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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

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ClinicalTrials.gov Identifier: NCT03061188
Recruitment Status : Recruiting
First Posted : February 23, 2017
Last Update Posted : January 24, 2018
Sponsor:
Collaborators:
Bristol-Myers Squibb
AbbVie
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Young Kwang Chae, Northwestern University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Solid Neoplasm Aggressive Non-Hodgkin Lymphoma Recurrent Solid Neoplasm Refractory Mantle Cell Lymphoma T-Cell Non-Hodgkin Lymphoma Unresectable Solid Neoplasm Other: Laboratory Biomarker Analysis Biological: Nivolumab Other: Pharmacological Study Drug: Veliparib Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 23, 2017
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Treatment (veliparib, nivolumab)
Patients 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.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Pharmacological Study
Correlative studies

Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) [ Time Frame: Up to 28 days ]
    The MTD will be defined as the highest dose that causes dose-limiting toxicities (DLTs) in <2 of 6 patients.


Secondary Outcome Measures :
  1. Incidence of Adverse Events [ Time Frame: Up to 30 days after treatment discontinuation ]
    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.

  2. ORR [ Time Frame: Up to 30 days after the last dose of study treatment ]
    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.

  3. Clinical Benefit Rate (CBR) [ Time Frame: Up to 3 years ]
    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

  4. Progression Free Survival (PFS) [ Time Frame: Up to 3 years ]
    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.

  5. immune-related PFS (irPFS) [ Time Frame: Up to 3 years ]
    irPFS assessed by irRECIST criteria.

  6. Overall Survival (OS) [ Time Frame: Up to 3 years ]
    OS is defined as the time from treatment initiation until death due to any cause, assessed up to 3 years.

  7. Proportion of patients alive and progression free [ Time Frame: At 24 weeks ]
    Evaluate the proportion of patients alive and progression free at 24 weeks.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03061188


Contacts
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Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu

Locations
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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Young K. Chae, MD, MPH, MBA    312-695-0370      
Principal Investigator: Young K. Chae, MD, MPH, MBA         
Sub-Investigator: Benedito Carneiro, MD         
Sub-Investigator: Sunandana Chandra, MD         
Sub-Investigator: Jason Kaplan, MD         
Sub-Investigator: Aparna Kalyan, MD         
Sub-Investigator: Sarika Jain, MD         
Sub-Investigator: Massimo Cristofanilli, MD         
Sub-Investigator: Victoria Villaflor, MD         
Sub-Investigator: Cesar Santa-Maria, MD         
Sub-Investigator: Ricardo Costa, MD         
Sub-Investigator: Valerie Nelson, MD         
Sub-Investigator: Neal Christiansen, MD         
Sub-Investigator: Alok Pant, MD         
Sub-Investigator: Amanda Williams, PA         
Sub-Investigator: Hannah Garret, APN         
Sub-Investigator: Ellen Dammrich, APN         
Sub-Investigator: Mark Agulnik, MD         
Sub-Investigator: Frank Giles, MD         
Sponsors and Collaborators
Northwestern University
Bristol-Myers Squibb
AbbVie
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Young K. Chae, MD, MPH, MBA Northwestern University

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Responsible Party: Young Kwang Chae, Principal Investigator, Northwestern University
ClinicalTrials.gov Identifier: NCT03061188     History of Changes
Other Study ID Numbers: NU 16MH03
STU00204250 ( CTRP (Clinical Trial Reporting Program) )
NU 16MH03 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
NCI-2016-02018 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: February 23, 2017    Key Record Dates
Last Update Posted: January 24, 2018
Last Verified: January 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lymphoma
Neoplasms
Lymphoma, Non-Hodgkin
Lymphoma, Mantle-Cell
Lymphoma, T-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Nivolumab
Veliparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action