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

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