ivolumab and Trametinib in combination to treat colorectal cancer

Phase 1

Conditions: Metastatic colorectal cancer
MedDRA version: 21.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2017-001830-24-CZ

Lead Sponsor: Bristol-Myers Squibb International Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 405

Inclusion Criteria

•Age = 18, signed written informed consent
•Histological or cytological confirmed diagnosis of previously treated mCRC with adenocarcinoma histology and in Stage IV per AJCC
•Confirmed microsatellite status: only participants with pMMR/MSS mCRC are eligible
•Verified KRAS, NRAS (extended RAS) and BRAF mutation status: BRAF V600 mutant are not eligible
•Measurable disease per RECIST 1.1
•Provide Tumor Tissue sample at screening.
•ECOG Performance Status of 0-1

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 107

Exclusion Criteria

1) Target Disease Exceptions
a) Participants with BRAF V600 mutant colorectal cancer are NOT eligible for this study in Part 1, 1A, and 1B only.
2) Medical History and Concurrent Diseases
a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results.
b) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate/cervix/breast.
c) Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
e) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.
f) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE [current version]) or baseline before administration of study drug.
g) Toxicities from the prior anti-cancer treatment have not been resolved to Grade 1 (NCI CTCAE current version) at the time of study entry
h) Current use of a prohibited medication. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first dose of study treatment
i) Prior treatment with any MEK inhibitor
j) History of interstitial lung disease or pneumonitis.
k) Inability to take oral medication or significant nausea and vomiting, malabsorption, external biliary shunt, significant bowel resection that would preclude adequate absorption of oral medication.
l) Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule.
m) Additional criteria for Part 2 only:
i) Prior treatment with regorafenib or TAS-102
ii) Severe hepatic impairment (Child-Pugh C)
iii) Any evidence of active bleeding, or hemorrhage or bleeding event = NCI-CTCAE Grade 3 within 4 weeks prior to the start of study medication
iv) Prior or current gastrointestinal perforation or fistula
v) Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis, or pulmonary embolism within 6 months before the start of study medication
vi) Non-healing wound, non-healing ulcer, or non-healing bone fracture
vii) Active infection (ie, body temperature = 38°C due to infection)
3) Physical and Laboratory Test Findings
a) WBC < 2000/µL
b) Neutrophils < 1500/µL
c) Platelets < 100×103/µL
d) Hemoglobin < 9.0 g/dL
e) PT/INR and PTT > 1.5 ×ULN
f) Serum creatinine > 1.5 ×ULN, unless creatinine clearance > 50 mL/min (measured or calcula

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Parts 1, 1A and 1B (no EU subjects):<br>- To characterize the safety and tolerability of combination therapies<br>- To establish recommended dosing regimen for the combination (nivolumab plus ipilimumab plus trametinib OR nivolumab plus trametinib)<br><br>Part 2:<br>To evaluate the Objective Response Rate (ORR) in all participants and<br>subgroup of RAS mutation participants treated with nivolumab plus<br>trametinib;Secondary Objective: Parts 1, 1A and 1B (no EU subjects):<br>To evaluate preliminary efficacy<br><br>Part 2:<br>- To evaluate efficacy in all participants treated with nivolumab and trametinib in comparison with regorafenib and TAS-102<br>- To characterize the safety and tolerability of combination therapies;Primary end point(s): ORR by investigator;Timepoint(s) of evaluation of this end point: Under current accrual assumption, approximately 12 months from the FPFT.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): BOR, DCR, DOR, TTR, and PFS by investigator, OS and Safety;Timepoint(s) of evaluation of this end point: Under current accrual assumption, approximately 19 months from the FPFT.

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