Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Germ Cell Tumors

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00002558
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 108
• Location: 1
• Arm: 1
• Duration (Months): 183
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, ifosfamide, carboplatin, and etoposide work in different ways to stop the growth of tumor cells, either by killing them or by stopping them from dividing. Giving chemotherapy with a peripheral stem cell transplant may allow more chemotherapy to be given so that more tumor cells are killed.

The design of this trial is a phase I/II trial of sequential accelerated chemotherapy cycles with taxol/ifosfamide and carboplatin/etoposide administered with G-CSF and PBSC support.

PURPOSE: The purpose of this study is to determine the effects of an intensive sequence of chemotherapy drugs in patients with metastatic germ cell cancer. All of these chemotherapy drugs are known to be active in this disease.

Condition or Disease	Intervention/Treatment	Phase
Extragonadal Germ Cell Tumor; Ovarian Cancer; Testicular Germ Cell Tumor	Biological: filgrastim; Drug: carboplatin; Drug: etoposide; Drug: ifosfamide; Drug: paclitaxel; Procedure: peripheral blood stem cell transplantation	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

• Determine the safety of paclitaxel and ifosfamide followed by carboplatin and etoposide with stem cell support in patients with unfavorable germ cell tumors with unfavorable prognostic factors and resistance to cisplatin.

• Determine the efficacy of this regimen as salvage therapy in these patients.

• Escalate the dose of carboplatin based on a target area under the concentration time curve and renal function, and determine the pharmacokinetics of carboplatin in selected patients.

• Determine the qualitative effects of paclitaxel and ifosfamide on hematopoietic progenitors in these patients.

OUTLINE: This is a dose escalation study of carboplatin.

• Part A: Patients receive paclitaxel IV continuously on day 1 and ifosfamide IV over 4 hours on days 2-4. Autologous peripheral blood stem cells (PBSC) are harvested on days 11-13. Filgrastim (G-CSF) is administered subcutaneously (SC) twice daily beginning 6 hours after completion of paclitaxel and ifosfamide infusions and continuing until the last day of leukapheresis. Treatment continues every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Before beginning the first course of chemotherapy, autologous bone marrow (ABM) is harvested, if possible, in case insufficient peripheral blood stem cells (PBSC) are harvested. Patients who were unable to undergo harvest of ABM before the first course of chemotherapy undergo harvest of ABM before beginning the second course of chemotherapy.

• Part B : Beginning 2 weeks after completion of regimen A, patients receive etoposide IV over 2 hours and carboplatin IV over 1 hour on days 1-3. PBSC are reinfused on day 5. G-CSF is administered SC twice daily beginning 6 hours after completion of etoposide and carboplatin infusions and continuing until blood counts recover. G-CSF is held on the morning of PBSC transplantation and restarted beginning 6 hours after completion of PBSC transplantation. Treatment continues every 2 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients with insufficient PBSC for the second course receive PBSC combined with ABM. Patients with insufficient PBSC for the third course receive ABM.

During the second part, cohorts of 3-6 patients receive escalating doses of carboplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 6 patients experience dose-limiting toxicity.

After completion of parts A and B, some patients may undergo resection of residual masses.

Study Design

• Study Type: Interventional
• Actual Enrollment: 108 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PHASE I/II TRIAL OF SEQUENTIAL TAXOL/IFOSFAMIDE AND DOSEINTENSIVE CARBOPLATIN/ETOPOSIDE WITH STEM CELL SUPPORT IN CISPLATIN-RESISTANT GERM CELL TUMOR PATIENTS WITH UNFAVORABLE PROGNOSTIC FEATURES
• Study Start Date: Jan 1, 1994
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: chemotherapy administered with G-CSF and PBSC support The design of this trial is a phase I/II trial of sequential accelerated chemotherapy cycles with taxol/ifosfamide and carboplatin/etoposide administered with G-CSF and PBSC support.	Biological: filgrastim; Drug: carboplatin; Drug: etoposide; Drug: ifosfamide; Drug: paclitaxel; Procedure: peripheral blood stem cell transplantation

Outcome Measures

Primary Outcome Measures

1. Overall Objective Response [2 years]

   Overall Objective Response will be assessed prior to dose-intensive therapy and at the completion of therapy. Complete disappearance of all clinical, radiographic and biochemical (normal AFP and HCG) evidence of disease for a minimum of 4 weeks (CR to chemotherapy). Patients must be free of disease for a minimum of 4 weeks. Partial Response: Complete disappearance of all biochemical evidence of disease in patients without a surgical procedure for a residual radiographic mass. Patients must demonstrate no biochemical recurrence or progression of radiographic masses for a minimum of four weeks (PR to chemotherapy}

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Male/Female with histologically confirmed GCT with review by the Department of Pathology at this center.

• Patients with advanced GCT, including patients with:

measurable or evaluable disease,

• patients with only elevated serum tumor markers (AFP and/or HCG), or

• patients with known residual disease after postchemotherapy surgery. Eligible patients must have established clinical resistance to cisplatin by their failure to achieve a durable CR to a cisplatin-based regimen.

• Prior treatment limited to ≤ 6 prior cycles (≤ four cycles preferred) of cisplatin. (GROUP A)

• Prior therapy > 6 cycles of cisplatin. (GROUP B)

• Therapy must have been discontinued at least 3 weeks before entry onto protocol.

• Patients must have one or more unfavorable prognostic factors for achieving a CR to cisplatin-based salvage therapy. These are:

• Extragonadal primary site.

• Testis/ovarian primary site with the best response of an IR to first-line therapy, or a partial response with normal tumor markers of six months or less in duration.

• Prior treatment with ifosfamide-containing therapy

• General medical condition sufficient to allow for general anesthesia at the time of pheresis catheter placement.

• Patients must have negative serology for Human Immunodeficiency Virus.

• Laboratory criteria for protocol entry:

WBC ≥ 3000/ul Platelets 3 100,000/ul Cr Clearance > 50 cc/min*

• (unless renal dysfunction is due to tumor obstructing the ureters in which case eligibility will be determined by the Principal Investigator).

• Age ≥ 15 years.

• Signed informed consent.

Exclusion Criteria:

• Presence of active infection

• Concurrent treatment with chemotherapy or

• Inability to comply with the treatment protocol or to undergo the specified follow-up tests for safety or effectiveness.

• Prior high-dose therapy with AuBMT.

• Patients must have recovered from recent surgery.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• National Cancer Institute (NCI)

Investigators

• Study Chair: Gnanamba V. Kondagunta, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT00002558
• Other Study ID Numbers: 93-162; P30CA008748; MSKCC-93162; NCI-V94-0407
• First Posted: Jan 27, 2003
• Last Update Posted: May 23, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Memorial Sloan Kettering Cancer Center: recurrent malignant testicular germ cell tumor; recurrent ovarian germ cell tumor; extragonadal germ cell tumor
• Additional relevant MeSH terms: Neoplasms; Neoplasms, Germ Cell and Embryonal; Paclitaxel; Etoposide; Carboplatin; Ifosfamide

Study Results

Participant Flow

Arm/Group Title	Group A	Group B
Arm/Group Description	Group A: Prior Treatment Limited to <= 6 Cycles of Cisplatin	Group B: Prior Treatment Limited to > 6 Cycles of Cisplatin
Period Title: Overall Study
STARTED	92	16
COMPLETED	92	15
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Group A	Group B	Total
Arm/Group Description	Group A: Prior Treatment Limited to <= 6 Cycles of Cisplatin	Group B: Prior Treatment Limited to > 6 Cycles of Cisplatin	Total of all reporting groups
Overall Participants	92	16	108
Age (Count of Participants)
<=18 years	3 3.3%	0 0%	3 2.8%
Between 18 and 65 years	89 96.7%	16 100%	105 97.2%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 2.2%	1 6.3%	3 2.8%
Male	90 97.8%	15 93.8%	105 97.2%

Outcome Measures

1. Primary Outcome

Title	Overall Objective Response
Description	Overall Objective Response will be assessed prior to dose-intensive therapy and at the completion of therapy. Complete disappearance of all clinical, radiographic and biochemical (normal AFP and HCG) evidence of disease for a minimum of 4 weeks (CR to chemotherapy). Patients must be free of disease for a minimum of 4 weeks. Partial Response: Complete disappearance of all biochemical evidence of disease in patients without a surgical procedure for a residual radiographic mass. Patients must demonstrate no biochemical recurrence or progression of radiographic masses for a minimum of four weeks (PR to chemotherapy}
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A	Group B
Arm/Group Description	Group A: Prior Treatment Limited to <= 6 Cycles of Cisplatin	Group B: Prior Treatment Limited to > 6 Cycles of Cisplatin
Measure Participants	91	15
Complete Response (CR)	50 54.3%	4 25%
Incomplete Response (IR)	36 39.1%	8 50%
Partial Response (PR)	5 5.4%	3 18.8%

Adverse Events

Arm/Group Title	Group A: <= 6 Cycles of Cisplatin		Group: B > 6 Cycles of Cisplatin
Arm/Group Description	Group A: Prior Treatment Limited to <= 6 Cycles of Cisplatin		Group B: Prior Treatment Limited to > 6 Cycles of Cisplatin
All Cause Mortality
	Group A: <= 6 Cycles of Cisplatin		Group: B > 6 Cycles of Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group A: <= 6 Cycles of Cisplatin		Group: B > 6 Cycles of Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/92 (7.6%)		2/16 (12.5%)
Cardiac disorders
Hypotension	0/92 (0%)	0	1/16 (6.3%)	1
Gastrointestinal disorders
Diarrhea	0/92 (0%)	0	1/16 (6.3%)	1
General disorders
Febrile neutropenia	1/92 (1.1%)	1	0/16 (0%)	0
Syncope	1/92 (1.1%)	1	0/16 (0%)	0
Infections and infestations
Catheter related infection	0/92 (0%)	0	1/16 (6.3%)	1
Infection	0/92 (0%)	0	1/16 (6.3%)	1
Nervous system disorders
CNS hemorrhage	1/92 (1.1%)	1	0/16 (0%)	0
Neurology, other	1/92 (1.1%)	1	0/16 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary, other	3/92 (3.3%)	3	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	Group A: <= 6 Cycles of Cisplatin		Group: B > 6 Cycles of Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/92 (100%)		15/16 (93.8%)
Blood and lymphatic system disorders
Hemoglobin (Hgb)	92/92 (100%)	92	15/16 (93.8%)	15
Hemorrhage, other	0/92 (0%)	0	1/16 (6.3%)	1
Leukocytes	90/92 (97.8%)	90	15/16 (93.8%)	15
Lymphopenia	91/92 (98.9%)	91	15/16 (93.8%)	15
Neutrophils	89/92 (96.7%)	89	15/16 (93.8%)	15
Platelets	89/92 (96.7%)	89	15/16 (93.8%)	15
Prothrombin time (PT)	16/92 (17.4%)	16	1/16 (6.3%)	1
Partial thromboplastin time (PTT)	10/92 (10.9%)	10	3/16 (18.8%)	3
SGOT (AST)	17/92 (18.5%)	17	0/16 (0%)	0
SGPT (ALT)	24/92 (26.1%)	24	2/16 (12.5%)	2
Cardiac disorders
Erythema multiforme	5/92 (5.4%)	5	0/16 (0%)	0
Hypotension	6/92 (6.5%)	6	2/16 (12.5%)	2
Ear and labyrinth disorders
Hearing, other	0/92 (0%)	0	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal pain/cramping	8/92 (8.7%)	8	0/16 (0%)	0
Constipation	0/92 (0%)	0	1/16 (6.3%)	1
Diarrhea	8/92 (8.7%)	8	3/16 (18.8%)	3
Vomiting	10/92 (10.9%)	10	2/16 (12.5%)	2
General disorders
Alopecia	0/92 (0%)	0	1/16 (6.3%)	1
Edema	0/92 (0%)	0	1/16 (6.3%)	1
Fatigue	22/92 (23.9%)	22	2/16 (12.5%)	2
Fever	26/92 (28.3%)	26	4/16 (25%)	4
Pain, other	7/92 (7.6%)	7	0/16 (0%)	0
Infections and infestations
Catheter-related infection	6/92 (6.5%)	6	3/16 (18.8%)	3
Infection with grade 3/4 neutopenia	5/92 (5.4%)	5	1/16 (6.3%)	1
Metabolism and nutrition disorders
Alkaline phosphatase	16/92 (17.4%)	16	3/16 (18.8%)	3
Bilirubin	23/92 (25%)	23	4/16 (25%)	4
Creatinine	8/92 (8.7%)	8	3/16 (18.8%)	3
Hyperglycemia	80/92 (87%)	80	12/16 (75%)	12
Hyperkalemia	12/92 (13%)	12	0/16 (0%)	0
Hypermagnesmia	0/92 (0%)	0	1/16 (6.3%)	1
Hypernatremia	0/92 (0%)	0	2/16 (12.5%)	2
Hypertriglyceridemia	0/92 (0%)	0	1/16 (6.3%)	1
Hypoalbuminemia	12/92 (13%)	12	3/16 (18.8%)	3
Hypocalcemia	51/92 (55.4%)	51	11/16 (68.8%)	11
Hypoglycemia	19/92 (20.7%)	19	2/16 (12.5%)	2
Hypokalemia	44/92 (47.8%)	44	8/16 (50%)	8
Hypomagnesemia	65/92 (70.7%)	65	10/16 (62.5%)	10
Hyponatremia	30/92 (32.6%)	30	4/16 (25%)	4
Hypophosphatemia	63/92 (68.5%)	63	13/16 (81.3%)	13
Nervous system disorders
Dizziness	0/92 (0%)	0	1/16 (6.3%)	1
Neuropathy-sensory	0/92 (0%)	0	2/16 (12.5%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/92 (0%)	0	1/16 (6.3%)	1
Dyspnea	6/92 (6.5%)	6	2/16 (12.5%)	2
Thrombosis	7/92 (7.6%)	7	0/16 (0%)	0
Skin and subcutaneous tissue disorders
Dermatology, skin other	7/92 (7.6%)	7	1/16 (6.3%)	1
Rash, desquamation	0/92 (0%)	0	1/16 (6.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.