Timothy A. Yap, MD @MDanderson #ESMO20 #advancedsolidtumors Rucaparib + Sacituzumab Govitecan: Initial Data From the Phase 1b/2 SEASTAR Study

Timothy A. Yap, MD @MDanderson #ESMO20 #advancedsolidtumors Rucaparib + Sacituzumab Govitecan: Initial Data From the Phase 1b/2 SEASTAR Study

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Timothy A. Yap, MD of MD Anderson discusses ESMO 2020 Poster: Rucaparib + Sacituzumab Govitecan: Initial Data From the Phase 1b/2 SEASTAR Study (NCT03992131) SEASTAR study presented at ESMO.


SUMMARY 
Initial promising signs of antitumor activity were seen in patients with advanced solid tumors (n=6) with the combination of rucaparib + sacituzumab govitecan, including patients with prior polymerase inhibitor exposure (ADP-ribose) and without deleterious homologous recombination repair gene mutation.

* Despite premature toxicity, all 6 patients
* Continued treatment with successful treatment of emergent adverse reactions
* Controlled with dose adjustment and/or help for the growth factor
* Further consideration of the mixture is justified.

INTRODUCTION
* Preclinically, highly synergistic antitumor effects were demonstrated by poly(ADP-ribose) polymerase (PARP) inhibitors such as rucaparib and DNA topoisomerase I (TOP1) inhibitors such as irinotecan, but clinical development was hindered by conflicting toxicities 1-5
* Tumour-targeted delivery of a TOP1 inhibitor will reduce the combination's systemic toxicity.
* Sacituzumab govitecan is an antibody-drug conjugate consisting of an antiTrop-2 antibody coupled via a proprietary hydrolysable linker66 to the active metabolite of irinotecan (SN-38).
* An open-label, parallel-arm analysis of the PARP inhibitor rucaparib in combination with other anticancer agents explains the safety, tolerability, and preliminary efficacy of rucaparib + sacituzumab govitecan in the SEASTAR analysis.

* Eligible patients had metastatic triple-negative for the phase 1b portion
* Patients with breast, urothelial or platinum-resistant ovarian cancer; patients with
* With another strong type of tumor with a deleterious homologous mutation
(BRCA1, BRCA2, PALB2, RAD51C, or RAD51C) recombination repair (HRR) gene
RAD51D) were qualified, too, prior treatment with a PARP inhibitor was permitted; patients previously treated with any formulation of irinotecan, topotecan, or any derivative were exempt.
* A 3 + 3 model with a starting dose of 300 mg rucaparib orally twice daily + 6 mg/kg sacituzumab govitecan intravenously on days 1 and 8 of the 21-day period was used in cohort 1
* During cycle 1, dose-limiting toxicities (DLTs) were evaluated
* Except during the DLT era, haematopoietic growth factor support was enabled.
* The key phase 1b endpoints were the occurrence of grade 3 or 4 treatment-emergent adverse effects (TEAEs) and the number of DLTT participants.
* A primary-secondary endpoint was an objective response evaluated by the investigator per
* Criteria for Response Evaluation In Solid Tumors, version 1.1 (RECIST)

OUTCOMES
In 2 dose cohorts, six patients were enrolled; demographics, history of illness, and on-study outcomes for each patient.
Two out of three patients in cohort 1 encountered dose-limiting neutropenia grade 4

Throughout Cycle 1
* In Cohort 2, the starting dose of rucaparib was lowered from 300 mg twice daily to 300 mg once daily; grade 3/4 neutropenia resulted in a 1-2 week delay in cycle 2 in all 3 patients.
* All 6 patients were able to continue treatment for at least 12 weeks, with TEAEs controlled by interruption of treatment, reduction of dose and/or growth factor support.
* As of the data cutoff date, one patient remains on treatment (11 Aug 2020)
* Summaries of data on protection and efficacy

FINALLY
Both patients had the best or better response to a stable illness.
There was a confirmed partial response in three patients; all 3 patients had been
PARP inhibitor (2 niraparib, 1 veliparib) was previously studied before
Advancement of disease
There was no documented deleterious HRR gene mutation in two respondents: 1 patient had metastatic, triple-negative breast cancer and 1 patient had high-grade metastatic serous ovarian cancer.
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