Study of Gemcitabine, Carboplatin and VELIPARIB (ABT-888) in Refractory Testicular Germ Cell Cancer
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|ClinicalTrials.gov Identifier: NCT02860819|
Recruitment Status : Recruiting
First Posted : August 9, 2016
Last Update Posted : April 5, 2019
|Condition or disease||Intervention/treatment||Phase|
|Testicular Cancer||Drug: Veliparib Drug: Gemcitabine Drug: Carboplatin||Phase 2|
PARP proteins are involved in base excision repair (BER), one of the major DNA repair system in cells. Recently, it was showed that PARP inhibitors have striking efficacy in patients with BRCA1 deficient or triple negative breast cancer in monotherapy or in combination with cisplatin based chemotherapy, without increased systemic toxicity. Pertubations affecting homologous recombination (HR) involved in DNA repair are associated with higher probability of response to PARP inhibitors. Inactivation of PTEN, tumor suppressor protein, is associated with defects in HR and response to PARP inhibitors.
Recently, PARP expression was evaluated in TGCTs. It was showed that PARP is overexpressed in testicular germ cell tumours compared to normal testis and PARP overexpression is early event in TGCTs development. Patients with low PARP expression in primary tumour had non-significantly better OS compared to patients with high PARP expression (5-year OS 89.2% vs 78.7%; HR=0.50, 95% CI 0.21 to 1.17, p=0.12).Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in testicular tumor development, but is associated with progression of disease. Previously, it was showed, that testicular germ cell tumors cell lines have low activity of proteins involved in nuclear excision repair (NER) and it is assumed that low NER activity is related to the favorable response of testis tumors to cisplatin-based chemotherapy.
Gemcitabine and carboplatin showed activity in refractory TGCTs. Recently, maximal tolerated dose of Veliparib (ABT-888) with gemcitabine and carboplatin was established.
Based on aforementioned data, there is strong rationale to inhibit PARP in TGCT. Inactivation of PARP by Veliparib along with defects of homologous recombination due to PTEN inactivation in GCTs and low activity of nucleotide excision repair system will dramatically increase antitumor effect gemcitabine and carboplatin in patients with progressing or relapsing germ cell cancer.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||43 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Gemcitabine, Carboplatin and VELIPARIB (ABT-888) in Refractory Testicular Germ Cell Cancer|
|Study Start Date :||July 2016|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||December 2019|
Experimental: Gemcitabine, Carboplatin, Veliparib
Gemcitabine 800mg/m2 day 1 and 8 every 3 weeks; Carboplatin AUC = 4, day 1, every 3 weeks, Veliparib 250mg bid day continuously.
Veliparib 250mg BID, continuously
Other Name: ABT-888
Gemcitabine 800mg/m2, day 1 and 8
Carboplatin AUC = 4, day 1
- Percentage of patients that will be free of disease progression according to RECIST criteria 12-months after the first administration of the treatment. [ Time Frame: 12-months ]Percentage of patients that will be free of disease progression according to RECIST criteria 12-months after the first administration of the treatment.
- Response rate [ Time Frame: 6-weeks ]Response rate as measured by RECIST 1.1
- Median overall survival [ Time Frame: 12 months ]Median overall survival. Overall survival will be measured from the date of first administration of the treatment until death or date of last follow-up.
- Median progression-free survival [ Time Frame: 12-months ]Median progression-free survival. Progression-free survival will be measured from the date of first administration of the treatment until progression, death or date of last follow-up.
- Frequency of grade III and IV adverse events [ Time Frame: 3-weeks ]Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02860819
|Contact: Daniela Svetlovska, MD, PhD||+421-2-59378 ext firstname.lastname@example.org|
|National Cancer Institute||Recruiting|
|Bratislava, Slovakia, 83310|
|Contact: Michal Mego, Assoc. Prof +421259378 ext 366 email@example.com|
|Contact: Jozef Mardiak, Prof +421259378 ext 108 firstname.lastname@example.org|
|Principal Investigator: Jozef Mardiak, Prof|
|Principal Investigator: Michal Mego, Assoc. Prof|
|Study Chair:||Michal Mego, Assoc.Prof||National Cancer Institute (NCI)|