Rapid analysis and response evaluation of combination anti-neoplastic agents in rare tumors (RARE CANCER) trial: RARE 2 talazoparib and temozolomide.

3155 Background: Preclinical data generated from NIH/NCI Patient-Derived Models Repository (PDMR) demonstrated significant synergistic activity of talazoparib (a PARP inhibitor) combined with temozolomide (an alkylating agent) in patient-derived xenograft models of rare adult and pediatric cancers. This clinical trial aimed to evaluate the objective response (OR) rate of this combination in patients with advanced rare cancers in exploratory fashion. Correlatives include genomic and transcriptomic profiling of tumor tissue, circulating tumor DNA (ctDNA), circulating tumor cells, and assessments of apoptosis and epithelial-mesenchymal transition in relation to treatment activity. Methods: This open-label, non-randomized, phase 2 trial used a Simon two-stage design. Patients aged ≥18 years with advanced rare cancers received temozolomide (37.5 mg/m² orally, days 2–6) and talazoparib (750 mcg orally, daily) in 28-day cycles. Tumor response was assessed per RECIST v1.1, and adverse events (AEs) assessed using CTCAE v5.0. In the first stage, if 0/14 (across all histologies) responses are observed, the trial will be closed for futility. Otherwise, additional 16 patients were planned to be enrolled. There are no selection criteria based aside from rare tumor to allow for exploration of activity. Results: Fourteen patients were enrolled, all evaluable for response and toxicity. Median age was 57 years; 11 were female, and all had ECOG 0–1. Tumor histologies included uterine sarcoma (N = 3), cholangiocarcinoma (N = 2), and one each of adrenocortical carcinoma, adenoid cystic carcinoma, clear cell salivary carcinoma, MPNST, angiosarcoma, carcinoma of unknown primary, squamous urothelial carcinoma, small cell neuroendocrine carcinoma, and SDHB deficient renal cell carcinoma. Best responses included stable disease (N = 6), progressive disease (N = 5), and clinical progression (N = 3). One patient with clear cell salivary cancer and another with cholangiocarcinoma remained on treatment for 8 and 6 cycles, respectively. The median progression free survival is 3.81 months. The most common treatment related AEs (TRAEs) overall as well as ≥Grade 3 were hematologic including thrombocytopenia ( 13; ≥Grade 3 = 10), anemia (total12; ≥Grade 3 = 10), lymphopenia (total 12; ≥Grade 3 = 5), neutropenia (total 11; ≥Grade 3 = 6), and leukopenia (total 10, ≥Grade 3 = 4). No Grade 5 TRAEs were reported. Although none of the patients discontinued treatment due to TRAEs, planned dose reductions were needed for 7 patients. Conclusions: Despite promising preclinical activity, this tumor agnostic exploratory trial did not meet strict goal more design for single histology. Future efforts will focus on correlative analyses, exploring histology-specific expansion cohorts informed by preclinical response data, and optimizing dosing schedules to reduce overlapping toxicities. Clinical trial information: NCT05142241 .