Abstract 1385
Background
Hyper-radiation sensitivity is enhanced in cells with mutant p53, which is ubiquitous in high grade serous ovarian cancer (HGSOC). Preclinical data suggests LDWART is a “chemosensitizer” and enhances paclitaxel cytotoxicity. We evaluated the safety and activity of LDWART concurrent with wP (LDWART+wP) in PROC.
Methods
Patients (pts) with PROC (progressive disease (PD) < 6 mth from last platinum therapy) were enrolled in a 3 + 3 dose de-escalation (part A) design, combining wP concurrent with fixed dose LDWART in 60 cGy fractions (twice daily on D1-2 of each week of wP), for 6 continuous weeks. Planned dose levels of wP were 80mg/m2, 70mg/m2, 60mg/m2. After 6 weeks of LDWART+wP, pts received wP chemotherapy alone until PD. Dose expansion (part B) with up to 10 HGSOC pts at maximum tolerated dose (MTD) of LDWART+wP, proceeded to confirm toxicity and activity.
Results
As of 30/4/2019, 10 pts were enrolled (3 part A, 7 part B). All part B pts had HGSOC. Median lines of prior therapy was 5 (range 1-8), including prior wP in 70%, and prior bevacizumab (bev) in 50% of pts. There was no dose-limiting toxicity (DLT) at wP 80mg/m2 (DLT period = 1st 3 weeks of LDWART+wP), which was deemed the MTD. 6/10 pts completed 6 weeks of LDWART+wP. Discontinuations were due to PD (3/10) or pt withdrawal (1/10). Common related all-grade adverse events (AEs) were nausea (60%), neutropenia (60%), fatigue (60%), neuropathy (40%), diarrhea (30%); common related grade ≥3 AEs were neutropenia (50%) and anemia (20%). Median progression free survival was 3.2 mth and overall survival was 13.5 mth. 9 pts were evaluable for response. 44.4% (4/9) of pts achieved biochemical response, defined as CA125 decrease >50% from baseline, 2/4 were confirmed. 1 pt had partial response (PR) despite PD on prior wP, and 5 pts had stable disease (SD), giving an overall response rate of 11.1% (1/9) and disease control rate (PR + SD > 6 weeks) of 66.7% (6/9). 3 pts had durable disease control, and completed 12, 18 and 21 weeks of wP respectively.
Conclusions
LDWART+wP (80mg/m2) for 6 weeks was safe and tolerable. Encouraging efficacy was seen in this heavily pre-treated population and LDWART+wP may be useful in the context of PROC where bev is contraindicated.
Clinical trial identification
NCT02545010.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
RIE2015 National Medical Research Council, National University Cancer Institute Singapore (NCIS) Centre Grant – NCIS Seed Funding.
Disclosure
D.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. All other authors have declared no conflicts of interest.
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