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

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ClinicalTrials.gov Identifier: NCT01873326
Recruitment Status : Active, not recruiting
First Posted : June 10, 2013
Last Update Posted : September 29, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
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 or disease Intervention/treatment Phase
Germ Cell Tumors Drug: Paclitaxel Drug: Ifosfamide Drug: Cisplatin Drug: Mesna Drug: Bleomycin Drug: Etoposide Phase 2

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 92 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : June 2013
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :
  1. favorable best response rate [ Time Frame: 6 months ]
    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 :
  1. overall best response [ Time Frame: 3 years ]
    Overall best response refers to the best response achieved by a patient to either TIP or BEP over the course of the entire study.

  2. progression-free survival (PFS) [ Time Frame: 3 years ]
    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.

  3. overall survival (OS) [ Time Frame: 3 years ]
    Overall survival will be calculated from the date of treatment start until death, regardless of the cause.

  4. toxicity [ Time Frame: 30 days after completion of the last cycle of chemotherapy. ]
    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.

Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 must be classified as having intermediate or poor-risk germ cell tumor, as follows:

    • Intermediate-risk (Modified*) a) Testis or retroperitoneal primary NSGCT 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 b) 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 NSGCT primary with non-pulmonary visceral metastasis (liver, bone, brain, etc) regardless the STM values.
    2. Mediastinal NSGCT primary site of disease regardless the presence/absence of visceral metastasis or STM values.
    3. Testis or retroperitoneal NSGCT 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

    • 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. Even when PFTs can be completed in these cases, patients will still be eligible if the low DLCO can be attributed directly to the patient's disease (e.g., large mediastinal mass) rather than intrinsic lung disease. 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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01873326

United States, California
University of Southern California
Los Angeles, California, United States, 90033
Stanford University Medical Center
Stanford, California, United States, 94305-5408
United States, Illinois
University of Chicago
Chicago, Illinois, United States
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New Jersey
Memoral Sloan Kettering Cancer Center
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, United States, 07748
United States, New York
Memorial Sloan Kettering Cancer Center @ Suffolk
Commack, New York, United States, 11725
Memorial Sloan Kettering Westchester
Harrison, New York, United States, 10604
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Memorial Sloan Kettering Cancer Center at Mercy Medical Center
Rockville Centre, New York, United States, 11570
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27514
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
University of Southern California
Mayo Clinic
University of Pittsburgh
University of North Carolina
University of Chicago
Stanford University
University of Texas Southwestern Medical Center
Principal Investigator: Darren Feldman, MD Memorial Sloan Kettering Cancer Center
More Information

Additional Information:
Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01873326     History of Changes
Other Study ID Numbers: 13-074
First Posted: June 10, 2013    Key Record Dates
Last Update Posted: September 29, 2017
Last Verified: September 2017

Keywords provided by Memorial Sloan Kettering Cancer Center:
newly diagnosed GCT

Additional relevant MeSH terms:
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Etoposide phosphate
Isophosphamide mustard
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Protective Agents
Physiological Effects of Drugs
Antibiotics, Antineoplastic