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

Study ID
STU 052017-035

Study Sites

  • Children’s Medical Center (Dallas, Plano, Southlake)

Contact
AMANDA RICHARDS
2144566300
AMANDA.RICHARDS@childrens.com

Principal Investigator
Jonathan Wickiser, M.D.

Official Title

A Phase 3 Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Pediatric and Adult Patients With Germ Cell Tumors

Brief Overview

This partially randomized phase III trial studies how well active surveillance, bleomycin, carboplatin, etoposide, or cisplatin work in treating pediatric and adult patients with germ cell tumors. Active surveillance may help doctors to monitor subjects with low risk germ cell tumors after their tumor is removed. Drugs used in chemotherapy, such as bleomycin, carboplatin, etoposide, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Description

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- 50 years) with stage I (low risk) malignant germ cell tumors, and at least 98% 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 and nephrotoxicity 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.
III. To assess the utility of using an established panel of four circulating micro ribonucleic acid (RNA)s as a universal marker of diagnosis, recurrence and response to therapy.
IV. To identify novel genetic variants associated with an increased risk of platinum-associated ototoxicity as determined by standard audiology at the end of therapy using both a candidate gene and genome wide approach.
TERTIARY OBJECTIVES:
I. To prospectively determine the correlation of tumor marker decline (alpha-FP and beta-HCG) with clinical outcome in low and standard risk germ cell tumor patients.
II. To prospectively determine the clinical significance of activation of the BMP, Ras/MAPK and PI3K/mTOR signaling pathways in GCTs.
III. To investigate the prognostic significance of an established panel of four circulating microRNAs at diagnosis, during follow-up and at relapse in malignant GCTs.
IV. To identify integrated messenger RNA/microRNA profiles in primary malignant GCTs that correlate with poor clinical outcome.
V. To evaluate the significance of tumor deoxyribonucleic acid (DNA) methylation class.
VI. To characterize the incidence of nephrotoxicity in children, adolescents and young adults with standard risk germ cell tumors treated with carboplatin-based chemotherapy and treated with cisplatin-based chemotherapy.
VII. 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.
VIII. To determine the utility of novel biomarkers of kidney tubular injury to provide earlier diagnosis of nephrotoxicity and to compare the nephrotoxicity of cisplatin versus carboplatin.
IX. Identify novel genetic variants of platinum neurotoxicity, nephrotoxicity and hematologic toxicity using both a candidate gene and whole gene approach.
X. Assess the relationship between hearing loss as measured by audiometry with the effects of tinnitus as assessed on the 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 sulfate 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.

Eligibility

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, 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 and IB; 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: for IGCCC good risk: alpha-FP < 1,000 ng/mL, beta-HCG < 5,000 IU/mL and lactate dehydrogenase (LDH) < 1.5 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
- Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
- 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 group 1 of the pilot study of the AYA-Hears instrument Note: participants in group 1 will not receive protocol-directed therapy
- >= 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 with alpha-fetoprotein (AFP) >= 1000 ng/mL
- Pure immature teratoma COG stage II - IV or FIGO stage IC to IV
- Poor risk disease (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)
- SR1 and SR2 patients:
- Female patients who are pregnant; a pregnancy test is required for female patients of childbearing potential
- Lactating females who plan to breastfeed their infants
- Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation