| Eligibility |
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.
Exclusion Criteria:
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Previous enrolment in the present study
- Participation in another clinical study with an investigational product during the
last 14 days
- Mean QT interval corrected for heart rate (QTc) = 470 ms calculated from 3
electrocardiograms (ECGs) using Fredericia's Correction
- Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab or an
anti-CTLA-4, including tremelimumab
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) = 14 days prior to the first dose of study
drug
- Major surgery within 28 days of starting study treatment. There is no minimum time
requirement for minor procedures such as biopsy or vascular access placement.
- Radiation within 14 days of starting study treatment
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not to exceed10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
- A temporary period of steroids for different indications, at the discretion of
the principal investigator (e.g., chronic obstructive pulmonary disease,
radiation, nausea, etc)
- Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Subjects
with irreversible toxicity that is not reasonably expected to be exacerbated by the
investigational product may be included (e.g., alopecia, hearing loss, peripheral
neuropathy).
- History of pulmonary fibrosis by imaging or biopsy (including secondary to bleomycin),
pneumonitis (including drug induced) requiring steroids = 3 weeks, organizing
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or
evidence of active pneumonitis on screening chest computed tomography (CT) scan with
associated symptoms.
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis, celiac
disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome
(granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis,
hypophysitis, uveitis, etc)). The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active autoimmune disease in the last 5 years may be included
but only after consultation with the study physician
- Patients with diverticulosis
- Patients with celiac disease controlled by diet alone
- History of primary immunodeficiency
- History of allogeneic organ transplant
- History of hypersensitivity to durvalumab, tremelimumab or any excipient
- Uncontrolled intercurrent illness including, but not limited to, on-going or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses, evidence of acute or chronic hepatitis B, hepatitis C or human
immunodeficiency virus (HIV), or psychiatric illness/social situations that would
limit compliance with study requirements or compromise the ability of the subject to
give written informed consent
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
- Known history of previous clinical diagnosis of tuberculosis
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab or tremelimumab. Inactivated vaccines, such as the
injectable influenza vaccine, are permitted.
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
- Malignancies other than the disease under study within 5 years prior to Cycle 1, Day
1, with the exception of those with a negligible risk of metastasis or death and with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, localized prostate cancer treated surgically with
curative intent, or ductal carcinoma in situ treated surgically with curative intent)
or undergoing active surveillance per standard-of-care management (e.g. prostate
cancer with Gleason score 6, and prostate-specific antigen (PSA) 10 mg/mL, etc).
- Patients should agree to not donate blood while participating in this study or for at
least 90 days following the last infusion of durvalumab or tremelimumab
- Female patients who are pregnant or breastfeeding
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