ActivePhase 3ACTRN12618001236280

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

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

Sponsor

Alliance for Clinical Trials in Oncology

Enrollment

420 participants

Start Date

Sep 28, 2018

Study Type

Interventional

Conditions

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

Summary

The purpose of this study is to determined how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplants in patients with germ cell tumours. Who is it for? You may be eligible for this study if you are 14 years and older and have a germ cell tumour that have either improved or not responded to treatment. Study details Participants will be randomised to one of two treatments: 1. Standard dose chemotherapy: included 4 cycles of chemotherapy every 21 days (including paclitaxel, ifosfamide, cisplatin and pegylated G-CSF). 2. High dose chemotherapy and stem cell transplants: including 2 cycles of chemotherapy (including paclitaxel, ifosfamide and pegylated G-CSF) and 3 cycles of chemotherapy (including carboplantin, etoposide and pegylated G-CSF) plus stem cell therapy. Drugs used in chemotherapy such as those used in this study work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing or by stopping them spreading. Those in the high dose group will also be receiving stem cell transplants which should replace the blood-forming cells destroyed in chemotherapy. Blood tests and other physical examinations will be conducted throughout the trial. It is hoped that this research will determine whether high dose combination chemotherapy and stem cell transplants are more effective than standard dose combination chemotherapy in patients with refractory or relapsed germ cell tumours.

Eligibility

Sex: MalesMin Age: 14 Yearss

Inclusion Criteria42

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 pathological 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 greater than or equal to 500; AFP greater than or equal to 500} and typical pattern of metastases)
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.
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)
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)
Age more than 14 years or above (more than 18 years or above in Germany)
ECOG Performance Status 0 to 2
Male gender
Required Initial Laboratory Values:
Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mm^3
Platelet Count greater than or equal to 100,000/mm^3
Calculated creatinine clearance greater than or equal to 50 mL/min
Bilirubin less than or equal to 2.0 x upper limits of normal (ULN)
AST/ALT less than or equal to 2.5 x upper limits of normal (ULN)
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.
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
No late relapse with completely surgically resectable disease. Patients with late relapses (defined as relapse 2 or more 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.
No large (2 cm or more) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery). Treatment may begin 7 days or more 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.
No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression.

Exclusion Criteria11

Prior treatment with high-dose chemotherapy
Prior treatment with TIP
cycle of Prior TIP is allowed as bridge to the protocol
Prior radiation within 14 days
Prior chemotherapy within 16 days (bleomycin within 5 days)
Inadequate recovery from prior surgery
Concurrent malignancy
Large hemorrhagic or symptomatic brain metastases
Become eligible 7 days or more after local treatment (surgery or RT)
Fully resectable late relapse (2 years or more before relapse)
Concurrent malignancy

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Interventions

Arm A: TIP Arm A therapy will consist of 4 cycles of Paclitaxel, Ifosfamide, Cisplatin and Pegylated G-CSF administered every 21 days (+/- 4 days) as follows: - Paclitaxel: 250 mg/m^2 IV over 24

Arm A: TIP Arm A therapy will consist of 4 cycles of Paclitaxel, Ifosfamide, Cisplatin and Pegylated G-CSF administered every 21 days (+/- 4 days) as follows: - Paclitaxel: 250 mg/m^2 IV over 24 hours on Day 1 *Premedication (refers to the minimum allowed but institutional protocols administering additional or more intensive prophylaxis are allowed) *Dexamethasone: 20 mg orally approximately 14 (12-24) hours and 7 (6-9) hours before paclitaxel (taken by the patient at home the night before and morning of day 1 or 20 mg IV 30-60 minutes prior to the initiation of the paclitaxel infusion. *Diphenhydramine: 25 to 50 mg IVPB 30-60 minutes prior to paclitaxel. Oral can be substituted but must be given 60 minutes prior to paclitaxel. An equivalent H1 blocker (e.g., hydroxyzine) can be substituted for diphenhydramine. *H2 blocker: Ranitidine, Cimetidine, and Famotidine are acceptable, given orally 60 minutes prior or by IVPB 30-60 minutes prior to paclitaxel. - Ifosfamide: 1500 mg/m^2 IV daily on Days 2-5 with mesna protection *Mesna: 1500 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration. - Cisplatin 25 mg/m^2 IV daily on Days 2-5 - Pegylated Granulocyte Colony Stimulating Factor (G-CSF) 6 mg subcutaneous on Day 6, 7 or 8 (as determined by the investigator). - Hydration guidelines: At least one liter of normal saline prior to the initiation of cisplatin. Hydration should consist of normal saline infused at 100 mL/hr and continue throughout the 5 days of chemotherapy. At least one liter of normal saline should be given post the last dose of cisplatin. Hydration can be modified per institutional guidelines. - Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or Ciprofloxacin 500mg twice daily by mouth should be given from days 7 to 13 of each cycle for infectious prophylaxis. Arm B: TI-CE Arm B therapy will consist of 2 cycles (cycles 1-2) of Paclitaxel, Ifosfamide, and G-CSF folled by leukapheresis every 14 days. Then 3 cycles (cycles 3-5) of carboplatin, etoposide, stem cell reinfusion, and Pegylated G-CSF every 21 days. CYCLE 1 (14-21 days):- - Paclitaxel 200 mg/m^2 IV over 3 hours on Day 1 including pre-medication as defined above in Arm A (i.e. dexamethasone, diphenhydramine and H2 blocker) - Ifosfamide 2000 mg/m^2 IV daily on Days 1-3 with mesna protection *Mesna: 2000 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration. - G-CSF 10 µg/kg subcutaneously daily 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) - Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or Ciprofloxacin 500mg twice daily by mouth should be given from days 6 to 10. - Leukapheresis starting on day 11 (or earlier based on assessment of circulating CD34+ cells at the discretion of the investigator) and continued daily until reaching the target CD34+ cell collection of = 8 x 106 CD34+ cells/kg) or day 15, whichever occurs first. CYCLE 2 (14-21 days):- - Paclitaxel 200 mg/m2 IV over 3 hours on Day 1 including pre-medication as defined above (i.e. dexamethasone, diphenhydramine and H2 blocker) - Ifosfamide 2000 mg/m^2 IV daily on Days 1-3 with mesna protection *Mesna: 2000 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration. - G-CSF 10 µg/kg subcutaneously daily 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) - Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or Ciprofloxacin 500mg twice daily by mouth should be given from days 6 to 10. - Leukapheresis starting on day 11 (or earlier based on assessment of circulating CD34+ cells at the discretion of the investigator) and continued daily until reaching the target CD34+ cell collection of = 8 x 106 CD34+ cells/kg) or day 15, whichever occurs first. CYCLE 3-5 ( 21- 28 days each) Cycle 3 should start between 14 and 21 days after the start of cycle 2, with goal of starting as close to 14 days as possible. - Carboplatin: Area Under-the-Curve=8 daily intravenously on Days 1-3 (dose to be calculated by investigator depending on age of patient). - Etoposide 400 mg/m^2 daily on Days 1-3 *Hydration: dilute etoposide in 0.9 NS during infusion with hydration according to institution guidelines. - Stem cell re-infusion on day 5 (= 2 x 106 CD34+ cells/kg) *Hydration: NS 300 mL/hr 3 hours prior to re-infusion and for a minimum of 3 hours post re-infusion. - Pegylated G-CSF 6 mg subcutaneously 6 to 24 hours after completion of stem cell re-infusion. Or G-CSF at approximately 5 µg/kg daily on Days 5-15 - Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or Ciprofloxacin 500mg twice daily by mouth should be given from days 7 to 15 or ANC recovery to greater than or equal to 1.0. - Anti-fungal prophylaxis: is not required but may be given at the discretion of the treating investigator and institution - Additional antimicrobial prophylaxis (PCP, antiviral, antifungal, etc.) is not required but may be given at the discretion of the treating investigator and institution All medication will be administered under the supervision of a medical clinician or research nurse. This will ensure that all patients adhere to administered study medication.