Clinical Trials /

Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors

NCT02375204

Description:

This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

Related Conditions:
  • Germ Cell Tumor
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors
  • Official Title: A Randomized Phase III Trial Comparing Conventional-Dose Chemotherapy Using Paclitaxel, Ifosfamide, and Cisplatin (TIP) With High-Dose Chemotherapy Using Mobilizing Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin and Etoposide (TI-CE) as First Salvage Treatment in Relapsed or Refractory Germ Cell Tumors

Clinical Trial IDs

  • ORG STUDY ID: A031102
  • SECONDARY ID: U10CA180821
  • SECONDARY ID: NCI-2014-01696
  • NCT ID: NCT02375204

Conditions

  • Germ Cell Tumor
  • Teratoma
  • Choriocarcinoma
  • Germinoma
  • Mixed Germ Cell Tumor
  • Yolk Sac Tumor
  • Childhood Teratoma
  • Malignant Germ Cell Neoplasm
  • Extragonadal Seminoma
  • Non-seminomatous Germ Cell Tumor
  • Seminoma

Interventions

DrugSynonymsArms
paclitaxelTaxolArm A: TIP
ifosfamideIfex®, IFOSArm A: TIP
cisplatinCDDPArm A: TIP
pegylated G-CSFArm A: TIP
G-CSFArm A: TIP
carboplatinParaplatin®, CBDCAArm B: TI-CE
etoposide phosphateVePesid®, Toposar®, VP16Arm B: TI-CE

Purpose

This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

Detailed Description

      The study is an international collaboration with European sites. Collaborators on the study
      include the National Cancer Institute, the European Organization for Research and Treatment
      of Cancer and the Movember Foundation. Randomization will be stratified by region (North
      America and Europe) and by modified IPFSG (International Prognostic Factor Study Group) risk
      classification (low, intermediate and high). The primary and secondary objectives are
      described below.

      Primary Objective:

      1. To compare the overall survival in patients treated with conventional-dose chemotherapy
      using the TIP regimen with high-dose chemotherapy (HDCT) plus autologous stem cell transplant
      (ASCT) using the TI-CE regimen as initial salvage treatment of patients with relapsed or
      refractory germ cell tumors (GCT)

      Secondary Objectives:

        1. To compare the progression-free survival (PFS) of patients treated with initial salvage
           HDCT with TI-CE versus initial salvage CDCT with TIP

        2. To compare the favorable response rate (FRR) of patients treated with initial salvage
           HDCT with TI-CE versus initial salvage CDCT with TIP

        3. To compare the toxicity, including treatment-related mortality, associated with
           high-dose chemotherapy and ASCT using TI-CE compared with conventional-dose chemotherapy
           using TIP as initial salvage treatment for patients with relapsed or refractory GCT

        4. To prospectively evaluate the IPFSG scoring system as a predictor of outcome to initial
           salvage therapy in patients with relapsed or refractory GCT. In this trial,
           randomization will be stratified by a modification of their IPFSG category and we will
           prospectively evaluate whether or not actual outcomes vary by risk group in the
           appropriate manner (low risk patients have higher OS than high-risk group).

        5. To evaluate the association between tumor marker decline rates of Alpha-Fetoprotein
           (AFP) and Human Chorionic Gonadotropin (HCG) with OS and PFS.

      Treatment is to continue until disease progression, unacceptable toxicity or completion of
      all protocol treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: TIPOtherPatients will receive treatment for 4 cycles administered every 21 days. Cycles 1-4 (1 cycle = 21 days) paclitaxel 250 mg/m^2 IV over 24 hours on Day 1 including premedication as defined in the protocol (eg, dexamethasone, diphenhydramine and H2 blocker) ifosfamide 1500 mg/m^2 IV daily on Days 2-5 with mesna protection as defined in the protocol cisplatin 25 mg/m^2 IV daily on Days 2-5 pegylated G-CSF 6 mg subcutaneous on Day 6 or 7 or G-CSF as defined in the protocol on Days 6-18 Patients may commence with each Arm A cycle provided they meet the criteria as defined in the protocol.
  • paclitaxel
  • ifosfamide
  • cisplatin
  • pegylated G-CSF
  • G-CSF
Arm B: TI-CEOtherPatients will receive treatment for a total of 5 cycles. Cycles 1-2 (1 cycle = 14 days) paclitaxel 200 mg/m^2 IV over 3 hours on Day 1 including premedication as defined in the protocol (eg, dexamethasone, diphenhydramine and H2 blocker) ifosfamide 2000 mg/m^2 IV daily on Days 1-3 with mesna protection as defined in the protocol G-CSF 10 µg/kg subcutaneously on Days 3-15 (cycle 1) and Days 3-14 (cycle 2) or pegylated G-CSF 6 mg subcutaneous on Day 4 or 6 (cycle 1) and Day 4 or 5 (cycle 2) leukapheresis every 14 days, if there is an inadequate number of CD34+ cells/kg collected in cycle 1 Cycles 3-5 (1 cycle = 21 days) carboplatin daily on Days 1-3 etoposide 400 mg/m^2 daily on Days 1-3 stem cell reinfusion on day 5 pegylated G-CSF 6 mg subcutaneously or G-CSF at approximately 5 µg/kg daily on Days 5-15 Patients may commence with each Arm B cycle provided they meet the criteria as defined in the protocol.
  • paclitaxel
  • ifosfamide
  • pegylated G-CSF
  • G-CSF
  • carboplatin
  • etoposide phosphate

Eligibility Criteria

        1. Documentation of Disease

               -  Histologic Documentation: Confirmation of GCT histology (both seminoma and
                  nonseminoma) on pathologic review at the center of enrollment.

               -  Tumor may have originated in any primary site. NOTE: In rare circumstances,
                  patients will be allowed to enroll even if a pathologic diagnosis may not have
                  been established.

               -  This would require a clinical situation consistent with the diagnosis of GCT
                  (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor
                  marker levels {HCG ≥ 500; AFP ≥ 500} and typical pattern of metastases)

          2. Evidence of Disease

               -  Must have evidence of progressive or recurrent GCT (measurable or non-measurable)
                  following one line of cisplatin-based chemotherapy, defined as meeting at least
                  one of the following criteria:

                    -  Tumor biopsy of new or growing or unresectable lesions demonstrating viable
                       non-teratomatous GCT (enrollment on this study for adjuvant treatment after
                       macroscopically complete resection of viable GCT is not allowed). In the
                       event of an incomplete gross resection where viable GCT is found, patients
                       will be considered eligible for the study.

                    -  Consecutive elevated serum tumor markers (HCG or AFP) that are increasing.
                       Increase of an elevated LDH alone does not constitute progressive disease.

                    -  Development of new or enlarging lesions in the setting of persistently
                       elevated HCG or AFP, even if the HCG and AFP are not continuing to increase.

          3. Prior Treatment

               -  Must have received 3-6 cycles of cisplatin-based chemotherapy as part of
                  first-line (initial) chemotherapy.

                    -  Prior POMBACE, CBOP-BEP, or GAMEC are allowed.

                    -  Note: For patients requiring immediate treatment, 1 cycle of
                       conventional-dose salvage chemotherapy is allowed. Therefore, these patients
                       may have received 7 prior cycles of chemotherapy. 6 cycles as part of
                       first-line chemotherapy and 1 cycle of salvage conventional chemotherapy.

               -  No more than one prior line of chemotherapy for GCT (other than the 1 cycle of
                  salvage chemotherapy as defined in the protocol)

                    -  Definition of one line of chemotherapy: One line of therapy can in some
                       cases consist of 2 different cisplatin-based treatment combinations,
                       provided there is no disease progression between these two regimens.

                    -  Prior treatment with carboplatin as adjuvant therapy is allowed, provided
                       patients meet other eligibility criteria (e.g., the patient has also
                       received 3-4 cycles of cisplatin-based chemotherapy).

                    -  Prior treatment with 1-2 cycles of BEP or EP as adjuvant chemotherapy for
                       early stage GCT is allowed, provided the patient also received 3-4 cycles of
                       BEP or EP again at relapse. Patients treated with 3-4 cycles of VIP at
                       relapse following 1-2 cycles of BEP/EP are not eligible as this would be
                       considered more than 1 line of prior therapy.

               -  No prior treatment with high-dose chemotherapy (defined as treatment utilizing
                  stem cell rescue)

               -  No prior treatment with TIP with the exception when given as a bridge to
                  treatment on protocol for patients with rapidly progressive disease who cannot
                  wait to complete the eligibility screening process. Only one cycle is allowed.

               -  No concurrent treatment with other cytotoxic drugs or targeted therapies.

               -  No radiation therapy (other than to the brain) within 14 days of day 1 of
                  protocol chemotherapy except radiation to brain metastases, which must be
                  completed 7 days prior to start of chemotherapy.

               -  No previous chemotherapy within 17 days prior to enrollment. A minimum of three
                  weeks after the last day of the start of the previous chemotherapy regimen before
                  the first day of chemotherapy on study protocol.

               -  Must have adequate recovery from prior surgery (eg, healed scar, resumption of
                  diet)

          4. Age ≥ 14 years (≥ 18 years in Germany)

          5. ECOG Performance Status 0 to 2

          6. Male gender

          7. Required Initial Laboratory Values:

               -  Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3

               -  Platelet Count ≥ 100,000/mm^3

               -  Calculated creatinine clearance ≥ 50 mL/min

               -  Bilirubin ≤ 2.0 x upper limits of normal (ULN)

               -  AST/ALT ≤ 2.5 x upper limits of normal (ULN)

          8. No concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive
             (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell
             neoplasia. Patients with a prior malignancy, but at least 2 years since any evidence
             of disease are allowed.

          9. Negative Serology (antibody test) for the following infectious diseases:

               -  Human Immunodeficiency Virus (HIV) type 1 and 2

               -  Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in
                  Canada and Europe)

               -  Hepatitis B surface antigen

               -  Hepatitis C antibody

         10. No late relapse with completely surgically resectable disease. Patients with late
             relapses (defined as relapse ≥ 2 years from the date of completion of the last
             chemotherapy regimen) whose disease is completely surgically resectable are not
             eligible. Patients with late relapses who have unresectable disease are eligible.

         11. No large (≥ 2 cm) hemorrhagic or symptomatic brain metastases until local treatment
             has been administered (radiation therapy or surgery). Treatment may begin ≥ 7 days
             after completion of local treatment. Patients with small (< 2 cm) and asymptomatic
             brain metastases are allowed and may be treated with radiation therapy and/or surgery
             concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated.

             Radiation therapy should not be given concurrently with high-dose carboplatin or
             etoposide.

         12. No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant
             transformation) when it is actively part of the disease recurrence or progression.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:14 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:overall survival
Time Frame:Up to 36 months post-treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:progression free survival
Time Frame:Up to 36 months post-treatment
Safety Issue:
Description:
Measure:proportion of patients achieving either a complete response (CR) or partial response
Time Frame:Up to 3 months post-registration
Safety Issue:
Description:
Measure:treatment related mortality
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:
Measure:number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:Up to 3 months post-registration
Safety Issue:
Description:
Measure:Validation of International Prognostic Factor Study Group stratification system (eg, primary site, prior response, progression free interval)
Time Frame:Up to 3 years post-registration
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Last Updated

March 6, 2018