Clinical Trials /

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

NCT03067181

Description:

This 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.

Related Conditions:
  • Germ Cell Tumor
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: AGCT1531
  • SECONDARY ID: NCI-2017-00178
  • SECONDARY ID: AGCT1531
  • SECONDARY ID: AGCT1531
  • SECONDARY ID: AGCT1531
  • NCT ID: NCT03067181

Conditions

  • Adult Germ Cell Tumor
  • Childhood Extracranial Germ Cell Tumor
  • Childhood Germ Cell Tumor
  • Extragonadal Embryonal Carcinoma
  • Grade 2 Immature Ovarian Teratoma
  • Grade 3 Immature Ovarian Teratoma
  • Malignant Germ Cell Tumor
  • Stage I Ovarian Choriocarcinoma
  • Stage I Ovarian Embryonal Carcinoma
  • Stage I Ovarian Teratoma
  • Stage I Ovarian Yolk Sac Tumor
  • Stage I Testicular Choriocarcinoma
  • Stage I Testicular Embryonal Carcinoma
  • Stage I Testicular Yolk Sac Tumor
  • Stage II Ovarian Choriocarcinoma
  • Stage II Ovarian Embryonal Carcinoma
  • Stage II Ovarian Yolk Sac Tumor
  • Stage II Testicular Choriocarcinoma
  • Stage II Testicular Embryonal Carcinoma
  • Stage II Testicular Yolk Sac Tumor
  • Stage III Ovarian Choriocarcinoma
  • Stage III Ovarian Embryonal Carcinoma
  • Stage III Ovarian Yolk Sac Tumor
  • Stage III Testicular Choriocarcinoma
  • Stage III Testicular Embryonal Carcinoma
  • Stage III Testicular Yolk Sac Tumor
  • Stage IV Ovarian Choriocarcinoma
  • Stage IV Ovarian Embryonal Carcinoma
  • Stage IV Ovarian Yolk Sac Tumor
  • Testicular Mixed Choriocarcinoma and Embryonal Carcinoma
  • Testicular Mixed Choriocarcinoma and Teratoma
  • Testicular Mixed Choriocarcinoma and Yolk Sac Tumor

Interventions

DrugSynonymsArms
BleomycinBLEO, BLMArm I (bleomycin, carboplatin, etoposide)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (bleomycin, carboplatin, etoposide)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm II (bleomycin, etoposide, cisplatin)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Arm I (bleomycin, carboplatin, etoposide)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (bleomycin, carboplatin, etoposide)ExperimentalPatients receive bleomycin 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.
  • Bleomycin
  • Carboplatin
  • Etoposide
Arm II (bleomycin, etoposide, cisplatin)ExperimentalPatients 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.
  • Bleomycin
  • Cisplatin
  • Etoposide
Arm III (bleomycin, etoposide, carboplatin)ExperimentalPatients 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.
  • Bleomycin
  • Carboplatin
  • Etoposide
Arm IV (bleomycin, etoposide, cisplatin)ExperimentalPatients receive bleomycin IV over 10 minutes on days 1, 8, and 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.
  • Bleomycin
  • Cisplatin
  • Etoposide
Low-Risk (observation)ExperimentalPatients with stage I grade 2, 3 ovarian immature teratoma or low-risk stage I malignant germ cell tumors undergo observation and can transfer to standard risk arm when eligibility criteria are met.

    Eligibility Criteria

            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
          
    Maximum Eligible Age:49 Years
    Minimum Eligible Age:N/A
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:EFS
    Time Frame:The time from study entry to the date of death, date of disease progression or recurrence, date of second malignant neoplasm or date of last contact and ascertained as alive, whichever comes first, assessed up to 5 years
    Safety Issue:
    Description:A 1-sided lower 85% confidence limit for the 2-year survival will be constructed, and if this confidence limit is greater than 0.95, it will be concluded that the strategy provides sufficient OS.

    Secondary Outcome Measures

    Measure:Content validity and understandability of AYA-Hearing Screen assessed by questionnaire
    Time Frame:Baseline
    Safety Issue:
    Description:
    Measure:Incidence of ototoxicity
    Time Frame:4 weeks after the last dose of platin therapy
    Safety Issue:
    Description:Will compare the proportion of patients who demonstrate hearing loss according to the International Society of Pediatric Oncology criteria.
    Measure:Novel genetic variants associated with an increased risk of platinum-associated ototoxicity as determined by standard audiology
    Time Frame:Up to 10 years
    Safety Issue:
    Description:For each candidate gene, will perform an exact two-sided test for the equality of binomial proportions for the event - patient has the candidate gene. The two groups compared will be defined by the presence of SHL. Will use the Bonferroni correction to control experiment-wise error and designate the result as significant if the observed p-value is less than or equal to 0.0025.
    Measure:Utility of the 4-miRNA panel as markers diagnostic of MGCTs
    Time Frame:Up to 10 years
    Safety Issue:
    Description:Will use categorical data methods and estimate the probability of demonstrating an elevated miRNA value as the proportion of patients who have the particular miRNA elevated.
    Measure:Utility of the 4-miRNA panel as markers diagnostic of MGCTs
    Time Frame:Up to 10 years
    Safety Issue:
    Description:Will compare the diagnostic sensitivity of serum markers, particularly elevated alpha-fetoprotein, to that of elevated microRNA for each of the microRNAs, as well as the characteristic any microRNA elevated. Will perform McNemar's test. The result for each serum evaluation (elevated or not elevated) for each sample on which both serum marker and microRNA evaluation are obtained will be cross tabulated and the p-value associated with McNemar's test calculated. A p-value of 0.05 or less will be considered evidence of differential sensitivity.

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Children's Oncology Group

    Last Updated

    June 2, 2017