Paclitaxel, Ifosfamide, and Carboplatin Followed By Autologous Stem Cell Transplant in Treating Patients With Germ Cell Tumors That Did Not Respond to Cisplatin

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00423852
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 26
• Location: 1
• Arm: 1
• Duration (Months): 78.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, ifosfamide, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. An autologous peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. This may allow more chemotherapy to be given so that more tumor cells are killed.

PURPOSE: This phase I/II trial is studying the side effects and best dose of ifosfamide when given together with paclitaxel and carboplatin followed by an autologous stem cell transplant and to see how well they work in treating patients with germ cell tumors that did not respond to cisplatin.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors; Extragonadal Germ Cell Tumor; Ovarian Cancer; Teratoma; Testicular Germ Cell Tumor	Biological: filgrastim; Drug: carboplatin; Drug: ifosfamide; Drug: paclitaxel; Procedure: autologous hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

• Determine the safety of paclitaxel and ifosfamide followed by dose-escalated, dose-intensive paclitaxel, carboplatin, and ifosfamide with autologous peripheral blood stem cell support in patients with cisplatin-resistant germ cell tumor. (Phase I)

• Determine the maximum tolerated dose of paclitaxel, carboplatin, and ifosfamide when given with a high-dose treatment program in these patients. (Phase I)

• Determine the efficacy of this regimen when given as salvage therapy in the second-line or third-line setting, in terms of complete response, in these patients. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of paclitaxel, carboplatin, and ifosfamide followed by a phase II, open-label study.

• Phase I:

• Paclitaxel, ifosfamide, and autologous peripheral blood stem cell (PBSC) collection: Patients receive paclitaxel IV over 3 hours on day 1 and ifosfamide IV over 2 hours on days 1-3. Patients undergo leukapheresis on days 11-13. Patients also receive filgrastim (G-CSF) subcutaneously (SC) twice daily beginning on day 3 and continuing until leukapheresis is completed. Beginning on day 14 or 21, patients may receive a second course of paclitaxel, ifosfamide, and G-CSF. Patients may also undergo additional leukapheresis.

• Paclitaxel, carboplatin, ifosfamide, and autologous PBSC transplantation: Patients receive paclitaxel IV over 3 hours, high-dose carboplatin IV over 30 minutes, and ifosfamide IV over 4 hours on days 1-3. Patients also receive G-CSF SC beginning on day 3 and continuing until blood counts recover. Patients undergo reinfusion of autologous PBSCs on day 5. Treatment repeats every 21-28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of paclitaxel, carboplatin, and ifosfamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive treatment as in phase I with paclitaxel, carboplatin, and ifosfamide at the MTD determined in phase I.

After completion of study treatment, patients are followed periodically for 1 year and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Sequential Paclitaxel/Ifosfamide Followed by Dose-Escalated, Dose-Intensive Carboplatin, Paclitaxel and Ifosfamide With Stem Cell Support in Cisplatin-Resistant Germ Cell Tumor Patients
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: chemotherapy with Stem Cell Support This is a phase I/II trial of sequential accelerated chemotherapy cycles with paclitaxel/ifosfamide and paclitaxel/ifosfamide and carboplatin administered with G-CSF and PBSC support. During phase I, carboplatin, ifosfamide, and paclitaxel will be dose escalated to determine the MTD. Additional patients will be enrolled in the Phase II portion of the study following the determination of the MTD of Ifosfamide and paclitaxel, to bring the total possible number of patients treated at the MTD to 38.

Biological: filgrastim; Drug: carboplatin; Drug: ifosfamide; Drug: paclitaxel; Procedure: autologous hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation

Outcome Measures

Primary Outcome Measures

1. Response [2 year]

   Response assessed at the completion of therapy (after four to five cycles of chemotherapy and after surgery if necessary) Complete Response (CR): A complete response is defined as one of the following: Complete disappearance of all clinical and radiographic and biochemical (normal AFP and HCG) evidence of disease for a minimum of 4 weeks (CR to chemotherapy). Complete disappearance of all biochemical evidence of disease with resection of residual radiographic masses that prove to be negative for residual GCT; this includes both mature teratoma and necrotic debris (CR to chemotherapy) for a minimum of 4 weeks. Complete disappearance of all biochemical evidence of disease with complete surgical excision of all residual radiographic masses that, if pathologically positive for residual malignant GCT, show margins to microscopically free of disease (CR to chemotherapy + surgery). Patients must be free of disease for a minimum of 4 weeks.

2. Maximum Tolerated Dose of Ifosfamide [4 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed germ cell tumor (GCT)

• Primary CNS GCT allowed

• Unidimensionally measurable disease OR elevated serum tumor markers (alpha-fetoprotein and/or human chorionic gonadotropin)

• Advanced disease

• Disease resistant to a cisplatin-based chemotherapy regimen (i.e., failed to achieve a durable complete response to cisplatin)

• Known residual disease after post-chemotherapy surgery allowed

PATIENT CHARACTERISTICS:

• Platelet count ≥ 100,000/mm^3

• WBC ≥ 3,000/mm^3

• Creatinine clearance > 50 mL/min (unless due to tumor obstructing the ureters)

• AST and ALT < 2 times upper limit of normal (ULN)

• Bilirubin < 1.5 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No active infection

• Negative serology for HIV type I and II, human T-lymphotropic virus type I and II, hepatitis B or C virus, syphilis, and cytomegalovirus

• Hepatitis C negative serology by RIBA or PCR

• Adequate medical condition for general anesthesia

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from recent surgery

• At least 3 weeks since prior chemotherapy

• No prior high-dose therapy with autologous bone marrow transplantation

• No other concurrent chemotherapy

• No other concurrent treatment (e.g., surgery or radiotherapy)

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

• Principal Investigator: Darren Feldman, 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: NCT00423852
• Other Study ID Numbers: 06-077; MSKCC-06077
• First Posted: Jan 18, 2007
• Last Update Posted: May 18, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Memorial Sloan Kettering Cancer Center: recurrent ovarian germ cell tumor; stage III ovarian germ cell tumor; stage IV ovarian germ cell tumor; recurrent malignant testicular germ cell tumor; adult central nervous system germ cell tumor; stage III malignant testicular germ cell tumor; stage II malignant testicular germ cell tumor; recurrent extragonadal non-seminomatous germ cell tumor; recurrent extragonadal seminoma; stage III extragonadal non-seminomatous germ cell tumor; stage III extragonadal seminoma; stage IV extragonadal non-seminomatous germ cell tumor; stage IV extragonadal seminoma; recurrent extragonadal germ cell tumor; adult teratoma; testicular immature teratoma; testicular mature teratoma
• Additional relevant MeSH terms: Neoplasms; Neoplasms, Germ Cell and Embryonal; Nervous System Neoplasms; Central Nervous System Neoplasms; Teratoma; Paclitaxel; Carboplatin; Ifosfamide

Study Results

Participant Flow

Arm/Group Title	Chemotherapy With Stem Cell Support
Arm/Group Description	This is a phase I/II trial of sequential accelerated chemotherapy cycles with paclitaxel/ifosfamide and paclitaxel/ifosfamide and carboplatin administered with G-CSF and PBSC support. During phase I, carboplatin, ifosfamide, and paclitaxel will be dose escalated to determine the MTD. Additional patients will be enrolled in the Phase II portion of the study following the determination of the MTD of Ifosfamide and paclitaxel, to bring the total possible number of patients treated at the MTD to 38. filgrastim carboplatin ifosfamide paclitaxel autologous hematopoietic stem cell transplantation peripheral blood stem cell transplantation
Period Title: Overall Study
STARTED	26
COMPLETED	23
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Chemotherapy With Stem Cell Support
Arm/Group Description	This is a phase I/II trial of sequential accelerated chemotherapy cycles with paclitaxel/ifosfamide and paclitaxel/ifosfamide and carboplatin administered with G-CSF and PBSC support. During phase I, carboplatin, ifosfamide, and paclitaxel will be dose escalated to determine the MTD. Additional patients will be enrolled in the Phase II portion of the study following the determination of the MTD of Ifosfamide and paclitaxel, to bring the total possible number of patients treated at the MTD to 38. filgrastim carboplatin ifosfamide paclitaxel autologous hematopoietic stem cell transplantation peripheral blood stem cell transplantation
Overall Participants	26
Age (Count of Participants)
<=18 years	1 3.8%
Between 18 and 65 years	25 96.2%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 3.8%
Male	25 96.2%
Region of Enrollment (participants) [Number]
United States	26 100%

Outcome Measures

1. Primary Outcome

Title	Response
Description	Response assessed at the completion of therapy (after four to five cycles of chemotherapy and after surgery if necessary) Complete Response (CR): A complete response is defined as one of the following: Complete disappearance of all clinical and radiographic and biochemical (normal AFP and HCG) evidence of disease for a minimum of 4 weeks (CR to chemotherapy). Complete disappearance of all biochemical evidence of disease with resection of residual radiographic masses that prove to be negative for residual GCT; this includes both mature teratoma and necrotic debris (CR to chemotherapy) for a minimum of 4 weeks. Complete disappearance of all biochemical evidence of disease with complete surgical excision of all residual radiographic masses that, if pathologically positive for residual malignant GCT, show margins to microscopically free of disease (CR to chemotherapy + surgery). Patients must be free of disease for a minimum of 4 weeks.
Time Frame	2 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chemotherapy With Stem Cell Support
Arm/Group Description	This is a phase I/II trial of sequential accelerated chemotherapy cycles with paclitaxel/ifosfamide and paclitaxel/ifosfamide and carboplatin administered with G-CSF and PBSC support. During phase I, carboplatin, ifosfamide, and paclitaxel will be dose escalated to determine the MTD. Additional patients will be enrolled in the Phase II portion of the study following the determination of the MTD of Ifosfamide and paclitaxel, to bring the total possible number of patients treated at the MTD to 38. filgrastim carboplatin ifosfamide paclitaxel autologous hematopoietic stem cell transplantation peripheral blood stem cell transplantation
Measure Participants	23
Complete Response (CR)	12 46.2%
Incomplete Response (IR)	6 23.1%
Partial Response (PR)	5 19.2%

2. Primary Outcome

Title	Maximum Tolerated Dose of Ifosfamide
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Chemotherapy With Stem Cell Support
Arm/Group Description	This is a phase I/II trial of sequential accelerated chemotherapy cycles with paclitaxel/ifosfamide and paclitaxel/ifosfamide and carboplatin administered with G-CSF and PBSC support. During phase I, carboplatin, ifosfamide, and paclitaxel will be dose escalated to determine the MTD. Additional patients will be enrolled in the Phase II portion of the study following the determination of the MTD of Ifosfamide and paclitaxel, to bring the total possible number of patients treated at the MTD to 38. filgrastim carboplatin ifosfamide paclitaxel autologous hematopoietic stem cell transplantation peripheral blood stem cell transplantation
Measure Participants	23
Number [mg/m2]	9990

Adverse Events

Arm/Group Title	Chemotherapy With Stem Cell Support
Arm/Group Description	This is a phase I/II trial of sequential accelerated chemotherapy cycles with paclitaxel/ifosfamide and paclitaxel/ifosfamide and carboplatin administered with G-CSF and PBSC support. During phase I, carboplatin, ifosfamide, and paclitaxel will be dose escalated to determine the MTD. Additional patients will be enrolled in the Phase II portion of the study following the determination of the MTD of Ifosfamide and paclitaxel, to bring the total possible number of patients treated at the MTD to 38. filgrastim carboplatin ifosfamide paclitaxel autologous hematopoietic stem cell transplantation peripheral blood stem cell transplantation
All Cause Mortality
	Chemotherapy With Stem Cell Support
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Chemotherapy With Stem Cell Support
	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)
Blood and lymphatic system disorders
Thrombosis/thrombus/embolism	1/26 (3.8%)	1
Edema: head and neck	1/26 (3.8%)	1
Cardiac disorders
Hypotension	1/26 (3.8%)	1
Immune system disorders
Allerg react/hypersens (incl drug fever)	1/26 (3.8%)	1
Infections and infestations
Infection w/ Gr 3/4 neut, Blood	1/26 (3.8%)	1
Inf norm ANC/gr1/2 neut-Catheter-related	1/26 (3.8%)	1
Metabolism and nutrition disorders
Potassium, low (hypokalemia)	1/26 (3.8%)	1
Febrile neutropenia	1/26 (3.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	1/26 (3.8%)	1
Other (Not Including Serious) Adverse Events
	Chemotherapy With Stem Cell Support
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Leukocytes (total WBC)	25/26 (96.2%)	100
Lymphopenia	26/26 (100%)	100
Neutrophils/granulocytes (ANC/AGC)	23/26 (88.5%)	100
PTT	3/26 (11.5%)	5
Platelets	25/26 (96.2%)	100
Cardiac disorders
Hypotension	5/26 (19.2%)	6
Ear and labyrinth disorders
Tinnitus	4/26 (15.4%)	4
Gastrointestinal disorders
Constipation	2/26 (7.7%)	2
Mucositis (Clin exam)- Oral cavity	2/26 (7.7%)	2
Mucositis (func/sympt)- Oral cavity	2/26 (7.7%)	2
Nausea	5/26 (19.2%)	6
Vomiting	5/26 (19.2%)	5
General disorders
Fatigue (asthenia, lethargy, malaise)	12/26 (46.2%)	20
Infections and infestations
Febrile neutropenia	7/26 (26.9%)	10
Infection, other	2/26 (7.7%)	2
Metabolism and nutrition disorders
ALT, SGPT	19/26 (73.1%)	63
AST, SGOT	11/26 (42.3%)	24
Albumin, low (hypoalbuminemia)	2/26 (7.7%)	2
Alkaline phosphatase	3/26 (11.5%)	3
Amylase	2/26 (7.7%)	5
Bilirubin (hyperbilirubinemia)	9/26 (34.6%)	14
Creatinine	9/26 (34.6%)	35
Glucose, high (hyperglycemia)	23/26 (88.5%)	115
Hemoglobin	25/26 (96.2%)	100
Magnesium, high (hypermagnesemia)	2/26 (7.7%)	2
Magnesium, low (hypomagnesemia)	18/26 (69.2%)	45
Phosphate, low (hypophosphatemia)	24/26 (92.3%)	100
Potassium, high (hyperkalemia)	3/26 (11.5%)	4
Potassium, low (hypokalemia)	12/26 (46.2%)	75
Sodium, high (hypernatremia)	2/26 (7.7%)	7
Sodium, low (hyponatremia)	8/26 (30.8%)	10
Lipase	4/26 (15.4%)	18
Nervous system disorders
Neuropathy: sensory	7/26 (26.9%)	12
Renal and urinary disorders
Renal failure	2/26 (7.7%)	2

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.