Gemcitabine Hydrochloride, Paclitaxel, Oxaliplatin, High-Dose Chemotherapy, and Stem Cell Transplant in Treating Patients with Recurrent or Refractory Central Nervous System Germ Cell Tumors
This phase II trial studies how well gemcitabine hydrochloride, paclitaxel, oxaliplatin, high dose chemotherapy, and stem cell transplant work in treating patients with central nervous system germ cell tumors that have come back after a period of improvement or that have not responded to previous treatment. Drugs used in chemotherapy, such as gemcitabine hydrochloride, paclitaxel and oxaliplatin 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 helps kill any cancer cells that are in the body and helps make room in the patient’s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More 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. Giving gemcitabine hydrochloride, paclitaxel, oxaliplatin, high dose chemotherapy, and stem cell transplant may work better in treating patients with central nervous system term cell tumors.
- Patients must be enrolled before treatment begins; the date protocol therapy is to start must be no later than 42 days from the time of recurrence and within 7 days from enrollment
- CNS GCT including pure germinoma and MMGCT; patients with histologically proven germinoma and MMGCT, including endodermal sinus tumor (yolk sac tumor), embryonal carcinoma, choriocarcinoma and mixed germ cell tumor will be eligible for the study; patients with mature/immature teratoma who have tumor marker elevations are eligible on this study; patient with ONLY mature and/or immature teratoma are ineligible in the absence of the tumor marker elevations
- Lumbar CSF must be assayed for cytology, alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (HCGbeta); a quantitative serum determination of AFP and HCGbeta should be performed at the time of the lumbar CSF assay
- For the diagnosis of pure germinoma, HCGbeta (serum and CSF) must be =< 100 mIU/ml, serum AFP must be =< 10 IU/l (ng/ml) and =< institutional norm and initial CSF AFP =< 2 IU/l (ng/ml) and =< institutional norm with histologically proven diagnosis of germinoma at diagnosis or subsequent relapse
- For histologically unconfirmed MMGCT, serum and/or CSF tumor markers of HCGbeta > 100 mIU/ml or any elevation of above AFP > 10 IU/L (ng/ml) and/or above institutional norm in the serum and CSF AFP >= 2 IU/L (ng/ml) and/or institutional norm
- Patients with no elevations of serum and/or CSF HCGbeta and AFP must have histological diagnosis of malignant GCT or germinoma
- Patient must either have recurrence of CNS GCT or should be refractory to initial therapy
- Magnetic resonance imaging (MRI) scans of the brain and spine must be completed within 21 days prior to patient registration; all MRI scans should be with and without gadolinium
- All patients who do not have surgery performed must have MRI scans obtained prior to induction
- All patients who have surgery performed must have a cranial MRI pre-operative and post-operative (should be done within 72 hours of surgery or within 21 days following surgery)
- A MRI of the spine is required within 10 days prior to or at least 10 days after surgery
- Serum HCGbeta and AFP levels must be assessed within 7 days prior to registration
- Patient must have lumbar CSF for cytology, protein, AFP and HCGbeta within 7 days prior to registration
- Have a Karnofsky performance status greater than or equal to 50 for patients aged 16 years or older and a Lansky performance status greater than or equal to 50 for patients less than 16 years old
- Life expectancy must be >= 8 weeks
- Must not have received cytotoxic chemotherapy within 14 days of entry on to this study
- Patient must not have received any prior marrow-ablative chemotherapy and autologous hematopoietic cell transplant
- Patient must have not received gemcitabine, oxaliplatin and/or paclitaxel chemotherapy agents
- Must not have received any biological modifier within 14 days of entry on to this study
- At least 4 weeks for focal radiation therapy (RT) or >= 6 weeks for craniospinal RT must have elapsed prior to study entry
- Patient must have recovered from the surgery
- Corticosteroid therapy and endocrine replacement therapy (L-thyroxine, testosterone, estrogen, desmopressin acetate [DDAVP]) are permissible; any patient already receiving human growth replacement therapy should discontinue this prior to commencing chemotherapy, and should not restart until 3 years from diagnosis
- Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general supportive care are to be used as necessary
- Concomitant use of any enzyme inducing anticonvulsants is not allowed
- Absolute neutrophil count (ANC) greater than or equal to 750/mm^3
- Platelets (Plts) greater than or equal to 75,000/mm^3 (transfusion independent)
- Hemoglobin (Hgb) greater than 8.0 g/dL (may have packed red blood cell [PRBC] transfusion)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional upper limit of normal for age
- Total bilirubin =< 2 x institutional upper limit of normal for age
- Liver function test must be obtained within 14 days prior to registration
- Patients must have adequate renal function defined as < 1.5 x normal serum creatinine as adjusted for age: Age: < 5 years; maximum serum creatinine: 0.8 mg/dL Age: > 5 and < 10 years; maximum serum creatinine: 1.0 mg/dL Age: > 10 and < 15 years; maximum serum creatinine: 1.2 mg/dL Age: > 15 years; maximum serum creatinine: 1.5 mg/dL
- Or a calculated or measured creatinine clearance or radioisotope GFR >= 70ml/min/1.73m^2 obtained within 14 days prior to registration
- Patients who are pregnant or breast-feeding are not eligible; nursing mothers must agree not to breastfeed during therapy; females of childbearing potential must practice an effective method of birth control while participating in this study and for those who have achieved menarche, must have a negative pregnancy test prior to study entry
- All patients and/or their parents or legal guardians must sign a written informed consent
- All institutional and Food and Drug Administration (FDA) requirements for human studies must be met
- Patients with CNS GCTs who are newly diagnosed are excluded from the study
- Patients with the diagnosis of mature or immature teratoma in the absence of tumor marker elevations are excluded from the study
- Patients who are pregnant or breastfeeding are excluded from the study
- Patients who have received previously a high dose chemotherapy regimen and autologous transplant are excluded from this study
- Patients who have received gemcitabine, oxaliplatin and/or paclitaxel are excluded from this study
Locations & Contacts
Trial Objectives and Outline
I. To estimate response rate after at least two and up to four courses of induction chemotherapy with gemcitabine hydrochloride, paclitaxel, oxaliplatin (GemPOx) regimen in patients with recurrent central nervous system (CNS) mixed malignant germ cell tumors (MMGCT).
II. To estimate the rate of completion of induction chemotherapy and progression to high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell rescue (AuHPCR).
III. To assess the toxicity of GemPOx regimen in all patients with CNS germ cell tumor (GCT) (pure germinoma and MMGCT).
I. To correlate serum and cerebrospinal fluid (CSF) tumor marker (AFP and human chorionic gonadotropin beta [HCGbeta]) responses with radiographic response after two and/or four GemPOx cycles and also after HDC followed with AuHPCR.
II. To identify specific exosomal micro ribonucleic acid (RNA)s in the CSF specific for recurrent CNS GCT at study entry and to determine if decrease/disappearance of such CSF micro RNAs (MiRNAs) correlates with radiographic and/or tumor marker documentation of response to induction and consolidation therapies, and correlates with event-free survival.
III. To assess the overall survival (OS) and event-free survival (EFS) of patients treated on the GemPOx induction regimen followed by the HDC and AuHPCR in patients with progressive or recurrent CNS GCT.
IV. To determine the feasibility of peripheral hematopoietic stem cell mobilization with GemPOx induction regimen.
V. To evaluate the toxicity of HDC and AuHPCR following GemPOx induction.
INDUCTION TREATMENT: Patients receive paclitaxel intravenously (IV) over 3 hours, gemcitabine hydrochloride IV over 1 hours, and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 14 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients fail to achieve a sufficient response and do not have progression disease receive 2 additional courses for up to 4 courses.
CONSOLIDATION HDC TREATMENT: Patients receive carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3.
RE-INFUSION OF PERIPHERAL HPC: Patients undergo autologous hematopoietic stem cell transplantation on day 0.
After completion of study treatment, patients are followed up at 3, 6, 9, 12, 16, 20, 24, 30, and 36 months, and annually thereafter.
Trial Phase & Type
Nationwide Children's Hospital
Jonathan Lester Finlay
Secondary IDs NCI-2016-01836, 2016N0036
Clinicaltrials.gov ID NCT01270724