Phase I/Ib Study of Nivolumab & Veliparib in Patients With Advanced Solid Tumors & Lymphoma

Phase 1

Completed

• Conditions: Refractory Mantle Cell Lymphoma; Advanced Solid Neoplasm; Aggressive Non-Hodgkin Lymphoma; Recurrent Solid Neoplasm; T-Cell Non-Hodgkin Lymphoma; Unresectable Solid Neoplasm
• Interventions: Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Pharmacological Study; Drug: Veliparib

• Registration Number: NCT03061188
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2017-02-17
• Study First Submitted QC: 2017-02-17
• Study First Posted: 2017-02-23
• Study Start: 2017-05-23
• Primary Completion: 2018-03-11
• Study Completion: 2020-08-04
• Results First Submitted: 2020-08-12
• Results First Submitted QC: 2020-10-27
• Results First Posted: 2020-11-19
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-15
• Last Update Posted: 2024-06-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment (veliparib, nivolumab)	Laboratory Biomarker Analysis	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.
Treatment (veliparib, nivolumab)	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.
Treatment (veliparib, nivolumab)	Pharmacological Study	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.
Treatment (veliparib, nivolumab)	Veliparib	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.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD)	First Cycle of Treatment with velaparib and nivolumab (28 days)	The MTD will be defined as the highest dose that causes dose-limiting toxicities (DLTs) in \<2 of 6 patients. Toxicity will be assessed using CTCAEv4.03. A DLT is defined as an Adverse Event (AE) or abnormal laboratory value assessed as at least possibly related to the study medication, occurs ≤ 28 days (1 cycle) following the first dose of veliparib and nivolumab and meets any of the following criteria: Grade ≥ 3 non-hematologic toxicities that represent at least a 2-grade increase from baseline excluding Nausea, vomiting, diarrhea lasting ≤48 hours, Electrolyte abnormalities resolving within ≤24 hours, Hypersensitivity reactions,and Alopecia.; Grade 4 thrombocytopenia (platelets \< 25.0 x 109 /L) Grade 3 thrombocytopenia with bleeding (platelets \< 0.5 x 109 /L) 5. Grade 3 febrile neutropenia with fever lasting for \> 7 days 6. Grade 4 febrile neutropenia of any duration 7. Dosing delay due to toxicity for \> 14 consecutive days from the date nivolumab or veliparib is due.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	From the start of treatment and every 2 cycles during treatment, and up to three years, where 1 cycle =28 days, and range of cycles is 1-12.	To evaluate Progression Free Survival (PFS) for patients treated with nivolumab and veliparib, defined as the time from treatment initiation to documented disease progression. Evaluated by RECIST criteria v1.1 for solid tumors or Lugano 2014 classification for assessment of Lymphoma. RECIST v. 1.1 definition for PD (Progressive disease): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Lugano 2014 classification, scored on a Deauville 5-point scale (an internationally-recommended scale using FDG PET-CT in the initial staging and assessment of treatment response in Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphomas (NHL). Per Lugano criteria: Partial metabolic disease (PMD):Score 4 or 5 with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment.
Number of Participants With Adverse Events Possibly Related to Study Drugs Graded 3, 4, and 5	Up to 30 days after treatment discontinuation, where 1 cycle =28 days, and range of cycles is 1-12.	Toxicity, both frequency and severity, will continue to be measured by monitoring the occurrence of adverse events. Adverse events will be defined as those included in CTCAE v 4.03. AEs that were determined to be at least possibly related to study drug and graded 3, 4, 5 are included here. Grade 1 (mild): the event causes discomfort without disruption of normal daily activities. Grade 2 (moderate): the event causes discomfort that affects normal daily activities. Grade 3 (severe): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Grade 4 (Life-threatening): the patient was at risk of death at the time of the event. Grade 5 (fatal): the event caused death.
ORR (Overall Response Rate)	after 2 cycles at first response time point (1 cycle = 28 days)	Overall response rate or ORR, (partial response (PR) + complete response (CR)) will be evaluated using RECIST criteria v1.1 or Lugano 2014 classification for assessment of Lymphoma.; Per RECIST v. 1.1: PR= : At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR= Disappearance of all target lesions.; Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.; Per Lugano 2014 classification, scored on a Deauville 5-point scale (an internationally-recommended scale using FDG PET-CT in the initial staging and assessment of treatment response in Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphomas (NHL).; * Partial metabolic response (PMR): score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size.; * Complete metabolic response (CMR): Score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass
Clinical Benefit Rate (CBR)	From the start of treatment and every 2 cycles during treatment where 1 cycle =28 days, average number of cycles is 4 and range of cycles is 1-12.	CBR= stable disease for ≥12 weeks + Partial Response + Complete Response per RECIST v1.1 for solid tumors or Lugano 2014 classification for lymphomas. Lugano scored on a Deauville 5-point scale. RECIST v. 1.1: PR= : At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR= Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Lugano 2014 classification: PR: score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. CR: Score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass. SD: No metabolic response, Score 4 or 5 with no significant change in FDG uptake from baseline at interim or end of treatment.
Overall Survival (OS)	From the start of treatment and up to 3 years, where 1 cycle =28 days, and range of cycles is 1-12.	Overall Survival is defined as the time from treatment initiation until death due to any cause, assessed up to 3 years from the start of treatment.
Number of Patients Alive and Progression Free at 24 Weeks	At 24 weeks	To evaluate the number of patients alive and progression free at 24 weeks. -Per RECIST v. 1.1 (for solid tumors) progression is defined as : At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) -Lugano 2014 classification, scored on a Deauville 5-point scale (an internationally-recommended scale using FDG PET-CT in the initial staging and assessment of treatment response i Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphomas (NHL). Per Lugano criteria: Partial metabolic disease (PMD):Score 4 or 5 with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment.

Trial Locations

Locations (1)

Northwestern University; 🇺🇸 Chicago, Illinois, United States