Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 16 of 1645 for:    Slovakia

Study of Gemcitabine, Carboplatin and VELIPARIB (ABT-888) in Refractory Testicular Germ Cell Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02860819
Recruitment Status : Recruiting
First Posted : August 9, 2016
Last Update Posted : April 5, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute, Slovakia

Brief Summary:
This is a proof-of-concept study to define efficacy of gemcitabine, carboplatin and VELIPARIB (ABT-888) in patients with refractory germ cell tumors (GCTs). PARP proteins are involved in base excision repair (BER), one of the major DNA repair system in cells and PARP is overexpressed in testicular GCTs (TGCTs) compared to normal testis and data suggest that 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). The aim of this study is to evaluate PARP inhibitor VELIPARIB in combination with gemcitabine, carboplatin in patients with refractory germ cell tumors (GCTs).

Condition or disease Intervention/treatment Phase
Testicular Cancer Drug: Veliparib Drug: Gemcitabine Drug: Carboplatin Phase 2

Detailed Description:

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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


Arm Intervention/treatment
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.
Drug: Veliparib
Veliparib 250mg BID, continuously
Other Name: ABT-888

Drug: Gemcitabine
Gemcitabine 800mg/m2, day 1 and 8

Drug: Carboplatin
Carboplatin AUC = 4, day 1




Primary Outcome Measures :
  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.


Secondary Outcome Measures :
  1. Response rate [ Time Frame: 6-weeks ]
    Response rate as measured by RECIST 1.1

  2. 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.

  3. 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.

  4. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed written informed consent
  2. Men aged 18 years or older
  3. ECOG performance status: 0-1,
  4. Histologically confirmed extracranial primary germ cell cancer, seminoma, or nonseminoma
  5. Rising serum markers (i.e., alpha-fetoprotein and human chorionic gonadotropin) on sequential measurement or biopsy-proven unresectable germ cell cancer
  6. Refractory GCTs e.g. patients relapsing after high-dose chemotherapy or for patients non fit enough for high-dose chemotherapy
  7. Primary mediastinal GCTs in first relapse
  8. Patient's disease must not be amenable to cure with either surgery or chemotherapy in the opinion of investigator,
  9. Measurable disease radiologically
  10. Adequate hematologic function defined by ANC > 1500/mm3, platelet count > 100 000/mm3 and hemoglobin level > 9g/dl.
  11. Adequate liver function defined by a total bilirubin level < 1.5 ULN, and ALT, AST < 3 ULN or < 5 in case of liver metastases. For subjects with Gilbert's syndrome bilirubin > 1.5 × ULN is allowed if no symptoms of compromised liver function are present
  12. Adequate renal function: measured or calculated (by Cockcroft formula) creatinine clearance > 50 ml/min. Cockcroft formula: CLcr = [(140-age) x weight(Kg)]/[72 x creatinine (mg/dl)]
  13. At least 4 weeks must have elapsed since the last radiotherapy and/or chemotherapy before study entry,
  14. At least 4 weeks must have elapsed since the last major surgery
  15. Complete recovery from prior surgery, and/or reduction of all adverse events from previous systemic therapy or radiotherapy to grade 1,
  16. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Exclusion Criteria:

  1. Patients who do not fit inclusion criteria
  2. Other prior malignancy except successfully treated nonmelanoma skin cancer
  3. Prior PARP1 inhibitor
  4. Other concurrent approved or investigational anticancer treatment, including surgery, radiotherapy, chemotherapy, biologic-response modifiers, hormone therapy, or immunotherapy
  5. Female patients
  6. Patients infected by the Human Immunodeficiency Virus (HIV)
  7. Patients with other severe acute or chronic medical condition, or laboratory abnormality that would impair, in the judgment of investigator, excess risk associated with study treatment, or which, in judgment of the investigator, would make the patient inappropriate for entry into this study
  8. Inability of oral intake, or drug absorption (e.g. malabsorption syndrome)
  9. Hypersensitivity to any compound of the drug
  10. Sexually active men not using highly effective birth control if their partners are women of child-bearing potential
  11. Patients with history of or current CNS metastasis
  12. Patients with history of seizures

Information from the National Library of Medicine

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


Contacts
Layout table for location contacts
Contact: Daniela Svetlovska, MD, PhD +421-2-59378 ext 592 daniela.svetlovska@nou.sk

Locations
Layout table for location information
Slovakia
National Cancer Institute Recruiting
Bratislava, Slovakia, 83310
Contact: Michal Mego, Assoc. Prof    +421259378 ext 366    michal.mego@nou.sk   
Contact: Jozef Mardiak, Prof    +421259378 ext 108    jozef.mardiak@nou.sk   
Principal Investigator: Jozef Mardiak, Prof         
Principal Investigator: Michal Mego, Assoc. Prof         
Sponsors and Collaborators
National Cancer Institute, Slovakia
Investigators
Layout table for investigator information
Study Chair: Michal Mego, Assoc.Prof National Cancer Institute (NCI)

Layout table for additonal information
Responsible Party: National Cancer Institute, Slovakia
ClinicalTrials.gov Identifier: NCT02860819     History of Changes
Other Study ID Numbers: GCTSK004
First Posted: August 9, 2016    Key Record Dates
Last Update Posted: April 5, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by National Cancer Institute, Slovakia:
Multiple relapsed/refractory testicular germ cell tumors
PARP inhibition
Chemotherapy
Gemcitabine
Carboplatin
Additional relevant MeSH terms:
Layout table for MeSH terms
Testicular Neoplasms
Neoplasms, Germ Cell and Embryonal
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
Endocrine System Diseases
Testicular Diseases
Gonadal Disorders
Neoplasms by Histologic Type
Gemcitabine
Carboplatin
Veliparib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Poly(ADP-ribose) Polymerase Inhibitors