| Eligibility |
Inclusion Criteria:
- Subjects with platinum-resistant or refractory, recurrent or metastatic gynecological
malignancies, including ovarian, endometrial, or cervical cancer are eligible for
enrollment. Subjects unsuitable or refusing platinum-based chemotherapy are allowed to
enrolled
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
version (v)1.1 criteria. Thus, subjects with metastatic disease must have at least 1
lesion, not previously irradiated, that can be accurately measured at baseline as >=10
mm in the longest diameter (except lymph nodes which must have a short axis =15 mm)
with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable
for accurate repeated measurement as per RECIST v1.1 guidelines
- Disease amenable to be treated safely with brachytherapy
- Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of >= 12 weeks
- Subjects must consent to provide an archived tumor specimen from within 12 months
prior to study entry (ie, from subject signing consent to participate in the study).
If not available, subjects should have at least 1 lesion amenable to biopsy and
consent to provide a pre-treatment fresh biopsy. Additional archival tissue from
beyond 12 months prior to study entry is also requested, if available, to support
exploratory analyses
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 (or 1.0) x (>= 1500 per mm^3)
- Platelet count >= 100 (or 75) x 10^9/L (>= 75,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- This will not apply to subjects with confirmed Gilbert's syndrome (persistent or
recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
hemolysis or hepatic pathology), who will be allowed only in consultation with
their physician
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal unless liver metastases are present, in
which case it must be =< 5 x ULN
- Creatinine < 3 x upper limit of normal
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal subjects. 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 treatments
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)
- 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:
- Prior use of checkpoint inhibitors
- Prior radiation in which the 50% isodose line overlaps with intended site for
brachytherapy
- Radiation treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks of the first dose of study drug
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Participation in another clinical study with an investigational therapeutic
pharmaceutical agent i.e. chemotherapy, targeted therapy, or immunotherapy =< 21 days
or =< 5 half-lives
- Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study
- Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies) =< 21 days or 5 half-lives prior to the first dose of study drug. If
sufficient wash-out time has not occurred due to the schedule or pharmacokinetics (PK)
properties of an agent, a longer wash-out period will be required, as agreed by
AstraZeneca/MedImmune and the investigator
- Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
- Subjects with grade >= 2 neuropathy will be evaluated on a case-by-case basis after
consultation with the study physician
- Subjects with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation with
the study physician
- Any concurrent chemotherapy, investigation product (IP), biologic, or hormonal therapy
for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (e.g., hormone replacement therapy) is acceptable
- Major surgical procedure (as defined by the investigator) within 28 days prior to the
first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
acceptable
- History of allogenic organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], 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:
- Subjects with vitiligo or alopecia
- Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Subjects without active disease in the last 5 years may be included but only
after consultation with the study physician
- Subjects with celiac disease controlled by diet alone
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring adverse events (AEs) or compromise the ability of the subject to
give written informed consent
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease >= 5
years before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- Brain metastases or spinal cord compression. Subjects with suspected brain metastases
at screening should have an MRI (preferred) or CT each preferably with IV contrast of
the brain prior to study entry. Brain metastases will not be recorded as RECIST target
lesions at baseline if study allows subjects with brain metastasis (mets)
- Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
identified either on the baseline brain imaging (RECIST) obtained during the screening
period or identified prior to signing the ICF. Subjects whose brain metastases have
been treated may participate provided they show radiographic stability (defined as 2
brain images, both of which are obtained after treatment to the brain metastases.
These imaging scans should both be obtained at least four weeks apart and show no
evidence of intracranial progression). In addition, any neurologic symptoms that
developed either as a result of the brain metastases or their treatment must have
resolved or be stable either, without the use of steroids, or are stable on a steroid
dose of =< 10 mg/day of prednisone or its equivalent for at least 14 days prior to the
start of treatment. Brain metastases will not be recorded as RECIST target lesions at
baseline
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms
calculated from 3 electrocardiogram (ECG)s (within 15 minutes at 5 minutes apart)
- For durvalumab monotherapy and durvalumab + tremelimumab combination studies this
criterion can be removed. For durvalumab +/- tremelimumab in combination with an
agent with pro-arrhythmic potential or where effect of the combination on QT is
not known if this criterion should be retained. Subject safety and the cardiac
SKG should be consulted as needed
- History of active primary immunodeficiency
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis (TB) testing
in line with local practice), hepatitis B (known positive hepatitis B virus [HBV]
surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus
(positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined
as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Current or prior use of immunosuppressive medication within 14 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 exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP
- Female subjects who are pregnant or breastfeeding or male or female subjects of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy or180 days after
the last dose of durvalumab + tremelimumab combination therapy
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment
- Determined by the investigator that the subject is unsuitable to participate in the
study and the subject is unlikely to comply with study procedures, restrictions and
requirements
- Known allergy or hypersensitivity to IP or any excipient
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