Clinical Trials /

Nivolumab Ipilimumab in Patients With hyperMutated Cancers Detected in Blood (NIMBLe)

NCT03461952

Description:

The purpose of this study is to determine the safety and effectiveness of nivolumab alone or in combination with ipilimumab in patients with metastatic or unresectable tumors harbouring mutations in genes, POLE and POLD1. These mutations will be determined by plasma cfDNA. Nivolumab and ipilimumab have been given to patients across multiple types of cancer, and safe doses and schedules have been determined.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab Ipilimumab in Patients With hyperMutated Cancers Detected in Blood (NIMBLe)
  • Official Title: A Phase II Open Label, Randomized Non-Comparative Trial of Nivolumab Alone or in Combination With Ipilimumab for the Treatment of Patients With Advanced Hypermutated Solid Tumors Detected by a Blood Based Assay

Clinical Trial IDs

  • ORG STUDY ID: I235
  • SECONDARY ID: 0001
  • NCT ID: NCT03461952

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
NivolumabNivolumab
IpilimumabNivolumab + Ipilimumab

Purpose

The purpose of this study is to determine the safety and effectiveness of nivolumab alone or in combination with ipilimumab in patients with metastatic or unresectable tumors harbouring mutations in genes, POLE and POLD1. These mutations will be determined by plasma cfDNA. Nivolumab and ipilimumab have been given to patients across multiple types of cancer, and safe doses and schedules have been determined.

Detailed Description

      Participants in this study have been diagnosed with metastatic or unresectable solid tumors
      that have a mutation in POLE and/or POLD1. Nivolumab alone or in conjunction with ipilimumab
      is predicted to be effective against tumors with POLE and/or POLD1 mutations as these genetic
      changes cause increased rates of mutations in the DNA of tumor cells. These high mutation
      rates have been associated with response to immunotherapy agents such as nivolumab and
      ipilimumab.
    

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimental240mg Q2W
  • Nivolumab
Nivolumab + IpilimumabExperimentalNivolumab 240mg Q2Wk + Ipilimumab 1mg/kg Q6W
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed advanced (metastatic or unresectable)
             solid tumors.

          -  Patients must have received at least 1 standard cancer therapy for their tumor type
             and progressed on their most recent regimen; patients may be treatment naïve if they
             refuse standard treatment or there is no standard treatment for their cancer.

          -  Prior adjuvant/neoadjuvant therapy with curative intent is considered a prior therapy
             if disease recurrence occurs within at least 6 months.

          -  Patients may not have received prior immunotherapy

          -  Patients must consent to blood collection for testing after registration by a central
             reference laboratory.

          -  Patients must have clinically and/or radiologically documented disease with at least
             one lesion measurable as defined by RECIST 1.1.

          -  Patients must be ≥ 18 years of age.

          -  ECOG performance status 0 or 1.

          -  Patients must have adequate hematology and organ function

          -  Patient consent for screening must be appropriately obtained in accordance with
             applicable local and regulatory requirements.

          -  Patients must have solid tumors that demonstrate POLE or POLD1 mutations identified at
             study entry via plasma cfDNA testing or tumor tissue testing for POLE and POLD1
             mutations. A CLIA-certified testing of tumor tissue demonstrating POLE or POLD1
             mutation can qualify for eligibility and randomization, however, plasma will be
             submitted for central cfDNA testing. In the event of discordance between tissue and
             central laboratory testing, the patient will continue in study but will not be
             included in the primary analysis. These patients will however be included in the
             secondary analysis.

          -  Patients must have recovered to ≤ grade 1 from all reversible toxicity related prior
             systemic or radiation therapy and have a 2 weeks washout.

          -  Previous major surgery is permitted provided that it has been at least 28 days prior
             to patient registration and that wound healing has occurred.

          -  White Blood Cells ≥ 2.0 x 109/L (2000/µL)

          -  Absolute neutrophils ≥ 1.5 x 109/L (1500/µL)

          -  Platelets ≥ 100 x 10^9/L (100 x103/µL)

          -  Hemoglobin ≥80 g/L* (8.0 g/dL)

          -  Bilirubin ≤ 1.5 x ULN (upper limit of normal)**

          -  AST and/or ALT ≤ 3 x ULN

          -  Serum creatinine ≤ 1.5 x ULN or: Creatinine clearance ≥40 mL/min

          -  Patients must be willing to consent to provision of archival tissue

          -  Patient consent must be appropriately obtained in accordance with applicable local and
             regulatory requirements

          -  Patients must be willing and able to comply with scheduled visits, treatment schedule,
             laboratory testing, and other requirements of the trial.

          -  In accordance with CCTG policy, protocol treatment is to begin within 2 working days
             of patient randomization.

          -  Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP
             must have agreed to use a highly effective contraceptive method

        Exclusion Criteria:

          -  Patients with a history of other untreated malignancies or malignancies, which
             required therapy within the past 2 years. Patients with a prior or concurrent
             malignancy whose natural history or treatment does not have the potential to interfere
             with the safety or efficacy assessment of the investigational regimen may be eligible
             after consultation with the CCTG.

          -  Patients with primary CNS tumors are not eligible.

          -  Patients with active brain metastases or leptomeningeal metastases are not eligible.
             Patients with brain metastases are eligible if these have been treated and clinically
             stable. There must also be no requirement for immunosuppressive doses of systemic
             corticosteroids (> 10 mg/day prednisone equivalents). Physiologic replacement doses of
             systemic corticoidsteroids are permitted, even if >10mg/day prednisone equivalents

          -  History of primary immunodeficiency, history of allogenic organ transplant that
             requires therapeutic immunosuppression and the use of immunosuppressive agents within
             14 days of study drug administration*

          -  Active or prior documented autoimmune or inflammatory disorders. Including,
             inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the
             exception of diverticulosis, celiac disease or other serious gastrointestinal chronic
             conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis
             syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid
             arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of
             treatment. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism
             due to autoimmune condition only requiring hormone replacement, psoriasis not
             requiring systemic treatment, or conditions considered to be of low risk for
             recurrence are permitted to enroll.

          -  History of hypersensitivity to nivolumab or ipilimumab or any excipient.

          -  Any previous treatment with a PD-1 or anti-PD-L1, anti-PD-L2 inhibitor, including
             nivolumab or an anti-CTLA4, including ipilimumab, or drug specifically targeting
             T-cell stimulation or immune checkpoint pathways.

          -  Patients with serious illnesses or medical conditions which would not permit the
             patient to be managed according to the protocol (including corticosteroid
             administration), or would put the patient at risk. This includes but is not limited
             to:

               -  History of significant neurologic or psychiatric disorder which would impair the
                  ability to obtain consent or limit compliance with study requirements.

               -  Active infection requiring systemic therapy; (including any patient known to have
                  active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or
                  tuberculosis or any infection requiring systemic therapy).

               -  Active peptic ulcer disease or gastritis

               -  Active pneumonitis.

          -  Patients receiving concurrent treatment with other anti-cancer therapy or other
             investigational anti-cancer agents.

          -  Patients who have experienced untreated and/or uncontrolled cardiovascular conditions
             and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart
             failure, myocardial infarction within the previous year or cardiac ventricular
             arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular
             conduction defects).

          -  Pregnant or lactating women.

          -  Men who are sexually active with women of childbearing potential and women of
             childbearing potential must agree to use adequate contraception.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate by RECIST 1.1
Time Frame:36 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Efficacy as measured by objective response rate
Time Frame:36 months
Safety Issue:
Description:Will be reported using percentages over all randomized patients with 90% exact confidence intervals
Measure:Duration of response
Time Frame:36 months
Safety Issue:
Description:Response rates will be reported using percentages over all patients who have received at least one dose of treatment with 90% exact CI of each arm in a non-comparative analysis
Measure:Number and severity of adverse events using CTCAE 5.0
Time Frame:36 months
Safety Issue:
Description:AE rates will be reported using percentages with 90% exact CI
Measure:Correlation between POLE or POLD1 mutations in tumor and POLE or POLD1 mutations in blood
Time Frame:36 months
Safety Issue:
Description:Will be assessed by Fischer's exact test in each arm
Measure:To evaluate response by iRECIST
Time Frame:36 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Canadian Cancer Trials Group

Last Updated