Clinical Trials /

Nivolumab and Veliparib in Treating Patients With Recurrent or Refractory Stage IV Solid Tumors That Cannot Be Removed by Surgery or Lymphoma With or Without Alterations in DNA Repair Genes

NCT03061188

Description:

The purpose of this research study is to determine the highest and safest dose of the experimental drug veliparib when combined with nivolumab. We will also study how safely this combination of medication can be given in advanced cancer and lymphoma and benefits of receiving this therapy. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Veliparib is not yet approved for use in the United States, and is considered experimental. Veliparib inhibits (blocks) the activity of the enzyme PARP. This blocking activity may prevent the cancer cell from repairing itself and resume growing. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your cancer.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Malignant Solid Tumor
  • Mantle Cell Lymphoma
  • Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Veliparib in Treating Patients With Recurrent or Refractory Stage IV Solid Tumors That Cannot Be Removed by Surgery or Lymphoma With or Without Alterations in DNA Repair Genes
  • Official Title: Phase I/Ib Study of Nivolumab and Veliparib in Patients With Advanced Solid Tumors and Lymphoma With and Without Alterations in Selected DNA Repair Genes

Clinical Trial IDs

  • ORG STUDY ID: NU 16MH03
  • SECONDARY ID: STU00204250
  • SECONDARY ID: NU 16MH03
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2016-02018
  • NCT ID: NCT03061188

Conditions

  • Advanced Solid Neoplasm
  • Aggressive Non-Hodgkin Lymphoma
  • Recurrent Solid Neoplasm
  • Refractory Mantle Cell Lymphoma
  • T-Cell Non-Hodgkin Lymphoma
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (veliparib, nivolumab)
VeliparibABT-888, PARP-1 inhibitor ABT-888Treatment (veliparib, nivolumab)

Purpose

The purpose of this research study is to determine the highest and safest dose of the experimental drug veliparib when combined with nivolumab. We will also study how safely this combination of medication can be given in advanced cancer and lymphoma and benefits of receiving this therapy. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Veliparib is not yet approved for use in the United States, and is considered experimental. Veliparib inhibits (blocks) the activity of the enzyme PARP. This blocking activity may prevent the cancer cell from repairing itself and resume growing. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To identify maximum tolerated dose (MTD) for the combination treatment of nivolumab and
      veliparib in patients with advanced refractory solid cancers and lymphoma.

      SECONDARY OBJECTIVES:

      I. To evaluate the safety and tolerability of nivolumab and veliparib in patients with
      advanced refractory solid cancers and lymphoma with and without mutations in selected DNA
      repair genes.

      II. To evaluate the efficacy of treatment with nivolumab and veliparib in this population by
      objective response rate (ORR, defined as partial response [PR] + complete response [CR]),
      clinical benefit rate (CBR, defined as stable disease [SD] for >= 12 weeks, PR, + CR), and
      progression free survival (PFS, defined as the time from treatment initiation to documented
      disease progression) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
      version (v)1.1 or Lugano criteria.

      III. To evaluate efficacy of treatment with nivolumab and veliparib in this population by
      ORR, CBR, and immune-related PFS (irPFS) using irRECIST criteria.

      IV. To evaluate overall survival (OS) in this population at 3 years from the start of
      treatment.

      V. To evaluate the proportion of patients alive and progression free at 24 weeks in this
      population.

      VI. To evaluate ORR to nivolumab and veliparib in patients with prior exposure to single
      agent PD-1/PD-L1 inhibitors.

      TERTIARY OBJECTIVES:

      I. To evaluate if any of the following predict response to veliparib in combination with
      nivolumab: tissue PD-L1 protein expression, immune cell infiltration markers.

      II. To demonstrate the pharmacodynamic effects of veliparib and nivolumab on biomarkers
      including PD-L1, TILs, T cell subpopulations, and T cell receptor genotype.

      III. To explore the pattern of clonal changes through circulating cell free DNA assay.

      IV. To assess the dynamic change in both immune and genomic biomarkers in blood that may
      correlate with response to veliparib.

      OUTLINE: This is a dose-escalation study of veliparib.

      Patients receive veliparib orally (PO) twice daily (BID) on day 1 and nivolumab intravenously
      (IV) over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of
      subsequent courses. Courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months and
      then every 6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (veliparib, nivolumab)ExperimentalPatients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Veliparib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a histologically documented (either primary or metastatic site)
             diagnosis of advanced solid tumor cancer (stage IV or unresectable) or aggressive
             lymphoma (diffuse large B cell lymphoma, mantle cell lymphoma, T cell lymphoma, and
             natural killer [NK] cell lymphoma)

               -  NOTE: The following histologies will be excluded given known response to
                  PD-1/PD-L1 inhibitor monotherapy: non-small cell lung cancer, squamous cell
                  carcinoma of head and neck, melanoma, renal cell carcinoma, bladder cancer,
                  Hodgkin's lymphoma, Merkel cell carcinoma, and high-frequency microsatellite
                  instability (MSI-H) colorectal cancer

          -  All patients must have received, and be relapsed/refractory to at least one line of
             systemic therapy

               -  NOTE: This does not include surgery or radiation alone; patients may have
                  received any number of systemic therapies

          -  All patients with relapsed/refractory lymphoma must have received or be ineligible for
             autologous stem cell transplant or be ineligible for allogeneic stem cell transplant

               -  NOTE: Patients must not have had a prior allogeneic stem cell transplant

          -  Patients must have measurable disease as per appropriate guidelines:

               -  Solid tumors: by RECIST v1.1

               -  Lymphoma: patient has at least one measurable nodal lesion (>= 2 cm) according to
                  Lugano classification; if the patient has no measurable nodal lesions >= 2 cm in
                  the long axis at screening, then the patient must have at least one measurable
                  extra-nodal lesion

          -  Patients must have the ability to understand and the willingness to sign a written
             consent prior to registration in the study

          -  For expansion cohort patients, the profiling must reveal at least one mutation in the
             following selected DNA repair genes involved in cell cycle arrest signal transduction,
             BRCA1 pathway, Fanconi's proteins pathway, and RAD51 pathway: (ATR, ATM, CHEK1, CHEK2,
             BRCA1, BAP1, BARD1, FANCD2, FANCE, FANCC, RAD50, FANCA, RAD51, BRCA2, PALB2, CDK12
             [ENSG00000167258, also known as CRK7, CRKR, CRKRS], POLE, POLD1, BRAC2, PRKDC, ERCC2,
             POLQ, MRE11A, NBN [MBS1]), or at least one gene amplification in FANCD2, FANCE, FANCC,
             FANCA, C11orf30 (EMSY)

               -  NOTE: Tissue or blood cell free DNA are allowed for genomic profiling of tumor;
                  profiling should have been performed at a Clinical Laboratory Improvement Act
                  (CLIA) certified lab =< 1 year prior to registration

               -  NOTE: Patients in the dose escalation phase are not required to have such
                  mutations; although genomic profiling is not required for dose escalation
                  patients, it is encouraged in these patients prior to or after study registration
                  if feasible

          -  Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
             of =< 2

          -  Patients must have adequate organ and bone marrow function =< 14 days prior to
             registration, as defined below (Note: blood transfusion or growth factors is not
             permitted within 14 days of registration):

          -  Absolute neutrophil count >= 1.5 x 10^9/L

          -  Hemoglobin >= 9 g/dL

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN)

          -  Alanine aminotransferase and aspartate aminotransferase =< 5 x ULN

          -  Calculated creatinine clearance according to the Cockcroft and Gault equation >= 50
             mL/min

          -  Females of child-bearing potential (FOCBP) and men who are sexually active with FOCBP
             must agree to follow instructions for method(s) of contraception for the duration of
             treatment and the designated post-treatment period

               -  NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
                  tubal ligation, or remaining celibate by choice) who meets the following
                  criteria:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy

                    -  Has had menses at any time in the preceding 12 consecutive months (and
                       therefore has not been naturally postmenopausal for > 12 months)

          -  FOCBP must have a negative pregnancy test =< 7 days prior to registration

          -  Patients must be able to swallow oral medication

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy =< 14 days prior to entering the
             study are not eligible

               -  NOTE: Patients may not have had systemic chemotherapy within 28 days

          -  Patients are not eligible who have had major surgery =< 14 days of registration;
             please contact principle investigator (PI) and quality assurance monitor (QAM) for
             questions about specific surgical procedures

          -  Patients are not eligible who have received prior PARP inhibitors (including but not
             limited to veliparib, talazoparib, rucaparib, and olaparib)

          -  Patients are not eligible who have received systemic chemotherapy or investigational
             agents =< 28 days prior to registration

          -  Patients are not eligible who have received prior immunotherapy including
             interleukin-2 and immune checkpoint antagonists and/or agonists (including but not
             limited to PD-1, PD-L1, CD137, or OX40)

               -  NOTE: Single agent anti-CTLA4 monoclonal antibody treatments are permitted;
                  cancer vaccine therapies are permitted

          -  Patients with the following histologies are not eligible for either study cohort given
             known response to PD-1/PD-L1 inhibitor monotherapy:

               -  Non-small cell lung cancer, squamous cell carcinoma of head and neck, melanoma,
                  renal cell carcinoma, bladder cancer, Hodgkin's lymphoma, Merkel cell carcinoma,
                  and MSI-H colorectal cancer

          -  Patients are not eligible who have had a prior allogeneic stem cell transplant

               -  NOTE: Autologous stem cell transplant is acceptable

          -  Patients who are taking any herbal (alternative) medicines are NOT eligible for
             participation; patients must be off any such medications by the time of registration
             for >= 14 days

               -  NOTE: Vitamin supplements are acceptable

          -  Patients must have no history of central nervous system (CNS) metastasis at the
             screening assessment

               -  NOTE: Patients with stable brain metastases (mets) which have been treated are
                  eligible; patients with suspected symptoms of CNS metastasis should undergo CNS
                  imaging at the time of screening to rule out active metastasis

          -  Patients who have had a prior severe infusion reaction to a monoclonal antibody are
             not eligible

          -  Patients are not eligible who have a history of or active autoimmune disease within
             the past 3 years with the following exceptions:

               -  Vitiligo or alopecia

               -  Hypothyroidism on stable doses of thyroid replacement therapy

               -  Psoriasis not requiring systemic therapy within the past 3 years

          -  Patients with a history of primary immunodeficiency disease or tuberculosis are not
             eligible

          -  Patients who have an uncontrolled current illness including, but not limited to any of
             the following, are not eligible:

               -  Uncontrolled pulmonary, renal, or hepatic dysfunction

               -  Ongoing or active infection requiring systemic treatment including hepatitis B
                  and hepatitis C

               -  Known active or chronic viral hepatitis or human immunodeficiency virus (HIV)

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

               -  Clinically significant gastrointestinal disease or digestive dysfunction
                  compromising absorption of veliparib

               -  Any other illness or condition that the treating investigator feels would
                  interfere with study compliance or would compromise the patient's safety or study
                  endpoints

          -  Female patients who are pregnant or nursing are not eligible

          -  Patients with a prior diagnosis of cancer must not have received treatment in the last
             3 years prior to registration

               -  NOTE: Patients with a history of completely resected non-melanomatous skin
                  carcinoma or successfully treated in situ carcinoma are eligible

          -  Patients must not have a history of prior stroke, transient ischemic attack (TIA),
             pulmonary embolism, or untreated deep vein thrombosis

               -  NOTE: Patients may be eligible if they have received at least 3 months of
                  anticoagulation for a deep vein thrombosis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD will be defined as the highest dose that causes dose-limiting toxicities (DLTs) in <2 of 6 patients.

Secondary Outcome Measures

Measure:Incidence of Adverse Events
Time Frame:Up to 30 days after treatment discontinuation
Safety Issue:
Description:Evaluate the safety and tolerability of nivolumab and veliparib by assessing the number, frequency, and severity of adverse events as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Measure:ORR
Time Frame:Up to 30 days after the last dose of study treatment
Safety Issue:
Description:ORR (partial response (PR) + complete response (CR)) will be evaluated using RECIST criteria v1.1 or Lugano 2014 classification for assessment of Lymphoma and irRECIST.
Measure:Clinical Benefit Rate (CBR)
Time Frame:Up to 3 years
Safety Issue:
Description:CBR (defined as stable disease (SD) for ≥12 weeks, PR + CR) assessed by RECIST criteria v1.1 or Lugano 2014 classification for assessment of Lymphoma, and irRECIST
Measure:Progression Free Survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:PFS, defined as the time from treatment initiation to documented disease progression, evaluated by RECIST criteria v1.1 or Lugano 2014 classification for assessment of Lymphoma.
Measure:immune-related PFS (irPFS)
Time Frame:Up to 3 years
Safety Issue:
Description:irPFS assessed by irRECIST criteria.
Measure:Overall Survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:OS is defined as the time from treatment initiation until death due to any cause, assessed up to 3 years.
Measure:Proportion of patients alive and progression free
Time Frame:At 24 weeks
Safety Issue:
Description:Evaluate the proportion of patients alive and progression free at 24 weeks.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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