Active Surveillance, Bleomycin, Carboplatin, Etoposide, or Cisplatin in Treating Pediatric and Adult Patients With Germ Cell Tumors

PRIMARY OBJECTIVES:

I. To evaluate whether a strategy of complete surgical resection followed by surveillance can
maintain an overall survival rate of at least 95.7% at two years for pediatric, adolescent
and adult patients (ages 0 to < 50 years) with stage I (low risk) malignant germ cell tumors,
and at least 95% for patients with ovarian pure immature teratoma.

II. To compare the event-free survival of a carboplatin versus (vs.) cisplatin-based regimen
in the treatment of pediatric, adolescent and young adult patients with standard risk germ
cell tumors.

III. To compare the event free survival (EFS) of a carboplatin-based regimen (carboplatin [C]
etoposide [E] bleomycin [b]) vs. a cisplatin-based regimen (cisplatin [P]Eb) in children
(less than 11 years in age) with standard risk germ cell tumors (GCT).

IV. To compare the EFS of a carboplatin-based regimen (BEC) vs. a cisplatin-based regimen
(BEP) in adolescents and young adults (ages 11 - < 25 years) with standard risk GCT.

SECONDARY OBJECTIVES:

I. To compare the incidence of ototoxicity in children, adolescents and young adults with
standard risk germ cell tumors treated with carboplatin-based chemotherapy as compared to
cisplatin-based chemotherapy.

II. To refine and validate a novel patient-reported measure of hearing outcomes for children,
adolescents and young adults with standard risk germ cell tumors.

EXPLORATORY OBJECTIVES:

I. To prospectively determine the correlation of tumor marker decline (alpha-fetoprotein [FP]
and beta-human chorionic gonadotropin [HCG]) with clinical outcome in low and standard risk
germ cell tumor patients.

II. To compare self-reported peripheral neuropathy and other patient-reported outcomes
between children, adolescents and young adults with standard risk germ cell tumors treated
with carboplatin-based chemotherapy as compared to cisplatin based chemotherapy.

III. Assess the relationship between hearing loss as measured by audiometry with the effects
of tinnitus as assessed on the Adolescent and Young Adult Hearing Screening (AYA-HEARS)
instrument.

OUTLINE:

Patients with low-risk stage I grade 2, 3 ovarian immature teratoma or stage I malignant germ
cell tumors undergo observation and can transfer to standard risk arm when eligibility
criteria are met.

Patients with standard risk 1 are randomized into 1 of 2 arms.

ARM I (CEb): Patients receive bleomycin intravenously (IV) over 10 minutes and carboplatin IV
over 1 hour on day 1. Patients also receive etoposide IV over 1-2 hours on days 1-5.
Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity.

ARM II (PEb): Patients receive bleomycin IV over 10 minutes on day 1. Patients also receive
etoposide IV over 1-2 hours and cisplatin IV over 1-3 hours on days 1-5. Treatment repeats
every 21 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity.

Patients with standard risk 2 are randomized into 1 of 2 arms.

ARM III (BEC): Patients receive bleomycin IV over 10 minutes on days 1, 8, and 15, etoposide
IV over 1-2 hours on days 1-5, and carboplatin IV over 1 hour on day 1. Treatment repeats
every 21 days for up to 3 courses in the absence of disease progression or unacceptable
toxicity.

ARM IV (BEP): Patients receive bleomycin IV over 10 minutes on days 1, 8, 15, etoposide IV
over 1-2 hours on days 1-5, and cisplatin IV over 1-3 hours on days 1-5. Treatment repeats
every 21 days for up to 3 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up monthly to 12 months, every 2
months to 24 months, every 6 months for years 3-5, and then annually for up to 10 years.

Inclusion Criteria:

- Low risk stratum (stage I ovarian immature teratoma and stage I malignant GCT [all
sites]): Patients must be < 50 years of age at enrollment

- Standard risk 1: Patient must be < 11 years of age at enrollment

- Standard risk 2: Patients must be >= 11 and < 25 years of age at enrollment

- Newly diagnosed patients must have histologic verification of a primary extracranial
germ cell tumor in any of the categories outlined; elevation of serum tumor markers
without histologic confirmation is not sufficient for entry on the trial

- NOTE: for low risk patients, materials for rapid surgical central review must be
sent within 7 days of study enrollment

- Low risk stage I immature teratoma (IT); site: ovarian; stage: Children's Oncology
Group (COG) stage I, Federation of Gynecology and Obstetrics (FIGO) stage IA and IB;
grade: 2 or 3; histology: pure immature teratoma (may contain =< 5% of microscopic
yolk sac tumor), mixed immature and mature teratoma, (no pathological evidence of
mediastinal germ cell tumor [MGCT]); tumor markers: alpha-FP =< 1,000 ng/mL, beta-HCG
institutional normal; age (years) < 50

- Low risk stage I MCGT; site: ovarian, testicular, or extragonadal; stage: COG stage I,
FIGO stage IA and IB, American Joint Committee on Cancer (AJCC) testicular stage IA,
IB and IS; histology: must contain at least one of the following: yolk sac tumor,
embryonal carcinoma, or choriocarcinoma (pure or mixed); age (years) < 50

- Standard risk 1 (SR1); site: ovarian, testicular, or extragonadal; stage: COG stage
II-IV, FIGO stage IC, FIGO stage II-IV; histology: must contain at least one of the
following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma (pure or mixed);
age (years) < 11

- Standard risk 2 (SR2)

- Site: ovarian; stage: COG stage II and III, FIGO stage IC, II and III; histology:
must contain at least one of the following: yolk sac tumor, embryonal carcinoma,
or choriocarcinoma (pure or mixed); age (years) >= 11 and < 25

- Site: testicular; stage: COG stage II-IV, AJCC stage II, III, International Germ
Cell Consensus Classification (IGCCC) good risk; histology: must contain at least
one of the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma
(pure or mixed); tumor markers: must be IGCCC good risk; post op: alpha-FP <
1,000 ng/mL, beta-HCG < 5,000 IU/mL and lactate dehydrogenase (LDH) < 3.0 x
normal; age (years) >= 11 and < 25

- Site: extragonadal; stage: COG stage II; histology: must contain at least one of
the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma (pure or
mixed) age (years) >= 11 and < 25

- Notes:

- IGCCC criteria only apply to SR2 patients with a testicular primary tumor

- Use post-op tumor marker levels to determine IGCCC risk group

- For the low risk stage I MGCT and the standard risk arms, components of yolk sac
tumor, embryonal carcinoma, or choriocarcinoma can be mixed with other forms of
GCT, such as seminoma or mature or immature teratoma; if yolk sac tumor is the
only malignant component present, then it must be deemed by the pathologist to be
greater than a ?microscopic component? of yolk sac tumor (i.e. > 5%)

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, 2 or 3; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age

- Organ function requirements apply ONLY to patients who will receive chemotherapy (SR1
and SR2 patients)

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2

- A serum creatinine based on age/gender as follows: (mg/dL)

- 1 month to < 6 months male: 0.4 female: 0.4

- 6 months to < 1 year male: 0.5 female: 0.5

- 1 to < 2 years male: 0.6 female: 0.6

- 2 to < 6 years male: 0.8 female: 0.8

- 6 to < 10 years male: 1 female: 1

- 10 to < 13 years male: 1.2 female: 1.2

- 13 to < 16 years: male: 1.5 female: 1.4

- >= 16 years male: 1.7 female: 1.4

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age (for the purpose of this study, the ULN for SGPT
is 45 U/L)

- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if
there is clinical indication or determination; pulmonary function tests (PFTs) are not
required

- Eligibility criteria to participate in the pilot study of the AYA-Hears instrument
(patient reported outcomes [PROs] of ototoxicity) Note: participants in group 1 will
not receive AGCT1531 protocol-directed therapy; all other AYA-HEARS patients must be
enrolled on the AGCT1531 SR2 arm in order to participate

- >= 11 and < 25 years old at enrollment

- Able to fluently speak and read English

- Has received prior cisplatin- or carboplatin-based chemotherapy regimen for malignancy
including diagnoses other than germ cell tumor

- Followed for cancer or survivorship care at one of the following institutions:

- Dana Farber/Harvard Cancer Center

- Hospital for Sick Children

- Children?s Hospital of Eastern Ontario

- Oregon Health and Science University

- Seattle Children?s Hospital

- Yale University

- Has experienced prior or ongoing hearing impairment due to chemotherapy or
radiotherapy as defined by one of the following:

- Society of Pediatric Oncology (SIOP) grade 1 hearing loss

- Subjective (patient-reported) hearing difficulties

- Subjective (patient-reported) tinnitus

Exclusion Criteria:

- Patients with any diagnoses not listed including:

- Stage I testicular cancer patients who have undergone primary RPLND
(retroperitoneal lymph node dissection)

- Pure dysgerminoma and pure seminoma

- Pure mature teratoma

- Pure immature teratoma COG stage I, grade I

- Pure immature teratoma COG stage I, grade 2,3 with alpha-fetoprotein (AFP) >=
1000 ng/mL

- Pure immature teratoma COG stage II - IV or FIGO stage IC to IV

- "Poor risk" GCT (age >= 11 years old and COG stage IV ovarian, COG stage III or
IV EG, or IGCCC intermediate or poor risk testicular), or

- Primary central nervous system (CNS) germ cell tumor

- Patients must have had no prior systemic therapy

- Patients must have had no prior radiation therapy with the exception of CNS
irradiation of brain metastases; (this exception only applies to SR1 patients; any
patients over age 11 with distant metastases to brain [stage IV disease] would be
considered poor risk and therefore not eligible for this trial)

- Patients with significant respiratory compromise due to either abdominal tumor
limiting diaphragmatic excursion or pulmonary metastases should not receive bleomycin
and are ineligible for the trial

- Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs; a pregnancy test is required for female
patients of childbearing potential; (this criteria applies ONLY to patients who will
receive chemotherapy [SR1 and SR2 patients])

- Lactating females who plan to breastfeed their infants; (this criteria applies ONLY to
patients who will receive chemotherapy [SR1 and SR2 patients])

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation; (this
criteria applies ONLY to patients who will receive chemotherapy [SR1 and SR2
patients])