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.
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.
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
