Clinical Trials /

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

NCT02860819

Description:

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).

Related Conditions:
  • Malignant Germ Cell Tumor
  • Seminoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Gemcitabine, Carboplatin and VELIPARIB (ABT-888) in Refractory Testicular Germ Cell Cancer
  • Official Title: Phase II Study of Gemcitabine, Carboplatin and VELIPARIB (ABT-888) in Refractory Testicular Germ Cell Cancer

Clinical Trial IDs

  • ORG STUDY ID: GCTSK004
  • NCT ID: NCT02860819

Conditions

  • Testicular Cancer

Interventions

DrugSynonymsArms
VeliparibABT-888Gemcitabine, Carboplatin, Veliparib
GemcitabineGemcitabine, Carboplatin, Veliparib
CarboplatinGemcitabine, Carboplatin, Veliparib

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
Gemcitabine, Carboplatin, VeliparibExperimentalGemcitabine 800mg/m2 day 1 and 8 every 3 weeks; Carboplatin AUC = 4, day 1, every 3 weeks, Veliparib 250mg bid day continuously.
  • Veliparib
  • Gemcitabine
  • Carboplatin

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Response rate
Time Frame:6-weeks
Safety Issue:
Description:Response rate as measured by RECIST 1.1
Measure:Median overall survival
Time Frame:12 months
Safety Issue:
Description: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.
Measure:Median progression-free survival
Time Frame:12-months
Safety Issue:
Description: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.
Measure:Frequency of grade III and IV adverse events
Time Frame:3-weeks
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute, Slovakia

Trial Keywords

  • Multiple relapsed/refractory testicular germ cell tumors
  • PARP inhibition
  • Chemotherapy
  • Gemcitabine
  • Carboplatin

Last Updated

April 4, 2019