Randomised Phase 2 Study of Nivolumab Versus Nivolumab and Ipilimumab Combination in EGFR Mutant Non-small Cell Lung Cancer

National Cancer Centre, Singapore3 sites in 1 country31 target enrollmentApril 7, 2017

ConditionsNon-Small Cell Lung Cancer

InterventionsNivolumab Ipilimumab

DrugsIpilimumab Nivolumab

Overview

Phase: Phase 2
Intervention: Nivolumab
Conditions: Non-Small Cell Lung Cancer
Sponsor: National Cancer Centre, Singapore
Enrollment: 31
Locations: 3
Primary Endpoint: Overall Response Rate
Status: Terminated
Last Updated: 3 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this study is to determine whether Nivolumab in combination with Ipilimumab is associated with superior response rate compared to Nivolumab alone in patients with advanced Epidermal Growth Factor Receptor (EGFR) mutation positive Non-small Cell Lung Cancer who have failed one line of standard EGFR tyrosine kinase inhibitor and not more than one line of chemotherapy regimen. This study also aims to determine predictive biomarkers of response/benefit in patients with EGFR mutation positive NSCLC.

Detailed Description

This study examines the outcome of nivolumab single agent versus nivolumab-ipilimumab combination in patients with advanced EGFR+ NSCLC who have failed one line of standard EGFR Tyrosine Kinase Inhibitor (TKI) and not more than one line of chemotherapy regimen. The use of 3rd generation EGFR TKI for patients with acquired mutation that substitute a threonine (T) with a methionine (M) at position 790 of exon 20 (T790M) is allowed. Patients will be randomized in a 1:1 ratio to treatment with either nivolumab monotherapy (Arm A) or nivolumab/ipilimumab combination therapy (Arm B) and will be stratified according to the following factors: * Programmed Death-Ligand 1 (PDL1) status: \<1% vs ≥1% * Presence of brain metastasis * Institution: National Cancer Centre Singapore, National University Cancer Institute, and Johns Hopkins Singapore-Tan Tock Seng Hospital Both arms will continue with treatment regimen till disease progression or discontinuation of treatment due to adverse events. Arm A patients are allowed to cross over to Arm B in the event of clear-cut disease progression. On-study tumor assessments will be conducted every 6 weeks for 24 weeks and then every 12 weeks till clear-cut disease progression. The radiologist will be blinded to the treatment arm that the patient is randomised to ensure an objective response evaluation.

Registry

clinicaltrials.gov

Start Date

April 7, 2017

End Date

November 18, 2019

Last Updated

3 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

National Cancer Centre, Singapore

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•i. Signed informed consent
•ii. Male or female, 21 years or older
•Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
•Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab
•Women must not be breastfeeding
•Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
•WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 milli-international units per millilitre (mIU/mL).
•Women of childbearing potential (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days.
•iii. Advanced EGFR+ NSCLC
•iv. Eastern Cooperative Oncology Group (ECOG) 0-2 performance status

Exclusion Criteria

•i. Symptomatic brain or leptomeningeal metastases (patients who have treated stable brain or Leptomeningeal disease are eligible; there is no magnetic resonance imaging (MRI) evidence of progression for \[lowest minimum is 4 weeks or more\] after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration).
•ii. Poor performance status of ECOG 3-4
•iii. Tumour sites not amenable to CT-guided core biopsies or trucut biopsies; However waiver for this criterion can be given for selected patients on a case-by-case basis for patients with sites of disease that are technically difficult to access after discussion with interventional radiologist. Waivers are allowed for not more than 70 patients for this study in order to allow sufficient number of quality tumour biopsies for biomarker analysis in this study. Waivers would have to be approved by the Principal Investigator.
•iv. Unwilling to undergo 2 biopsies and contribute research bloods for the study
•v. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
•vi. Concurrent Autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
•vii. Prior treatment with other anti-Programmed cell death protein 1 (anti-PD1) or anti-PDL1 or anti-CTLA4 therapies
•viii. 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 randomization
•Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study.
•Patients with history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments done by MRI.

Arms & Interventions

Nivolumab

Intervention: Nivolumab

Nivolumab and Ipilimumab

Intervention: Ipilimumab

Nivolumab and Ipilimumab

Intervention: Nivolumab

Outcomes

Primary Outcomes

Overall Response Rate

Time Frame: From baseline until best overall response of Complete Response (CR) or Partial Response (PR), up to 2 years

Secondary Outcomes

Progression-Free Survival(From time of randomisation until first documented disease progression or death due to any cause, up to 2 years)
Duration of Response(From time of first response until first documented disease progression or death due to any cause, up to 2 years)
Evaluate capability of the addition of Ipilimumab to patients who progress on Nivolumab alone (Arm A) to achieve clinical benefit by measuring the time taken to achieve CR, PR or Stable Disease (SD)(From time of first dose of Ipilimumab until best overall response of CR, PR, or SD, up to 2 years)
Overall Survival(From time of randomisation until death due to any cause, up to 2 years)
Evaluate the toxicity profiles of Nivolumab with or without Ipilimumab by measuring the number of participants with treatment-related adverse events(From the time the Informed Consent Form is signed until at least 100 days after discontinuation of dosing, up to 2 years)
Evaluate an array of biomarkers in predicting response to Nivolumab and/or Ipilimumab(From time of first dose of study treatment until clear-cut disease progression, up to 2 years)