For patients with metastatic, unresectable bone and soft-tissue sarcomas, trabectedin plus olaparib had acceptable safety and tolerability, a phase 1b study dubbed TOMAS reported (ClinicalTrials.org Identifier: NCT02398058).1 Olaparib is a poly(ADP-ribose) polymerase-1 and polymerase-2 (PARP1/2) inhibitor.2 The trial findings were reported online September 11, 2018, in Lancet Oncology.

The open-label, multicenter trial enrolled 50 adults from the national Italian sarcoma network between 2014 and 2017. Eligible patients had histologically confirmed bone and soft-tissue sarcomas that did not respond to standard treatment.

Per the standard 3 + 3 dose-escalation design, patients received a 24-hour infusion of trabectedin on day 1 and olaparib orally twice a day in 21-day cycles across 6 dose levels (trabectedin 0.675-1.3 mg/m² every 3 weeks; olaparib 100-300 mg twice a day from day 1 to 21).

Twenty-eight patients were in the dose-escalation phase and 22 in the dose-expansion phase. A median of 4 cycles of treatment were administered (IQR 2-6; range, 1-17). Overall, 47 patients discontinued treatment (44 for progressive disease, 2 for surgery, and 1 at patient’s request) and 3 patients remained on treatment at last follow-up.

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Across all dose levels, lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase concentration increase (18%) were the most common grade 3 or grade 4 adverse events. No treatment-related life-threatening adverse events or deaths were reported. Dose-limiting toxicities included thrombocytopenia and neutropenia.

The study met its primary end point, establishing a recommended phase 2 dose of trabectedin 1.1 mg/m² every 3 weeks plus olaparib 150 mg twice a day. Seven patients had a partial response, which was the best response achieved.

“The combination was tolerable and we observed an acceptable toxicity profile at drug concentrations deemed active,” the study authors wrote. “Although preliminary, the proportion of patients who achieved an overall response and the duration of response were both encouraging.”

Separate phase 2 studies are now planned to assess trabectedin plus olaparib in ovarian cancer and soft tissue sarcoma.

Authors of a corresponding editorial wrote, “We agree with the authors’ call for further investigation of trabectedin and olaparib in a randomised phase 2 trial in soft tissue sarcoma.” 2

References

  1. Grignani G, D’Ambrosio L, Pignochino Y, et al. Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group [published online September 11, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30438-8
  2. Nacev BA and Tap WD. TOMAS: revisiting PARP inhibitor combination therapy [published online September 11, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30494-7