Primary:* Phase 1b:o Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of binimetinib administered in combination with nivolumabo Determine the MTD and RP2D of binimetinib administered in combination with nivolumab plus…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Phase 1b:
o Incidence of dose-limiting toxicities (DLTs) resulting from binimetinib in
combination with nivolumab
o Incidence of DLTs resulting from binimetinib in combination with nivolumab
plus ipilimumab
* Phase 2: Objective response rate (ORR) per RECIST v1.1
Secondary outcome
Secondary:
* Phase 1b only: ORR per RECIST v1.1 Both Phases:
* Duration of response (DOR) per RECIST v1.1
* Rate of complete response (CR) per RECIST v1.1
* Incidence and severity of adverse events (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
Exploratory:
* PFS per RECIST v 1.1
* OS
* PFS per iRECIST
* ORR per iRECIST
* DOR per iRECIST
* Rate of CR per iRECIST
* Model-based correlations between binimetinib PK and measures of safety and
efficacy
* Status of genomic, proteomic, and immune biomarkers in blood and tissue
samples at baseline
* Change from baseline in genomic, proteomic, and immune biomarkers
Background summary
Colorectal cancer is a serious, life-threatening condition. In 2015, colorectal
cancer accounted for 774,000 deaths world wide. In the US and Europe, it is the
second and fourth most common cancer type, respectively. Approximately 130,000
new cases are diagnosed per year in the US and it is the second leading cause
of cancer mortality). In Europe, approximately 450,000 new cases are diagnosed
per year and colorectal cancer was responsible for 215,000 deaths in 2012. A
quarter of patients initially present with metastases and the majority of
patients will eventually develop metastatic disease. Standard systemic therapy
in patients with unresectable metastatic colorectal cancer (mCRC) includes
combination regimens with cytotoxic and targeted agents. In the last decade,
substantial advances in the treatment of mCRC have resulted in an improvement
in overall survival (OS) from 10 to 12 months to more than 20 months. This
improvement has occurred with the addition of irinotecan, oxaliplatin,
bevacizumab, cetuximab, and panitumumab to the standard treatment with
5-fluorouracil (5-FU)/folinic acid (leucovorin).
The proposed study will be conducted in adult patients with advanced mCRC with
MSS and presence of a RAS mutation. Patients with colorectal tumors that have
defects in the DNA mismatch repair system, also referred to as having a MSI,
will be excluded. The central objective of the study will be to determine if
nivolumab in combination with binimetinib, or nivolumab in combination with
ipilimumab and binimetinib demonstrates a clinically meaningful ORR. For
the doublet arm, the targeted response rate is 20%, and for the triplet arm,
the targeted response rate is 30% in these patients with MSS mCRC and a RAS
mutation. The addition of binimetinib to both nivolumab and nivolumab plus
ipilimumab will potentially increase antigen presentation and enhance response
to checkpoint inhibitors in MSS tumors.
Study objective
Primary:
* Phase 1b:
o Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose
(RP2D) of binimetinib administered in combination with nivolumab
o 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
Secondary:
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 pharmacokinetics (PK) of binimetinib in both treatment
combinations
Exploratory:
* Obtain preliminary estimates of progression-free survival (PFS) and overall
survival (OS)
* Assess the preliminary antitumor activity of the treatment combinations based
on immune Response Evaluation Criteria in Solid Tumors (iRECIST)
* Explore binimetinib exposure-response relationships with respect to safety
and efficacy
* Assess blood- and tissue-based predictive biomarkers of activity and immune
effects
Study design
This is a multicenter, open-label Phase 1b/2 study to determine the MTD and
RP2D and schedule of binimetinib, and to assess the safety, efficacy, and PK of
binimetinib administered in combination with nivolumab or nivolumab plus
ipilimumab in patients with previously treated MSS metastatic colorectal cancer
(mCRC) with documented RAS mutation. The study will include a dose-finding
period in Phase 1b followed by a randomized Phase 2 period.
The total number of patients enrolled in Phase 1b of the study will depend on
the number of dose levels tested and the number of patients treated in each
cohort before the MTD has been determined for each arm.
Approximately 90 patients are required to complete this study. A maximum of
approximately 42 patients will be enrolled in Phase 1b and a minimum
of approximately 48 patients will be enrolled in Phase 2.
* Phase 1b:
o Arm 1A - binimetinib plus nivolumab (Doublet): To determine the MTD and
RP2D and schedule of binimetinib in combination with nivolumab.
o Arm 1B - binimetinib with nivolumab plus ipilimumab (Triplet): To determine
the MTD and RP2D and schedule of binimetinib in combination with nivolumab plus
ipilimumab.
* Phase 2:
* Arm 2A - binimetinib plus nivolumab (Doublet): To determine the efficacy of
binimetinib in combination with nivolumab.
o Arm 2B - binimetinib with nivolumab plus ipilimumab (Triplet): To determine
the efficacy of binimetinib in combination with nivolumab plus ipilimumab.
One treatment cycle is defined as 28 days (4 weeks) for all arms. Individual
treatments will be dosed on the schedules as outlined below.
Phase 1b of the study will consist of dose-finding cohorts in Arm 1A and Arm
1B. All dose-escalation decisions will be driven by the modified toxicity
probability interval (mTPI-2) design.
* Patients assigned to Arm 1A (Doublet) will be dosed with 480 mg nivolumab
every 4 weeks (Q4W) and 45 mg twice daily (BID) of binimetinib initially as
starting Dose Level 4. In the event that this dose level is not tolerated,
lower dose levels, or an intermittent binimetinib dosing schedule.
* Patients assigned to Arm 1B (Triplet) will be dosed with the RP2D of
binimetinib from Arm 1A plus 480 mg nivolumab Q4W and
1 mg/kg ipilimumab Q8W. Dose de-escalation will proceed if the treatment is not
tolerated..
Intra-patient dose escalation will not be permitted.
Note: In both arms, there will be flexibility to evaluate intermittent dosing
schedule of binimetinib (30 or 45 mg BID; e.g., 3 weeks on/1 week off) if
continuous dosing is not tolerated depending on the time of onset of DLTs.
In Phase 1b: The target DLT probability for Cycle 1 is 30%, with an equivalence
interval, i.e., an acceptable interval, of 25% to 35%. Dosing in Phase 1b will
continue within an arm until 9 patients (from the dose- determining set) have
been treated at one dose level with a recommendation to stay (or a
recommendation to escalate if there is not a higher dose level
or if the tolerability of the next dose level is unacceptable), or the maximum
sample size within a Phase 1b arm (n=21) has been reached. If further safety
evaluations are required, additional patients may be added to a cohort.
Toxicities will only be considered DLTs if they occur in Cycle 1 although
overall safety including later cycles will be considered for dose escalations
and for each RP2D determination.
Patients are required to complete Cycle 1 (* 75% of the planned cumulative dose
of binimetinib) to be considered evaluable for MTD determination unless
discontinuation occurred due to a DLT (i.e, in the dose-determining set).
Phase 2 of the study will consist of 2 arms to investigate the safety and
clinical activity of the RP2Ds established from Phase 1b: Arm 2A (nivolumab in
combination with binimetinib) and Arm 2B (nivolumab plus ipilimumab in
combination with binimetinib).
Intervention
Phase 1b:
Arm Dose Level (*Starting Dose Level)
Binimetinib Nivolumab Ipilimumab
1A 4 45
mg BID 480mg Q4W N/A
(Doublet) 3 45 mg
BID 3W on / 1W off 480mg Q4W N/A
2 30
mg BID 480mg Q4W N/A
1 30
mg BID 3W on / 1W off 480mg Q4W N/A
4 45
mg BID 480mg Q4W 1mg/kg Q8W
1B (Triplet)** 3 45 mg BID
3W on / 1W off 480mg Q4W 1mg/kg Q8W
2 30
mg BID 480mg Q4W 1mg/kg Q8W
1 30
mg BID 3W on / 1W off 480mg Q4W 1mg/kg Q8W
* The starting Dose Level of Arm 1B (Triplet) will be the RP2D of binimetinib
from Arm 1A. If tolerated, the RP2D from Arm 1A plus ipilimumab will be
considered the RP2D for Arm 1B. If not tolerated, any dose level below the RP2D
for Arm 1B may be explored.
Phase 2:
Arm 2A: Patients randomized to the nivolumab and binimetinib arm will receive
nivolumab administered as 480 mg Q4W as a 30-minute intravenous (IV) infusion
on Day 1 of each treatment cycle and the recommended dose of binimetinib in Arm
1A of Phase 1b.
Arm 2B: Patients randomized to the nivolumab, ipilimumab, and binimetinib arm
will receive nivolumab administered as 480 mg Q4W as a 30-minute IV infusion on
Day 1 of each treatment cycle, ipilimumab IV as a dose of 1 mg/kg Q8W, and the
recommended dose of binimetinib in
Arm 1B of Phase 1b.
Study burden and risks
Side Effects of Binimetinib
Because binimetinib is an investigational drug all of the side effects are not
known, and serious side effects, including death, are a possibility. Long-term
effects of this treatment are also unknown.
The side effects on binimetinib in combination with nivolumab (double
combination) or nivolumab plus ipilumumab (triple combination) are not known.
Side effects in cancer patients treated with binimetinib may include those
described below.
Most likely side effects (occur in 1 in 5 people or more):
* Alteration of the light sensing part of the back of the eye that may affect
your vision including blurred or impaired vision
* Rash, acne or skin irritation including redness, raised bumps, dryness or
itching
* Swelling due to fluid retention or a worsening of pre-existing fluid
retention in specific areas of the body. This can occur throughout your body or
in specific areas such as your abdomen or arms, legs, hands, feet or face.
* Feeling weak, tired, or lacking in energy
Less likely side effects (greater than 1 in 10 people up to 1 in 5 people):
* Muscle spasms, muscle pain or inflammation
Binimetinib has caused mild to moderate visual changes in some patients
(swelling and/or inflammation in and around the eyes and changes in the retina,
blurred vision and, in some cases, loss of vision). While this type of visual
impairment may resolve, there is a risk that the visual changes may continue.
Side Effects of Nivolumab:
Nivolumab may cause one or more of the side effects listed below. This
information is based on data from cancer subjects in other clinical trials with
nivolumab. In addition, there may be side effects that are not yet known that
may occur.
Very common side effects of nivolumab are (greater than 1 in 10 people):
* Fatigue
* Diarrhea
* Itching
* Rash
Risks Associated with Nivolumab combined with ipilimumab
Very common side effects (greater than 1 in 10 people):
* ALT and/or ASAT increased: lab test result associated with abnormal liver
function
* Decreased appetite
* Diarrhea
* Fatigue
* Fever (Temperature of 38°C or higher)
* Itching
* Lipase increased: lab result associated with pancreaqs inflammation
* Musculoskeletal pain
* Nausea
* Rash
* Thyroid function decreased
Prolonged treatment with medicines that suppress inflammation, sometimes needed
to manage the side effects of nivolumab treatment, may lower thebody*s ability
to fight off certain infections (i.e., opportunistic infections). These
infections may require treatment with antibiotic or antifungal medications and
may be fatal.
Walnut Street 3200
Boulder CO 80301
US
Walnut Street 3200
Boulder CO 80301
US
Listed location countries
Age
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 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 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/*L
b. Neutrophils * 1500/*L
c. Platelets * 100 ×103/*L
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) or
estimated glomerular filtration rate > 50 mL/min/1.73 m2 (using the
Modification of Diet in Renal Disease [MDRD] Study 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.
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, 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 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003464-12-NL |
| ClinicalTrials.gov | NCT03271047 |
| CCMO | NL63366.031.17 |