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

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 Tumours

Summary:

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 tumours. Active surveillance may help doctors to monitor subjects with low risk germ cell tumours after their tumour is removed. Drugs used in chemotherapy, such as bleomycin, carboplatin, etoposide, and cisplatin, work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Trial Description

Primary Outcome:

• Overall survival
• Event-free survival

Secondary Outcome:

• Incidence of ototoxicity
• Content validity and understandability of Adolescents and Young Adults-Hearing Screen
• Utility of the 4-micro ribonucleic acid panel as markers diagnostic of mediastinal germ cell tumours
• Utility of the 4-micro ribonucleic acid panel as markers diagnostic of mediastinal germ cell tumours
• Novel genetic variants associated with an increased risk of platinum-associated ototoxicity as determined by standard audiology

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 tumours, 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 tumours. 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 tumours (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 tumours 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 tumours. 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 tumour marker decline (alpha-FP and beta-HCG) with clinical outcome in low and standard risk germ cell tumour 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 tumour deoxyribonucleic acid (DNA) methylation class. VI. To characterize the incidence of nephrotoxicity in children, adolescents and young adults with standard risk germ cell tumours 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 tumours 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 Adolescents and Young Adults-Hearing Screen (AYA-HEARS) instrument.

OUTLINE:

Patients with low-risk stage I grade 2, 3 ovarian immature teratoma or stage I malignant germ cell tumours 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.

View this trial on ClinicalTrials.gov