(P 143) A PHASE 1 B LEAD-IN TO A RANDOMIZED PHASE 2 TRIAL OF LURBINECTEDIN PLUS DOXORUBICIN IN LEIOMYOSARCOMA (LMS): RESULTS FROM THE PHASE 1B SOFT-TISSUE SARCOMA (STS) LEAD-IN

Objective: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in patients (pts) with metastatic LMS. However, objective response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) binds to DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin; trabectedin is FDA-approved for the treatment of LMS. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was well-tolerated, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D in pts with STS, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS.

Methods: Pts age > 18 years with locally advanced or metastatic, unresectable non-GIST STS (Phase 1b only), without prior anthracycline or lurbinectedin/trabectedin exposure, ECOG PS < 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing includes a fixed dose of lurbinectedin (3.2 mg/m2 day 1) and two dose levels (DL) of doxorubicin (DL1: 25 mg/m2 day 1 only; DL2 25 mg/m2 day 1 and day 8). The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). A minimum of 6 pts must be treated at the recommended Phase 2 dose (RP2D). Tumor assessments are conducted every two cycles. Once the RP2D is confirmed, Phase 2 will be initiated. Fifty pts with LMS will be randomized 1:1 to receive doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance.

Results: In DL1, 3 pts were enrolled and there were no DLT’s. In DL2, 1/3 pts experienced a DLT in the first cohort (G3 neutropenia on day 8). A 4th pt was enrolled at this DL and experienced a DLT (G2 ALT increase on day 8). Three additional slots have opened for DL1 confirmation. Other than the DLT’s above, no other grade 3 or 4 AEs have occurred. AEs have been typical for doxorubicin or lurbinectedin, including grade 1-2 nausea and fatigue.

Response assessments are available for 6 pts at the time of this abstract. Two patients have demonstrated RECIST 1.1 partial response (PR, -54% [undifferentiated pleomorphic sarcoma] and -43% [LMS]) and 3 pts with SD (-21% [LMS], -7% [endometrial stromal sarcoma], -6% [LMS]). All 5 pts with PR or SD have had disease control for 3 months or more. One patient experienced progressive disease as best response.

Updated safety and response data will be provided at the time of the meeting.

Conclusion: Lurbinectedin plus doxorubicin is well-tolerated and has demonstrated signals of efficacy in pts with STS. The RP2D will be determined based on the safety outcomes of the remaining Phase 1b pts. We anticipate the randomized Phase 2 study will open in Q3 2022.

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