:<br /><br>o Incidence of dose-limiting toxicities (DLTs) resulting from binimetinib in<br /><br>combination with nivolumab<br /><br>o Incidence of DLTs resulting from binimetinib in combination with nivolumab<br /><br>plus ipilimumab<br /><br>* Phase 2: Objective response rate (ORR) per RECIST v1.1</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary:<br /><br>* Phase 1b only: ORR per RECIST v1.1 Both Phases:<br /><br>* Duration of response (DOR) per RECIST v1.1<br /><br>* Rate of complete response (CR) per RECIST v1.1<br /><br>* Incidence and severity of adverse events (AEs) graded according to the<br /><br>National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events<br /><br>(CTCAE) v4.03, and changes in clinical laboratory parameters<br /><br>* Sparse plasma concentrations for binimetinib<br /><br><br /><br>Exploratory:<br /><br>* PFS per RECIST v 1.1<br /><br>* OS<br /><br>* PFS per iRECIST<br /><br>* ORR per iRECIST<br /><br>* DOR per iRECIST<br /><br>* Rate of CR per iRECIST<br /><br>* Model-based correlations between binimetinib PK and measures of safety and<br /><br>efficacy<br /><br>* Status of genomic, proteomic, and immune biomarkers in blood and tissue<br /><br>samples at baseline<br /><br>* Change from baseline in genomic, proteomic, and immune biomarkers</p><br>