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Now published in The Lancet

First-in-Human Phase 1 Study of Veliparib, a PARP-1/2 Inhibitor, with Gemcitabine and Radiotherapy in Locally Advanced Pancreatic Cancer

71 Pages Posted: 21 Dec 2018

See all articles by Richard Tuli

Richard Tuli

Cedars Sinai Medical Center - Department of Radiation Oncology

Stephen Shiao

Cedars Sinai Medical Center - Department of Radiation Oncology

Nicholas Nissen

Cedars Sinai Medical Center

Mourad Tighiouart

Cedars Sinai Medical Center - Department of Medicine

Sungjin Kim

Cedars Sinai Medical Center - Department of Medicine

Arsen Osipov

Cedars Sinai Medical Center - Department of Radiation Oncology

Miranda Bryant

Cedars Sinai Medical Center - Department of Radiation Oncology

Lindsey Ristow

Cedars Sinai Medical Center - Department of Radiation Oncology

Veronica Placencio

Cedars Sinai Medical Center - Department of Radiation Oncology

David Hoffman

Cedars Sinai Medical Center - Department of Medicine

Sepehr Rokhsar

Cedars Sinai Medical Center - Department of Medicine

Kevin Scher

Cedars Sinai Medical Center - Department of Medicine

Samuel Klempner

Cedars Sinai Medical Center - Department of Medicine

Paul Noe

Cedars Sinai Medical Center - Department of Medicine

MJ Davis

Cedars Sinai Medical Center - Department of Medicine

Ashley Wachsman

Cedars Sinai Medical Center

Simon Lo

Cedars Sinai Medical Center - Department of Medicine

Laith Jamil

Cedars Sinai Medical Center - Department of Medicine

Howard Sandler

Cedars Sinai Medical Center - Department of Radiation Oncology

Steven Piantadosi

Cedars Sinai Medical Center - Department of Medicine

Andrew Hendifar

Cedars Sinai Medical Center - Department of Medicine

More...

Abstract

Background: Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC.    

Methods: This was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status.    

Findings: Thirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2-27.2) and 14 months (95% CI: 10.0-21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS.  

Interpretation: This is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study.

Clinical Trial Number:  (NCT01908478)

Funding Statement: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.

Declaration of Interests: RT has served as an advisor for Astra Zeneca. SJK has served as a consultant/advisor for Lilly Oncology, Astellas, and Boston Biomedical, and is on the speaker bureau for Foundation Medicine, Inc. All remaining authors have declared no conflicts of interest.

Ethics Approval Statement:  The authors state that the study is "institutional review board approved".

Keywords: parp inhibitor, radiation, gemcitabine, pancreas cancer, Veliparib

Suggested Citation

Tuli, Richard and Shiao, Stephen and Nissen, Nicholas and Tighiouart, Mourad and Kim, Sungjin and Osipov, Arsen and Bryant, Miranda and Ristow, Lindsey and Placencio, Veronica and Hoffman, David and Rokhsar, Sepehr and Scher, Kevin and Klempner, Samuel and Noe, Paul and Davis, MJ and Wachsman, Ashley and Lo, Simon and Jamil, Laith and Sandler, Howard and Piantadosi, Steven and Hendifar, Andrew, First-in-Human Phase 1 Study of Veliparib, a PARP-1/2 Inhibitor, with Gemcitabine and Radiotherapy in Locally Advanced Pancreatic Cancer (December 19, 2018). Available at SSRN: https://ssrn.com/abstract=3304271

Richard Tuli (Contact Author)

Cedars Sinai Medical Center - Department of Radiation Oncology ( email )

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Stephen Shiao

Cedars Sinai Medical Center - Department of Radiation Oncology

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Nicholas Nissen

Cedars Sinai Medical Center

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Mourad Tighiouart

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Sungjin Kim

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Arsen Osipov

Cedars Sinai Medical Center - Department of Radiation Oncology

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Miranda Bryant

Cedars Sinai Medical Center - Department of Radiation Oncology

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Lindsey Ristow

Cedars Sinai Medical Center - Department of Radiation Oncology

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Veronica Placencio

Cedars Sinai Medical Center - Department of Radiation Oncology

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

David Hoffman

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Sepehr Rokhsar

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Kevin Scher

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Samuel Klempner

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Paul Noe

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

MJ Davis

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Ashley Wachsman

Cedars Sinai Medical Center

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Simon Lo

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Laith Jamil

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Howard Sandler

Cedars Sinai Medical Center - Department of Radiation Oncology

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Steven Piantadosi

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

Andrew Hendifar

Cedars Sinai Medical Center - Department of Medicine

8700 Beverly Blvd.
Los Angeles, CA
United States

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