Paclitaxel, Ifosfamide and Cisplatin (TIP) Versus Bleomycin, Etoposide and Cisplatin (BEP) for Patients With Previously Untreated Intermediate- and Poor-risk Germ Cell Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborators:
University of Southern California-James Hu, MD (national Co-PI)
Mayo Clinic
University of Pittsburgh
University of North Carolina
University of Chicago
Stanford University
University of Texas Southwestern Medical Center
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01873326
First received: June 5, 2013
Last updated: August 19, 2014
Last verified: August 2014
  Purpose

The purpose of this study is to learn about the safety and effectiveness of two different drug combinations in patients who have intermediate- and poor-risk germ cell tumors (GCT). One combination of drugs, paclitaxel, ifosfamide and cisplatin (TIP), is experimental. The other combination of drugs, bleomycin, etoposide and cisplatin (BEP), is the standard of care treatment for intermediate- and poor-risk germ cell tumors. However, BEP does not cure every patient and therefore newer treatments are needed.


Condition Intervention Phase
Germ Cell Tumors
Drug: Paclitaxel
Drug: Ifosfamide
Drug: Cisplatin
Drug: Mesna
Drug: Bleomycin
Drug: Etoposide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Paclitaxel, Ifosfamide and Cisplatin (TIP) Versus Bleomycin, Etoposide and Cisplatin (BEP) for Patients With Previously Untreated Intermediate- and Poor-Risk Germ Cell Tumors

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • favorable best response rate [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Favorable best response is defined as complete response or partial response with negative tumor markers. Patients will be considered evaluable for the primary endpoint of favorable response within the first 6 months if they complete at least 3 cycles of study treatment (without switch to an alternative chemotherapy regimen) and achieve a confirmed partial response with negative markers or confirmed complete response (considered as favorable responses). Patients will also be considered evaluable for the primary endpoint if they develop disease progression during the treatment portion of the study regardless of how many cycles of chemotherapy they received or if they achieve an incomplete response after completion of study treatment (considered as not having a favorable response)."


Secondary Outcome Measures:
  • overall best response [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Overall best response refers to the best response achieved by a patient to either TIP or BEP over the course of the entire study.

  • progression-free survival (PFS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Progression-free survival (PFS) will be calculated from the date of treatment start until disease progression, death, or last followup, whichever comes first. The following are included as PFS events: incomplete response (IR), relapse or disease progression, and death.

  • overall survival (OS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    Overall survival will be calculated from the date of treatment start until death, regardless of the cause.

  • toxicity [ Time Frame: 30 days after completion of the last cycle of chemotherapy. ] [ Designated as safety issue: Yes ]
    Toxicity will be assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The maximum grade of each toxicity will be recorded for each patient over the course of treatment (all cycles). Special emphasis will be placed on comparisons of the frequency of Grade 3/4 toxicities between the TIP and BEP arms.


Estimated Enrollment: 88
Study Start Date: June 2013
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Paclitaxel, Ifosfamide and Cisplatin (TIP)

Paclitaxel 120 mg/m2 IV over 120-180 min Days 1 and 2 (+/- 4 days)* Mesna 120 mg/m2 IV (duration of infusion per institutional guidelines) approximately 30 minutes prior to initiation of ifosfamide Days 1-5 (+/- 4 days)* Ifosfamide 1200 mg/m2 IV over approximately 60 to 120 min Days 1-5 or per institutional guidelines (mixed 1:1 with mesna) (+/- 4 days)* Mesna** 1200 mg/m2 IV over approximately 60-120 min or per institutional guidelines (mixed 1:1 with ifosfamide)(+/- 4 days)* Cisplatin 20 mg/m2 IV over approximately 30 min Days 1-5 (+/- 4 days)*

**Additional mesna may be given at the discretion of the investigator

*Paclitaxel or Ifosfamide or Mesna or Cisplatin or any combination of these agents can be held as needed for patient safety on a given day between days 1-5 but must be made up within 4 days to avoid a protocol violation.

Drug: Paclitaxel Drug: Ifosfamide Drug: Cisplatin Drug: Mesna
Active Comparator: Bleomycin, Etoposide and Cisplatin (BEP)

Cisplatin 20 mg/m2 IV over approximately 30 min Days 1-5 (+/- 4 days)* Etoposide 100 mg/m2 IV over approximately 1 hour Days 1-5 (+/- 4 days)* Bleomycin 30 U flat dose IV push Days 2, 8 and 15 (all +/- 4 days)

*Etoposide or Cisplatin or both can be held as needed for patient safety on a given day between days 1-5 but must be made up within 4 days to avoid a protocol violation.

Drug: Cisplatin Drug: Bleomycin Drug: Etoposide

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- Patients ≥ 18 years of age.

- Patients with newly diagnosed GCT

  • Pathology confirmation of GCT histology at MSKCC or a collaborating treating institution. In exceptional circumstances, patients without pathological diagnosis may be included in the study following discussion with the national principal investigator, Dr. Feldman,(or national Co-PI or MSKCC Co-PI if the national PI is unavailable) if they meet the one of the following criteria:

    • Patients with a testicular mass (detected clinically and/or by ultrasound), and/or mediastinal or retroperitoneal lymphadenopathy or pineal tumor AND elevated serum tumor markers (HCG and/or AFP). Patients with elevated LDH only will not be included without pathological confirmation of GCT since LDH is a nonspecific marker for GCT and could potentially be elevated in other malignancies such as lymphomas.

This is because patients may present with a clinical scenario consistent with GCT (elevated serum tumor markers, testicular mass and retroperitoneal lymphadenopathy) with a concurrent life-threatening oncologic emergency that require immediate treatment. In this case, initial treatment without biopsy confirmation is usually recommended and tissue confirmation may be obtained after initiating therapy.

  • Patients must have measurable or evaluable disease.
  • Patients who received prior radiation therapy (RT) for treatment of germ cell tumor are eligible for this study as long as there is evidence of progressive disease determined by tumor markers or other sites of metastases outside of the radiated site. Radiation must be completed prior to starting chemotherapy with the exception of brain metastases where chemotherapy and radiation can be given concurrently. Toxicity from radiation must have recovered to grade 1 or less prior to initiating chemotherapy.
  • Patients must have recovered from prior surgery based on treating physician's discretion.
  • Patients of reproductive potential must agree to use effective contraception during the period of therapy
  • Signed informed consent.
  • Diffusion lung capacity for carbon monoxide (DLCO) adjusted for hemoglobin ≥60% predicted, except if related to high volume metastatic GCT to the lungs in which case there is no minimum DLCO requirement. In some cases, patients may not be able to undergo PFT testing due to the severity of their presentation. such as those with high volume lung metastases or tumor-related pain (from large mediastinal masses, pleural disease, etc.) limiting their ability to complete PFTs. Since there is no minimum DLCO for these patients, under these extraordinary circumstances, this will be allowed. Most patients in this situation will be expected to receive disease-stabilizing chemotherapy. An unadjusted DLCO may be used in place of the DLCO adjusted for hemoglobin in certain situations as per institutional policy. For example, MSKCC policy is to not adjust the DLCO for hemoglobin when the hemoglobin is ≥ 14.6 g/dL for males and ≥ 13.4 g/dL for females. In these cases, the unadjusted DLCO must be >60% predicted.
  • Laboratory criteria for protocol entry (obtained ≤ 14 days before initiation of therapy):

    • WBC ≥ 3000/UL and Platelet count ≥ 100,000/UL
    • Serum creatinine ≤ 1.5 mg/dL or estimated GFR (by Cockcroft-Gault) ≥50mL/min or 12 or 24 hour urine creatinine clearance ≥ 50 mL/min, unless renal insufficiency is due to tumoral ureteral obstruction in which case eligibility will be determined by national the principal investigator (or national co-PI or MSKCC co-PI if the national PI is unavailable) with notification of the MSKCC IRB.
    • AST/ALT ≤ 3 x ULN and total bilirubin ≤ 2.0 x ULN. In the setting of metastatic disease to the liver, AST/ALT may be ≤5x ULN and total bilirubin ≤2.5 x ULN. If a patient is known or suspected to have Gilbert's disease, total bilirubin up to

      ≤2.5 x ULN is allowed..

Patients must be classified as having intermediate or poor-risk NSGCT, as follows:

o Intermediate-risk (Modified*)

a) Testis or retroperitoneal primary with lymph node and/or lung metastasis but without non-pulmonary visceral metastasis AND any of the following pretreatment serum tumor marker (STM) values:

i. Lactate dehydrogenase (LDH) from 3 to <10 x ULN (*This differs from the original IGCCCG criteria which includes patients with LDH from 1.5 to 10 x ULN).

ii. Serum human chorionic gonadotrophin (HCG) from 5,000 to < 50,000 MIU/mL

iii. Serum alpha-fetoprotein (AFP) from 1,000 to <10,000 ng/mL

  • Seminoma histology regardless the primary site or serum tumor markers with any non-pulmonary visceral metastasis (liver, bone, brain, etc)

    • Poor-risk (any of the following):

      1. Testis or retroperitoneal primary with non-pulmonary visceral metastasis (liver, bone, brain, etc) regardless the STM values.
      2. Mediastinal primary site of disease regardless the presence/absence of visceral metastasis or STM values.
      3. Testis or retroperitoneal primary without non-pulmonary visceral metastasis but with poor-risk STM values: i. LDH ≥ 10 x ULN ii. HCG ≥ 50,000 MIU/mL iii. AFP ≥ 10,000 ng/mL

Exclusion Criteria:

  • Any prior chemotherapy. The only exception will be patients with a history of stage I seminoma treated with adjuvant carboplatin for 1 or 2 cycles.
  • Concurrent treatment with any cytotoxic therapy.
  • Known concurrent malignancy (except for non-melanoma skin cancer).
  • Patients known to be HIV positive and receiving HAART.
  • Presence of an active infection. Patients with fever assessed to be "tumor fever" but without active evidence of infection (e.g. blood cultures are negative) are eligible. In addition, patients who have an infection but without evidence of fever for 48 hours on antibiotics will be eligible.
  • Inability to comply with the treatment protocol or to undergo prespecified follow-up tests for safety or effectiveness.
  • Pregnant patients are ineligible
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01873326

Contacts
Contact: Darren Feldman, MD 646-422-4491
Contact: Robert Motzer, MD 646-422-4312

Locations
United States, California
University of Southern California Not yet recruiting
Los Angeles, California, United States, 90033
Contact: James Hu, MD         
Principal Investigator: James Hu, MD         
Stanford University Medical Center Not yet recruiting
Stanford, California, United States, 94305-5408
Contact: Sandy Srinivas, MD         
Principal Investigator: Sandy Srinivas, MD         
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States
Contact: Walter Stadler, MD         
Principal Investigator: Walter Stadler, MD         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Brian Costello, MD         
Principal Investigator: Brian Costello, MD         
United States, New Jersey
Memoral Sloan Kettering Cancer Center Recruiting
Basking Ridge, New Jersey, United States
Contact: Darren Feldman, MD    646-422-4333      
United States, New York
Memorial Sloan-Kettering Cancer Center @ Suffolk Recruiting
Commack, New York, United States, 11725
Contact: Darren Feldman, MD    646-422-4491      
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Darren Feldman, MD    646-422-4491      
Contact: Robert Motzer, MD    646-422-4312      
Principal Investigator: Darren Feldman, MD         
Memorial Sloan-Kettering Cancer Center at Mercy Medical Center Recruiting
Rockville Centre, New York, United States, 11570
Contact: Darren Feldman, MD    646-422-4491      
Memoral Sloan Kettering Cancer Center@Phelps Memorial Hospital Recruiting
Sleepy Hollow, New York, United States
Contact: Darren Felman, MD    646-422-4491      
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Matthew I Milowsky, MD         
Principal Investigator: Matthew Milowsky, MD         
United States, Pennsylvania
University of Pittsburgh Medical Center Not yet recruiting
Pittsburg, Pennsylvania, United States, 15213
Contact: Leonard Appleman, MD         
Principal Investigator: Leonard Appelman, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
University of Southern California-James Hu, MD (national Co-PI)
Mayo Clinic
University of Pittsburgh
University of North Carolina
University of Chicago
Stanford University
University of Texas Southwestern Medical Center
Investigators
Principal Investigator: Darren Feldman, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01873326     History of Changes
Other Study ID Numbers: 13-074
Study First Received: June 5, 2013
Last Updated: August 19, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
newly diagnosed GCT
Intermediate
Poor-Risk
BLEOMYCIN
CISPLATIN
ETOPOSIDE (VP-16)
IFOSFAMIDE
TAXOL (PACLITAXEL)
13-074

Additional relevant MeSH terms:
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Mesna
Bleomycin
Etoposide phosphate
Isophosphamide mustard
Cisplatin
Etoposide
Ifosfamide
Paclitaxel
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Radiation-Sensitizing Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on August 26, 2014