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Pancreatic Cancer

Patients receive siRNA-transfected peripheral blood mononuclear cells APN401 IV over 30 minutes on days 1, 29, and 57 in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

siRNA-transfected Peripheral Blood Mononuclear Cells APN401

Pierre Triozzi

This phase I trial studies the side effects and best dose of APN401 in treating patients with pancreatic cancer, colorectal cancer, or other solid tumors that have spread to other places in the body or have come back. APN401 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the toxicities and establish the safety of multiple infusions of small interfering ribonucleic acid (siRNA)-transfected peripheral blood mononuclear cells APN401 (APN401).

SECONDARY OBJECTIVES:

I. To determine the immunologic effects of multiple infusions of APN401. II. To document clinical response and survival.

OUTLINE:

Patients receive siRNA-transfected peripheral blood mononuclear cells APN401 intravenously (IV) over 30 minutes on days 1, 29, and 57 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

APN401 in Treating Patients With Recurrent or Metastatic Pancreatic Cancer, Colorectal Cancer, or Other Solid Tumors That Cannot Be Removed by Surgery

Safety and Immunologic Activity of Multiple Infusions of APN401

Will be categorized by organ system and severity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events

Will be summarized as frequency counts and percentages.

Will be summarized as medians and ranges. The effects of treatment will be analyzed using paired t-tests or the non-parametric counterpart.

Exploratory survival plots will be estimated using the Kaplan Meier approach and median OS will be estimated if enough events occur.

Exploratory survival plots will be estimated using the Kaplan Meier approach and median PFS will be estimated if enough events occur.

National Cancer Institute (NCI)

Wake Forest University Health Sciences

Blood and Lymph Conditions

Immune System Diseases

Behaviors and Mental Disorders

Lymphoma

Lymphoma, T-Cell

Lymphoma, Mantle-Cell

Aggression

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Mantle Cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Veliparib

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

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.

Pharmacological Study

Young K. Chae, MD, MPH, MBA

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.

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

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

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.

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.

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

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.

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.

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.

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.

Bristol-Myers Squibb

AbbVie

Northwestern University

Principal Investigator

The starting dose was Cohort level 1. There were no dose-limiting toxicities on Cohort 1 so the dose was never de-escalated, Cohort -1 never opened to enrollment.

Patients receive veliparib 200 mg (oral medication) twice daily 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.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Phase 1:Cohort-1 (Velaparib 200 mg PO Twice Daily + Nivolumab)

Patients receive veliparib 300 mg (oral medication) twice daily 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.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Phase 1:Cohort 1 (Velaparib 300 mg PO Twice Daily + Nivolumab)

Patients receive veliparib 400 mg (oral medication) twice daily 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.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Phase 1:Cohort 2 (Velaparib 400 mg PO Twice Daily + Nivolumab)

Phase 2 MTD: Velaparib 400 mg PO Twice Daily + Nivolumab

Velaparib (oral medication) twice daily 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.

* Velaparib dose in Phase 1: Cohort -1: 200mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Cohort -1)

Velaparib (oral medication) twice daily 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.

* Velaparib dose in Phase 1: Cohort 1: 300 mg,
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Cohort 1)

Velaparib (oral medication) twice daily 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.

* Velaparib dose: 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Cohort 2)

Patients in all Phase 1 cohorts and Phase 2 receive velaparib (oral medication) twice daily 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.

* Velaparib dose 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1)

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Phase 2)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Patients counted under "Yes" tested positive for a mutation in the following selected DNA repair genes (involved in cell cycle arrest signal transduction): BRCA1 pathway, Fanconi's proteins pathway, and RAD51 pathway: \[ATR, ATM, CHEK1, CHEK2, BRCA1, BRIP1, BAP1, BARD1, FANCD2, FANCE, FANCC, RAD50, FANCA, RAD51, BRCA2, PALB2, CDK12 (ENSG00000167258, also known as CRK7, CRKR, CRKRS), POLE, POLD1, BRAC2, PRKDC, ERCC2, POLQ, MRE11A, NBN (MBS1)\], or at least one gene amplification in FANCD2, FANCE, FANCC, FANCA, C11orf30 (EMSY).

Mutation in DNA repair gene present

Solid Tumor

Lymphoma vs Solid Tumor

The starting dose (Cohort 1) was never de-escalated, so Cohort -1 never opened.

The original accrual goal was 50 patients. Due to funding issues the accrual goal was reduced to 15 patients.

Young Kwang Chae, MD, MPH, MBA

Patients in all Phase 1 cohorts receive velaparib (oral medication) twice daily 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.

\*Velaparib dose in Phase 1: Cohort -1: 200mg, Cohort 1: 300 mg, Cohort 2: 400 mg

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib PO Twice Daily + Nivolumab (Phase 1)

Maximum Tolerated Dose (MTD)

Incidence of Adverse Events

Complete Response

Partial Response

Velaparib (oral medication) twice daily 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.

* Velaparib dose in Phase 1: Cohort 1: 300 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib: Given PO

ORR (Overall Response Rate)

Stable Disease for or ≥12 weeks

Velaparib (oral medication) twice daily 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.

Velaparib dose in Phase 1: Cohort 1: 300 mg

Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory

Biomarker Analysis: Correlative studies

Nivolumab: Given IV Pharmacological Study: Correlative studies

Veliparib: Given PO

Velaparib (oral medication) twice daily 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.

* Velaparib dose: 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib: Given PO

Patients in all Phase 1 cohorts and Phase 2 receive velaparib (oral medication) twice daily 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.

* Velaparib dose 400 mg
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib

Clinical Benefit Rate (CBR)

Velaparib PO Twice Daily + Nivolumab (Cohort 2 + Phase 2)

Progression Free Survival (PFS)

Overall Survival (OS)

Velaparib (oral medication) twice daily 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.

* Velaparib dose in Phase 1: Cohort 1: 300 mg,
* Nivolumab dose: Cycle 1-4: 240 mg IV every 14 days (Days 1 \& 15) + Cycle 5+: 480mg IV every 28 days (Day 1) Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacological Study: Correlative studies Veliparib: Given PO

2 patients not included in these results as they came off treatment before 24 weeks - one withdrew consent and 1 came off treatment for palliative radiation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
APN401 in Treating Patients With Recurrent or Metastatic Pancreatic Cancer, Colorectal Cancer, or Other Solid Tumors That Cannot Be Removed by Surgery	NCT03087591	Metastatic Mali... Metastatic Soli... Recurrent Color... Recurrent Pancr... Recurrent Solid... Stage IV Colore... Stage IV Pancre... Stage IVA Color... Stage IVA Pancr... Stage IVB Color... Stage IVB Pancr... Unresectable So...	Laboratory Biom... siRNA-transfect...	18 Years -	Wake Forest University Health Sciences
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	Advanced Solid ... Aggressive Non-... Recurrent Solid... Refractory Mant... T-Cell Non-Hodg... Unresectable So...	Laboratory Biom... Nivolumab Pharmacological... Veliparib	18 Years -	Northwestern University

Spots Global Cancer Trial Database for recurrent solid neoplasm