Phase 1/2 Study Of PARP Inhibition With Olaparib To Enhance The Efficacy Of High-Dose Chemotherapy In Refractory And Relapsed Germ Cell Tumors

Prior treatment

• Major surgery within 30 days before the initiation of study treatment.
• Radiotherapy within 21 days prior to initiation of study treatment.
• HIV infection, unless the patient is receiving effective antiretroviral therapy with undetectable viral load and CD4+ ≥ 350 cells/uL.
• Patients who have had a previous autologous or allogeneic stem cell transplant in the previous 12 months.
• Grade =≥ 3 non-hematologic toxicity from prior therapy not improved to grade ≤ 2.
• Treatment within prior 2 weeks with any anti-cancer agent, investigational or approved.
• Pregnant women are excluded from this study because olaparib, gemcitabine, docetaxel, carboplatin, or etoposide are agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with those agents, breastfeeding should be discontinued if the mother is treated with any of those agents. These potential risks may also apply to other agents used in this study.
• Patients who are receiving any other investigational agents.

Other illness

• Patients with active CNS disease, defined as brain or meningeal metastases that are not in remission.
• Patients with active hepatitis B, either active carrier (HBsAg+ and not on suppressive antivirals) or viremic (HBV DNA ≥10,000 copies/mL, or ≥ 2,000 IU/mL) or hepatitis C (detectable viral load by HCV RNA PCR).
• Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients who either show chronic hepatitis C or positive hepatitis C serology.
• Active infection requiring parenteral antibiotics.
• Active infection requiring parenteral antibiotics.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib, gemcitabine, docetaxel, carboplatin, or etoposide or other agents used in study.
• Patients with uncontrolled intercurrent neurological illness.

Lab values

• Growing teratoma syndrome, defined as enlarging tumor masses with declining serum markers during chemotherapy for NSGCT.

• 12 - 60 years of age.
• Diagnosis of relapsed GCT, with one or more of the following criteria:
  • Extragonadal primary.
  • \>2 prior relapses.
  • Unresponsive disease (PD or SD) to the immediately prior therapy.
• ECOG PS ≤ 2 (Karnofsky ≥ 60%).in adults, Lansky Play-Performance Scale (LPPS) ≥ 60% in pediatric patients.
• A minimum apheresis collection of 5 million CD34+ cells/kg of autologous peripheral blood progenitor cells (PBPC).
• Adequate blood counts (WBC ≥ 2K, HGB ≥ 8 g/dL, platelets ≥ 50K).
• Creatinine clearance ≥ 50 ml/min/1.73 m2 (estimated by the Cockroft-Gault method in adults and the Schwartz formula in pediatric patients) and/or serum creatinine ≤ 1.8 mg/dL.
• ALT and/or AST ≤ 3 x institutional ULN, and bilirubin and alkaline phosphatase (ALP) ≤ 2 x institutional ULN.
• FE 1, F and DL Oc ≥ 0%
• L EF ≥ 0%, without active arrythmias
• If female of child-bearing potential, she must not be pregnant or breastfeeding and required to have a negative urine or serum pregnancy test prior to enrollment.
• For patients at risk for hepatitis B (HBV) reactivation (HBsAg+/negative HBV viremia, or HBsAg-/anti-HBc+) will be eligible as long as they are on suppressive antiviral therapy.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection still on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or lower.
• Male patients and women of child-bearing potential whose partners are participating in the study must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114).
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to treatment initiation (specify timeframe) and for the duration of study treatment (and if necessary, specify how long after treatment is completed) . (Refer to Pregnancy Assessment Policy UT MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
  • Postmenopausal (no menses in greater than or equal to 12 consecutive months).
  • History of hysterectomy or bilateral salpingo-oophorectomy.
  • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received whole pelvic radiation therapy).
  • History of bilateral tubal ligation or another surgical sterilization procedure.
  • Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post-vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study therapy.
• Ability to understand and willingness to sign a written informed document by patients and/ or their parents or legal guardians. Minors ages 7 and older must give their assent to participate