Gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumours: The GCT-SK-004 phase II trial

• Published in: Investigational new drugs Vol. 39; no. 6; pp. 1664 - 1670
• Main Authors: Mego, M., Svetlovska, D., Reckova, M., Angelis, De, Kalavska, K., Obertova, J., Palacka, P., Rejlekova, K., Sycova-Mila, Z., Chovanec, M., Mardiak, J.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2021; Springer Nature B.V
• Subjects: Adult; Anemia; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzimidazoles - therapeutic use; Carboplatin; Carboplatin - therapeutic use; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Female; Gemcitabine; Humans; Kaplan-Meier Estimate; Male; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Neoplasms, Germ Cell and Embryonal - drug therapy; Neoplasms, Germ Cell and Embryonal - pathology; Neutropenia; Oncology; Patients; Pharmacology/Toxicology; Phase II Studies; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Progression-Free Survival; Remission; Ribose; Survival; Thrombocytopenia; Toxicity; Tumors; Young Adult; Refractory; Carboplatin; PARP; Gemcitabine; Germ cell tumours; Veliparib
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-021-01130-5

Summary
Background 
Patients with multiple relapsed/refractory germ cell tumours (GCTs) have an extremely poor prognosis. PARP (poly-ADP-ribose polymerase) is overexpressed in GCTs compared to normal testes, and PARP overexpression is an early event in GCT development. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and the PARP inhibitor veliparib in patients with multiple relapsed/refractory GCTs.
Methods 
Fifteen patients with multiple relapsed/refractory GCTs were enrolled in this phase II study from October 2016 to October 2020. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 every 3 weeks; carboplatin at a target AUC of 4 on day 1 every 3 weeks; and veliparib at a dose of 250 mg b.i.d. throughout. The primary end point was 12-month progression-free survival (PFS).
Results 
The median number of treatment cycles was 4 (range 2–8). Twelve-month PFS was achieved in 1 (6.7 %) patient. The median PFS was 3.1 months (95 % CI 2.2–3.9), and the median overall survival was 10.5 months (95 % CI 8.9–11.1). Partial remission was achieved in 4 (26.7 %) patients, and disease stabilization was observed in 5 (33.3 %) patients. A favourable response was achieved in 3 (20.0 %) patients. Treatment was well tolerated; however, 11 (73.3 %) patients experienced grade 3/4 neutropenia, 10 (66.7 %) experienced thrombocytopenia, 5 (33.3 %) anaemia and 2 (13.3 %) febrile neutropenia.
Conclusions 
This study failed to achieve its primary endpoint, and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib for multiple relapsed/refractory GCTs. ClinicalTrials.gov Identifier: NCT02860819, registered August 9, 2016.