A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer.

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.

Successful patient recruitment in CT imaging clinical trials: what factors influence patient participation?

RATIONALE AND OBJECTIVES: Analyze factors that influence participation in research studies that use coronary computed tomography (CT) imaging. MATERIALS AND METHODS: A 12-point survey using a questionnaire was conducted on 80 subjects, of whom 40 agreed to participate in a cardiovascular CT imaging research study (enrolling subjects) and 40 declined participation (non-enrolling subjects). Potential factors that motivated the acceptance or refusal of enrollment were evaluated using a 5-point Likert scale. The following aspects were addressed: (1) additional health information, (2) free imaging, (3) altruistic benefit to society, (4) monetary compensation, (5) radiation exposure, (6) role as an experimental subject, (7) possible loss of confidentiality, (8) contrast or investigational drug use, (9) premedication use, (10) blood draw or intravenous placement, (11) time commitment, and (12) personal medical opinion. Response distributions were obtained for each question and compared between enrolling and non-enrolling groups. RESULTS: Enrolling subjects gave significantly higher ratings than non-enrolling subjects for the following factors: additional health information (P < .001), free imaging (P < .001), and the altruistic benefit to society (P < .001). For non-enrolling subjects, concern for possible drug use or contrast injection (P < .001), concern for possible premedication (P < .001), and personal availability or time commitment (P < .001) were all given significantly higher ratings. Concern for radiation exposure (P = .002) and personal medical opinion (P < .001) received significantly high ratings among both groups but did not differ between groups. CONCLUSIONS: Several influential concerns and benefits were identified from potential research subjects. Knowledge of what influences patient participation in studies involving CT imaging may allow researchers to effectively address concerns and highlight the potential benefits related to participation.