A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancerResearch in context
R. Tuli,
S.L. Shiao,
N. Nissen,
M. Tighiouart,
S. Kim,
A. Osipov,
M. Bryant,
L. Ristow,
V.R. Placencio-Hickok,
D. Hoffman,
S. Rokhsar,
K. Scher,
S.J. Klempner,
P. Noe,
M.J. Davis,
A. Wachsman,
S. Lo,
L. Jamil,
H. Sandler,
S. Piantadosi,
A. Hendifar
Affiliations
R. Tuli
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Corresponding author at: Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, AC1023, Los Angeles, CA 90048, USA.
S.L. Shiao
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
N. Nissen
Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
M. Tighiouart
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
S. Kim
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
A. Osipov
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
M. Bryant
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
L. Ristow
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
V.R. Placencio-Hickok
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
D. Hoffman
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
S. Rokhsar
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
K. Scher
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
S.J. Klempner
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
P. Noe
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
M.J. Davis
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
A. Wachsman
Department of Radiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
S. Lo
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
L. Jamil
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
H. Sandler
Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
S. Piantadosi
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
A. Hendifar
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
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. Fund: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie. Keywords: Parp inhibitor, Radiation, Gemcitabine, Pancreas cancer, Veliparib
