Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.

INTRODUCTION: We report results from a phase I, three-part, dose-escalation study of peposertib, a DNA-dependent protein kinase inhibitor, in combination with avelumab, an immune checkpoint inhibitor, with or without radiotherapy in patients with advanced solid tumors. MATERIALS AND METHODS: Peposertib 100-400 mg twice daily (b.i.d.) or 100-250 mg once daily (q.d.) was administered in combination with avelumab 800 mg every 2 weeks in Part A or avelumab plus radiotherapy (3 Gy/fraction × 10 days) in Part B. Part FE assessed the effect of food on the pharmacokinetics of peposertib plus avelumab. The primary endpoint in Parts A and B was dose-limiting toxicity (DLT). Secondary endpoints were safety, best overall response per RECIST version 1.1, and pharmacokinetics. The recommended phase II dose (RP2D) and maximum tolerated dose (MTD) were determined in Parts A and B. RESULTS: In Part A, peposertib doses administered were 100 mg (n = 4), 200 mg (n = 11), 250 mg (n = 4), 300 mg (n = 6), and 400 mg (n = 4) b.i.d. Of DLT-evaluable patients, one each had DLT at the 250-mg and 300-mg dose levels and three had DLT at the 400-mg b.i.d. dose level. In Part B, peposertib doses administered were 100 mg (n = 3), 150 mg (n = 3), 200 mg (n = 4), and 250 mg (n = 9) q.d.; no DLT was reported in evaluable patients. Peposertib 200 mg b.i.d. plus avelumab and peposertib 250 mg q.d. plus avelumab and radiotherapy were declared as the RP2D/MTD. No objective responses were observed in Part A or B; one patient had a partial response in Part FE. Peposertib exposure was generally dose proportional. CONCLUSIONS: Peposertib doses up to 200 mg b.i.d. in combination with avelumab and up to 250 mg q.d. in combination with avelumab and radiotherapy were tolerable in patients with advanced solid tumors; however, antitumor activity was limited. GOV IDENTIFIER: NCT03724890.

Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.