Parpvax: Niraparib + Ipilimumab or Nivolumab in Progression Free Pancreatic Adenocarcinoma After Platinum-Based Chemotherapy

Sponsor

University of Pennsylvania (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03404960

Collaborator

Bristol-Myers Squibb (Industry), GlaxoSmithKline (Industry)

Enrollment

Location

Arms

100

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to look at the effectiveness, safety, and anti-tumor activity (preventing growth of the tumor) of the drugs Niraparib with either Ipilimumab or Nivolumab on patients and their pancreatic cancer.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Adenocarcinoma	Drug: Niraparib + Nivolumab Drug: Niraparib + Ipilimumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

84 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

PARPVAX: Parpvax: A Phase 1b/2, Open Label Study of Niraparib Plus Either Ipilimumab or Nivolumab in Patients With Advanced Pancreatic Cancer Whose Disease Has Not Progressed on Platinum-based Therapy

Actual Study Start Date :

Jan 31, 2018

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A Niraparib + Nivolumab	Drug: Niraparib + Nivolumab Niraparib 200mg PO daily on days 1-28 of each 28-day cycle. Nivolumab 480mg IV day 1 of each cycle.
Experimental: Arm B Niraparib + Ipilimumab	Drug: Niraparib + Ipilimumab Niraparib 200mg PO daily on days 1-21 of each 21-day cycle. Ipilimumab 3mg/kg IV day 1 of each cycle, for the first 4 cycles only.

Arm

Intervention/Treatment

Experimental: Arm A

Niraparib + Nivolumab

Drug: Niraparib + Nivolumab

Niraparib 200mg PO daily on days 1-28 of each 28-day cycle. Nivolumab 480mg IV day 1 of each cycle.

Experimental: Arm B

Niraparib + Ipilimumab

Drug: Niraparib + Ipilimumab

Niraparib 200mg PO daily on days 1-21 of each 21-day cycle. Ipilimumab 3mg/kg IV day 1 of each cycle, for the first 4 cycles only.

Outcome Measures

Primary Outcome Measures

Progression-free survival. [6 months after initiation of study therapy]
Progression-free survival at 6 months (PFS6) for both combinations according to RECIST v1.1, as assessed by the investigator
Safety and tolerability of this combination as determined by CTCAE v5.0. [From the initiation of any study intervention through 3 weeks.]
Safety will be assessed in 6 patients (3 patients in each Arm). If 1 or fewer DLTs are observed in 6 patients, then the current Niraparib dose will be declared the MTD.

Secondary Outcome Measures

Safety and tolerability of this combination as determined by CTCAE v5.0. [From the initiation of any study intervention through 100 days (nivolumab patients) or 90 days (all patients) after patient End of Treatment Visit]
The incidence of adverse events (AEs), clinical laboratory abnormalities and dose modifications.
Proportion of tumors with homologous recombination deficits (HRD), in patients with stability or response to platinum therapy [Cycle 1 Day 1 through completion of study treatment (maximum 42 months)]
Identification of HRDs and allele specific LOH via whole exome sequencing
Correlation of HRDs with response to treatment with niraparib plus immune checkpoint blockade [Cycle 1 Day 1 through completion of study treatment (maximum 42 months)]
Identification of HRDs and allele specific LOH via whole exome sequencing
Immune activation prior to treatment [Prior to initiation of study therapy (maximum 36 months)]
Assessed using immune biomarkers, and RNAseq of PBMC
Immune activation during treatment [Following receipt of study therapy and through study completion (maximum 42 months)]
Assessed using immune biomarkers, and RNAseq of PBMC
Overall response rate [From first restaging assessment through completion of study treatment (maximum 42 months)]
Measured by CT scans and other studies (MRI, X-ray, PET, and ultrasound)
Duration of response (DOR) [From first restaging assessment until death, loss to follow-up, withdrawal of consent or until 5 years have passed, whichever occurs first]
Measured by CT scans and other studies (MRI, X-ray, PET, and ultrasound)
Overall survival (OS) [Cycle 1 Day 1 until death, loss to follow-up, withdrawal of consent or until 5 years have passed, whichever occurs first]
start of treatment to death due to any cause or last patient contact alive

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma with locally advanced or metastatic disease
≥18 years of age
Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent
Patients must have received treatment with platinum-based (cisplatin, oxaliplatin or carboplatin) treatment for locally advanced or metastatic pancreatic cancer and have received a minimum of 16 weeks of therapy without evidence of disease progression based on the investigator's opinion. This does not have to be the patient's current treatment.

This requires at least stable imaging and a stable or decreasing tumor marker as applicable and as determined by the investigator.
If a patient has demonstrated a biochemical and imaging response to platinum therapy and has not progressed within 16 weeks of starting this therapy but had to discontinue platinum prior to 16 weeks for a legitimate medical reason (as determined by the investigator), the patient may still be considered for the trial

Patients may have previously failed non-platinum containing therapy or may never have previously progressed on treatment

Discontinuation of the platinum component of the regimen for chemotherapy-related toxicity is permissible provided the patient has previously received at least 16 weeks of platinum-based therapy without evidence of disease progression ≤8 weeks after treatment with the platinum agent

Measurable disease is not a requirement for study entry
Female participant has a negative serum pregnancy test within 24 hours prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 6 months after the last dose of study treatment, or is of nonchildbearing potential
Male patient agrees to use an adequate method of contraception starting with the first dose through 90 days after the last dose of study treatment
Adequate organ function confirmed by the following laboratory values obtained ≤7 days prior to the first day of study therapy:

Absolute neutrophil count (ANC) ≥1.5 x 109/L
Platelets>100 x 109/L
Hemoglobin ≥9g/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN); if liver metastases, then ≤5 x ULN
Total bilirubin ≤1.5 x ULN; if liver metastases or metabolic disorder such as Gilbert's syndrome, then ≤2.5 x ULN.
Serum creatinine ≤1.5 x ULN or estimated glomerular filtration rate (GFR) ≥45 mL/min using Cockcroft Gault formula.

Eastern Cooperative Oncology (ECOG) performance status of 0 to 1.

Exclusion Criteria:

Prior treatment with a PARP inhibitor, ipilimumab, nivolumab or other cytotoxic T-lymphocyte-associated protein (CTLA-4), PD-1 or PD-L1 inhibitor.
Patients who have demonstrated resistance to platinum agents (e.g. oxaliplatin, cisplatin) are not eligible to participate in this study
Clinical evidence of uncontrolled malabsorption and/or any other gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with the absorption of niraparib
Acute infection requiring intravenous antibiotics, antiviral or antifungal agents during the 14 days prior to first dose of study therapy
Patients will be excluded if they have an active, known or suspected autoimmune disease, defined as: patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g. rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g. Wegener's Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).

NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

Has a history of interstitial lung disease or active, non-infectious pneumonitis
Has received a live vaccine within 4 weeks prior to the first dose of trial therapy (Note: seasonal influenza vaccines for injection are generally inactivated and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines and are not allowed
For fertile patient (female able to become pregnant or male able to father a child), refusal to use effective contraception during the period of the trial and:

Female patients refusing to use effective contraception for 6 months after the last dose of study drug.
Male patients refusing to use effective contraception for 90 days after the last dose of study drug.

Received any systemic treatment for pancreatic cancer ≤14 days prior to first dose of therapy. Patients must not have had investigational therapy administered ≤4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
Patients will be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses >10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Patient has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
Non-study related minor surgical procedure ≤5 days, or major surgical procedure ≤21 days, prior to the first dose of therapy; in all cases, patients must be sufficiently recovered and stable before treatment administration.
Active drug or alcohol use or dependence that would interfere with study compliance.
Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study.
Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
Patients must not be simultaneously enrolled in any therapeutic clinical trial
Patients must not have had radiotherapy within 4 weeks of the first dose of study treatment
Patients must not have a known hypersensitivity to the components of niraparib or the excipients
Patients must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks of the first dose of study treatment
Patients must not be undergoing treatment for an active cancer at the time of randomization. Exceptions include: local therapies for skin cancers and hormonal therapies for breast or prostate cancer.
Patients must not have a history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), and must not test positive for HIV during study screening.
Patients must not have known, symptomatic brain or leptomeningeal metastases