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

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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

Brief Summary

      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.
    

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 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
      non-seminomatous germ cell tumors.

      IIa. 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).

      IIb. 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.

      IV. To evaluate the prognostic significance of serum micro ribonucleic acid (miRNA)s in stage
      I testicular cancer (seminoma and non-seminoma) patients by collecting clinical data and
      serum specimens for future analysis.

      OUTLINE:

      Patients with low-risk stage I grade 2, 3 ovarian immature teratoma or stage I non-seminoma
      malignant germ cell tumors (MGCT)s undergo observation and can transfer to standard risk arm
      when eligibility criteria are met. Patients with stage I seminoma testicular MGCT undergo
      observation, and those with residual/recurrent disease are treated at the discretion of their
      physician.

      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 cycles 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 cycles 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 cycles 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 cycles in the absence of disease progression or unacceptable
      toxicity.

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

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Overall survival

Secondary Outcome

 Percentage of participants with hearing loss

Condition

Childhood Extracranial Germ Cell Tumor

Intervention

Best Practice

Study Arms / Comparison Groups

 Arm I (bleomycin, carboplatin, etoposide)
Description:  Patients 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 cycles in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

2059

Start Date

May 8, 2017

Completion Date

June 30, 2027

Primary Completion Date

June 30, 2027

Eligibility Criteria

        Inclusion Criteria:

          -  There is no age limit for the low risk stratum (stage I ovarian immature teratoma and
             stage I non-seminoma or seminoma malignant GCT [all sites])

          -  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

          -  Patients enrolling on one of the low risk arms must be newly diagnosed with a stage I
             germ cell tumor; for the standard risk arms, patients must be newly diagnosed with
             metastatic germ cell tumor (stage II or higher); histologic confirmation of a primary
             extracranial germ cell tumor in any of the categories outlined below is required of
             all patients at enrollment except for those who were initially diagnosed with stage I
             non-seminoma malignant GCT and later recur during observation post surgery off study;
             for these patients, if elevated tumor markers rise to > 5 x upper limit of normal
             (ULN) on at least 2 measurements taken at least 1 week apart, a diagnostic biopsy is
             not required for 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 microscopic foci of yolk
             sac tumor), mixed immature and mature teratoma, (no pathological evidence of MGCT);
             tumor markers: alpha-FP =< 1,000 ng/mL, beta-HCG institutional normal; all ages

          -  Low risk stage I non-seminoma MGCT; 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); all ages

          -  Low risk stage I seminoma-MGCT; site: testicular; stage: COG stage I; AJCC testicular
             stage IA IB, and IS; histology: must contain at least one of the following: may
             contain immature/mature teratoma; may NOT contain yolk sac tumor, embryonal carcinoma,
             or choriocarcinoma; all ages

          -  Standard risk 1 (SR1); site: ovarian, testicular, or extragonadal; stage: COG stage
             II-IV, FIGO stage IC, FIGO stage II-IV (International Germ Cell Consensus
             Classification [IGCCC] criteria DO NOT apply); histology: must contain at least one of
             the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; 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; age (years) >= 11 and < 25

               -  Site: testicular; stage: COG stage II-IV, AJCC stage II, III, IGCCC good risk;
                  histology: must contain at least one of the following: yolk sac tumor, embryonal
                  carcinoma, or choriocarcinoma; 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; 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

               -  Stage 1 seminoma patients are not eligible for the standard risk arms of the
                  study

               -  For the low risk stage I non-seminoma 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

          -  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)

          -  Peripheral absolute neutrophil count (ANC) >= 1,000/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Patients enrolling on the standard risk arms must be medically fit to receive protocol
             treatment and with no contraindications to protocol treatment

          -  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:

               -  Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

               -  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

        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

               -  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

               -  Germ cell tumor with somatic malignant transformation

               -  Spermatocytic seminoma

          -  Patients must have had no prior systemic therapy for the current cancer diagnosis

          -  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, pre-existing co-morbid respiratory disease that
             contraindicate the use of bleomycin, are ineligible for the standard risk arms of 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])
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

A. L Frazier, , 

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT03067181

Organization ID

AGCT1531

Secondary IDs

NCI-2017-00178

Responsible Party

Sponsor

Study Sponsor

Children's Oncology Group

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

A. L Frazier, Principal Investigator, Children's Oncology Group


Verification Date

December 2020