Evaluating Immune Therapy, Duravalumab (MEDI4736) With Tremelimumab for Relapsed/Refractory Germ Cell Tumors

Inclusion Criteria

• •Age ≥ 18 years at time of informed consent
• •Body weight \> 30 kg
• •Histologically confirmed diagnosis of GCT (nonseminoma or seminoma in men; non-dysgerminomas, dysgerminomas, or germinomas in women or patients with pineal gland GCT) at MSKCC of any primary site (includes female GCT and intracranial GCT).
• •Evidence of measurable disease either by RECIST 1.1 or elevation of serum tumor markers (AFP \> 15 ng/mL or HCG \>2.2 mIU/ml).
• •Patients must have progressed after at least one prior systemic therapy for GCT and meet one of the following criteria:
• •a. Patients with evidence of progressive or recurrent GCT after progression prior high dose chemotherapy (HDCT) treatment, defined as meeting at least on of the following criteria: i. Tumor biopsy of new or growing or unresectable lesions demonstrating viable GCT. In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for this study.
• •ii. Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease.
• •iii. Development of new or enlarging lesions in the the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to rise.
• •b. Patients deemed not to be a candidate for or benefit from potentially curative HDCT or other curative treatment options defined as follows: i. Patients with inadequate renal function for HDCT. ii. Patients who have had 3 or more lines of prior chemotherapy as this patient population has historically not benefitted from HDCT.
• •iii. Patients with late relapse (relapse \> 2 years after last therapy) as this patient population has historically not benefitted from HDCT.
• •iv. Patient with inadequate stem cell collection to move forward with HDCT. v. Patients with significant medical or psychosocial comorbidities that are felt to be a contraindication to HDCT by the treating investigator.
• •NOTE: There is no maximum number of prior treatments allowed "Progression" after prior therapy is defined as any one of the following: NOTE: Patients with clinically growing "teratoma" (normal declining tumor markers and radiographic or clinical progression) should be considered for surgery. In patients with rising tumor markers as their only evidence of disease progression where AFP is \<30 or HCG is \<15, alternate causes of increased levels of these markers should be ruled out. (e.g., hypogonadism by testosterone suppression of LH, hepatitis, use of marijuana).
• •Patients with brain metastases are allowed onto the study as long as patients have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic. Subjects with neurological symptoms should undergo a head CT scan or brain MRI to exclude brain metastasis, at the discretion of the treating physician.
• •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• •Adequate normal organ and marrow function as defined below:
• •* Hemoglobin ≥ 9.0 g/dL
• •* Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (\> 1000 per mm3)
• •* Platelet count ≥ 100 x 109/L (\>100,000 per mm3)
• •* Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (≤ 3 x institutional ULN in patient's with Gilbert's syndrome)
• •* AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5x ULN
• •* Calculated creatinine clearance \>30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
• •Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply.
• •* Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• •* Women \>/= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \> 1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• •A positive serum pregnancy test must be confirmed by a pelvic US since some NSGCT may secrete beta-hCG and cause a false positive pregnancy. A pelvic US does not need to be repeated with each cycle unless the treating physician thinks it is necessary to do so.
• •Female patients of reproductive potential, defined as not surgical sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (see above for definition) and non-sterilized males who are sexually active with a female partner of reproductive potential must be willing to adhere to the following restrictions:
• •* Females of childbearing potential who are sexually active with a non-sterilized male partner must agree to use at least 1 highly effective method of contraception from the time of screening until 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. It is strongly recommended that non-sterilized male partners of a female patient must use male condom plus spermicide throughout this period Not engaging in sexual activity for the total duration of the drug treatment and the drug washout period is an acceptable practice.
• •* Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Not engaging in sexual activity is an acceptable practice. Male patients should refrain from sperm donation throughout this period. It is strongly recommended that female partners (of childbearing potential) of male patients to also use a highly effective method of contraception throughout this period.
• •Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.