No abstract

No abstract

135 Background: Veliparib (V) (ABT-888) is an oral, potent inhibitor of PARP 1/2. PARP inhibitors have preclinical and clinical efficacy in BRCA+ malignancies. There are genotypic and phenotypic similarities between BRCA+ cancers, serous ovarian cancer and basal-like breast cancer and we postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose -limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed V in 2 cohorts of patients, BRCA+ and BRCA-wt (consisting of serous ovarian cancer and triple-negative breast cancer (TNBC). Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28 day cycle. BRCA+ and BRCA-wt patients were enrolled in 2 separate cohorts with 2 separate escalations. Results: 98 (70 BRCA+ and 28 BRCA-wt) pts have been enrolled. The maximum administered dose (MAD) was 500mg BID and the MTD/RP2D is 400mg BID for both cohorts. 59 BRCA+ pts and 24 BRCA-wt pts (21 TNBC and 3 ovary) were evaluable for response. ORR was defined as CR+PR and clinical benefit rate (CBR) as CR+PR+SD > 6 months. Results are summarized in the table. Conclusions: There is evidence of anti-tumor activity with V comparable to that of other PARP inhibitors in the BRCA+ population. There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly TNBC, BRCA-wt population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance. Clinical trial information: NCT00892736. [Table: see text]

99 Background: Although immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: Stage II/III patients (pts) with MSS rectal cancer undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT) followed by definitive surgery were eligible. Treatment included durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion followed by surgery within 8-12 wks of the final CRT dose. Primary end point (EP): Improvement in modified neoadjuvant rectal cancer (mNAR) score (goal 10.6) compared to historical controls (15.6) targeting a 20% DFS RR reduction and 3-4% absolute OS improvement. Secondary EPs: toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, and exploratory assessments of tumor-infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. We test H0: mNAR ≥15.6 vs HA: mNAR <15.6 at alpha 0.10 one-sided with statistical significance defined as p<0.1. Results: From May 2018 to October 2020, 45 pts were enrolled with 40 pts evaluable for mNAR. Mean mNAR was 12.03 (80% CI: 9.29-14.97) (p=0.06 one-sided). pCR=22.2%; cCR=31.1%; R0 resection=81.0%, and sphincter preservation=71.4%. Side effects were consistent with both CRT and durvalumab safety profile. Most common grade 3 AEs included diarrhea, lymphopenia, and back pain. There was one grade 4 AE (elevated amylase/lipase) and no grade 5 AEs. Remaining secondary and correlative immunologic end points are still being assessed. Conclusions: Durvalumab immediately following CRT prior to surgery for definitive management of rectal cancer was safe and without unexpected short-term toxicities. The primary end point of mean mNAR score was significantly less than our historical control, warranting further investigation. Correlative analyses for immunologic markers of response including PD-(L)1 expression and Immunoscore are ongoing. NCT 03102047. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.