Working…
Help guide our efforts to modernize ClinicalTrials.gov.
Send us your comments by March 14, 2020.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of Nivolumab Verses Nivolumab and Ipilimumab Combination in EGFR Mutant Non-small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03091491
Recruitment Status : Recruiting
First Posted : March 27, 2017
Last Update Posted : September 14, 2018
Sponsor:
Collaborators:
National University Hospital, Singapore
Johns Hopkins Singapore
Information provided by (Responsible Party):
National Cancer Centre, Singapore

Tracking Information
First Submitted Date  ICMJE March 6, 2017
First Posted Date  ICMJE March 27, 2017
Last Update Posted Date September 14, 2018
Actual Study Start Date  ICMJE April 7, 2017
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 21, 2017)
Overall Response Rate [ Time Frame: From baseline until best overall response of Complete Response (CR) or Partial Response (PR), up to 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03091491 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2017)
  • Progression-Free Survival [ Time Frame: From time of randomisation until first documented disease progression or death due to any cause, up to 2 years ]
  • Duration of Response [ Time Frame: From time of first response until first documented disease progression or death due to any cause, up to 2 years ]
  • Overall Survival [ Time Frame: 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 [ Time Frame: From the time the Informed Consent Form is signed until at least 100 days after discontinuation of dosing, up to 2 years ]
    Safety data of all adverse events and serious adverse events, will be graded according to the NCI CTCAE v 4.0.
  • 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) [ Time Frame: From time of first dose of Ipilimumab until best overall response of CR, PR, or SD, up to 2 years ]
  • Evaluate an array of biomarkers in predicting response to Nivolumab and/or Ipilimumab [ Time Frame: From time of first dose of study treatment until clear-cut disease progression, up to 2 years ]
    Biomarkers: PD-L1, mutational burden, microsatellite instability, blood-based biomarkers
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Nivolumab Verses Nivolumab and Ipilimumab Combination in EGFR Mutant Non-small Cell Lung Cancer
Official Title  ICMJE Randomised Phase 2 Study of Nivolumab Versus Nivolumab and Ipilimumab Combination in EGFR Mutant Non-small Cell Lung Cancer
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: Ipilimumab
    Ipilimumab 1 mg/kg administered every 6 weeks as a 30 min IV infusion
    Other Name: Yervoy
  • Drug: Nivolumab
    Nivolumab 3 mg/kg administered every 2 weeks as a 30 min IV infusion
    Other Name: Opdivo
Study Arms  ICMJE
  • Experimental: Nivolumab
    Intervention: Drug: Nivolumab
  • Experimental: Nivolumab and Ipilimumab
    Interventions:
    • Drug: Ipilimumab
    • Drug: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 21, 2017)
184
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

v. Progressed on one line of standard EGFR TKI and not more than one line of chemotherapy; 3rd generation EGFR TKI for patients with T790M mutation is allowed

  • A 14-day washout period is required for EGFR TKI for patients who received this as the last therapy before recruitment
  • A 28-day washout period is required for chemotherapy for patients who received this as the last therapy before recruitment. All drug-related toxicities should have returned to baseline with the exception of neuropathy, fatigue, and alopecia.

vi. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization/registration

  • White Blood Cell (WBC) ≥ 2000/µL
  • Neutrophils ≥ 1000/µL
  • Platelets ≥ 100 x 10^3/µL
  • Hemoglobin > 9.0 g/dL
  • Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula below):
  • Aspartate Aminotransferase/ Alanine Aminotransferase (AST/ALT) ≤ 3 x ULN
  • Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

vii. Measurable disease, as defined by RECIST v1.1; Previously irradiated lesions can only be considered as measurable disease if disease progression has been unequivocally documented at that site since radiation.

viii. Patients with a history of treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria:

  1. Measurable disease outside CNS
  2. No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed
  3. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization
  4. No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study

ix. Tumor sites amenable for CT-guided core biopsies or trucut biopsies

x. Willing to undergo 2 biopsies and contribute research bloods for the study. Archived tissue that is less than 6 months old is acceptable as an alternative to biopsy at screening if a biopsy is not feasible; patients from arm A must be willing to undergo biopsy as baseline upon clear-cut disease progression and on-treatment repeat biopsy before they are allowed to cross over to receive ipilimumab in addition to nivolumab.

xi. Patients with confirmed concomitant HBV infection that are eligible for inclusion must be treated with antiviral therapy prior to enrollment to ensure adequate viral suppression (HBV DNA < 2000 IU/mL), must remain on antiviral therapy for the study duration, and continue therapy for 6 months after the last dose of investigational product(s). Subjects with confirmed Hepatitis C (HCV) infection who are negative for HBsAg and positive for anti-HBc, are eligible but must be started on active antiviral therapy (for HBV) prior to their first dose of investigational product.

xi. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception and to continue its use for 90 days after the last dose of nivolumab

xii. Women who are not postmenopausal (≥12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 24 hours prior to initiation of study drug

xiii. Available for follow-up

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

  1. 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.
  2. Patients with history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments done by MRI.
  3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.

ix. Active interstitial lung disease or history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan; History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

x. Active tuberculosis

xi. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

xii. Prior allogeneic bone marrow transplantation or solid organ transplant

xiii. Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study

xiv. Not available for follow-up and unlikely to be compliant with follow-up or protocol requirements

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Tze Wei Lim +65 6436 8000 lim.tze.wei@nccs.com.sg
Listed Location Countries  ICMJE Singapore
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03091491
Other Study ID Numbers  ICMJE CA209-777
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party National Cancer Centre, Singapore
Study Sponsor  ICMJE National Cancer Centre, Singapore
Collaborators  ICMJE
  • National University Hospital, Singapore
  • Johns Hopkins Singapore
Investigators  ICMJE
Principal Investigator: Eng Huat Tan National Cancer Centre, Singapore
PRS Account National Cancer Centre, Singapore
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP