Based on findings from a study looking at niraparib plus cytotoxic agents, investigators have commenced a combination study of the niraparib plus temozolomide and irinotecan triplet in patients with pretreated Ewing sarcoma.
The phase 1 SARC025 study (NCT02044120) of the PARP1/2 inhibitor niraparib (Zejula) in combination with either temozolomide (Temodar) or irinotecan in patients with pretreated Ewing sarcoma (ES) suggested that either combination was tolerable when dose adjustments were made.
Based on these findings, SARC025 study has commenced a triple-combination study of niraparib plus temozolomide and irinotecan in this patient population.
“On the basis of preclinical data suggesting maximum synergy with the 3 agents, we hypothesize that with lower doses of all 3 agents, there may be less hematologic and gastrointestinal toxicity with the potential for synergistic efficacy,” noted the study authors who were led by Rashmi Chugh, MD. “However, whether this will offer any advantage over higher dose, standard temozolomide and irinotecan therapy remains to be determined.”
Patients enrolled in arm 1 of the study received continuous niraparib daily and escalating temozolomide on days 2 through 6 in cohort A; patients in cohort B received intermittent dosing of niraparib; and in cohort C, re-escalation of temozolomide was used. Patients enrolled in arm 2 were assigned to niraparib on days 1 through 7 and escalating doses of irinotecan on days 2 through 6.
From July 2014 to May 2018, a total of 29 eligible patients, including 23 men and 6 women, were enrolled in arms 1 and 2; there were 7 different dose levels combined. Overall, 5 patients experienced at least 1 dose-limiting toxicity (DLT) in arm 1 (grade 4 neutropenia for over a week or grade 4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (colitis, anorexia, and alanine aminotransferase elevation, all grade 3 in severity).
The maximum tolerated dose was found to be 200 mg of niraparib every day on days 1 through 7 plus temozolomide at 30 mg/m2 every day on days 2 through 6 in arm 1 or niraparib at 100 mg every day on days 1 through 7 plus irinotecan at 20 mg/m2 every day on days 2 through 6 in arm 2.
In arm 1, patients received a median of 2 cycles (range, 1-3) with a median progression-free survival (PFS) of 9.0 weeks (95% CI, 7.0-10.1 weeks). In arm 2, patients received a median of 2 therapy cycles (range, 1-16), of whom 1 patient achieved a partial response, for an objective response rate of 8.33%, and 6 patients had stable disease. The median PFS in arm 2 was 16.3 weeks (95% CI, 5.1-69.7). Notably, only 2 patients remained on study for more than 1 year, at 16 and 18 months, respectively).
Another objective of the current study was to determine the feasibility of obtaining tumor biopsies in a patient population that included both children and adults and their use for pharmacodynamic and biomarker analysis. However, not all institutional review boards approved of an on-treatment biopsy in those under 18 years, so these were required only in adult patients.
Overall, the approach was deemed to be feasible and acceptable to patients and their families, with 21 of the 29 patients (72%) undergoing pretreatment biopsies, including 2 patients who were under the age of 18 years. Further, 15 of the 29 patients (52%) were also able to undergo on-treatment biopsies, with exceptions made for patients with medical contraindications or those coming off the study before the biopsy time point.
“This was comparable to data observed in other trials of PARP inhibitors and thus supported the niraparib dosing strategy in arm 2, and it provided reassurance for ongoing study conduct,” wrote the authors. “An additional correlative analysis including PARP expression, Schlafen 11, and R-loops, recently reported as being determinants of PARP and irinotecan sensitivity, is ongoing as part of a wider analysis and will be reported separately.”
Chugh R, Ballman KV, Helman LJ, et al. SARC025 arms 1 and 2: a phase 1 study of the poly (ADP-ribose) polymerase inhibitor niraparib with temozolomide or irinotecan in patients with advanced Ewing sarcoma. Cancer. December 8, 2020. doi: 10.1002/cncr.33349