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

Status: Recruiting
Phase: Phase 3
DFCI Protocol ID: 16-701

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.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Lindsay Frazier, MD, Brigham and Women's Hospital

Site-responsible Investigators:

Christopher Sweeney, Dana-Farber Cancer Institute

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org
Dana-Farber Cancer Institute: Meghara Walsh, 617-632-5264, mwalsh10@partners.org
Dana-Farber Cancer Institute: Judith Prisby, 617-632-5068, jprisby@partners.org
Dana-Farber Cancer Institute: Amanda Fredericks, 617-632-5514, acfredericks@partners.org

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.

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