| Eligibility |
Inclusion Criteria:
- Patients with histologically or cytologically confirmed metastatic melanoma,metastatic
non-small cell lung cancer, metastatic breast cancer, or metastatic pancreatic
adenocarcinoma relapsed or refractory to therapy as outlined below or patients with
these malignancies who have declined, are or have become unable to tolerate (e.g.
progressive chemotherapy-associated peripheral neuropathy), or were not eligible for
standard therapy: Metastatic melanoma patients at any line of therapy, Metastatic
non-small cell lung cancer patients who have relapsed or are refractory to at least
one line of systemic anti-cancer therapy for metastatic disease, including cytotoxic
chemotherapy or targeted therapy, Metastatic breast cancer patients who have relapsed
or are refractory to at least one line of systemic anti-cancer therapy for metastatic
disease, such as cytotoxic chemotherapy, hormonal therapy, or targeted therapy,
Metastatic pancreatic adenocarcinoma who have relapsed or are refractory to at least
one line of systemic anti-cancer therapy for metastatic disease, such as cytotoxic
chemotherapy or targeted therapy
- At least two measurable lesions (including the index lesion) according to RECIST
guidelines v1.1
- An index lesion measuring between 1cm - 7cm that is amenable to hypofractionated
radiation therapy at the discretion of the treating radiation oncologist
o Index lesions in the pancreas are excluded in the second cohort
- Age greater than or equal to 18 years
- Signed, written informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Adequate hematological function documented within 3 weeks prior to initial treatment
based on: White blood cell = 2,500 cells/ul without growth factor support, Absolute
neutrophil count (ANC) = 1,500 cells/ul without growth factor support, Hemoglobin = 9
g/dL, Platelet count = 100,000 platelets/ul, Adequate hepatic and renal function
documented within 3 weeks prior to initial treatment based on: Aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x upper limit of
normal (ULN). For subjects with liver metastasis, ALT and AST = 5 x ULN, Total
bilirubin =1.5 x ULN except in patients with documented Gilbert's syndrome or liver
metastasis, who must have a baseline total bilirubin = 3.0 mg/dl, Serum creatinine =
2.0 mg/dL
- Full recovery from the acute effects of prior cancer treatments, defined as effects
having resolved to NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and
certain laboratory values as listed above. Subjects with irreversible toxicity that is
not reasonably expected to be exacerbated by MEDI4736 and tremelimumab may be included
(eg, hearing loss, neuropathy) upon approval of the PI.
- For patients with central nervous system (CNS) metastases, metastases must be
asymptomatic at the time of Day 1 of the study and meet the following criteria:
- At least 28 days without progression of CNS metastases as evidenced by magnetic
resonance imaging (MRI) or computed tomography (CT) after last day of treatment with
radiation to the CNS metastases
- At least 14 days since last dose of corticosteroids
- Must not have leptomeningeal disease or cord compression
- Females of childbearing potential who are sexually active with a nonsterilized male
partner must use highly effective method of contraception from the time of screening,
and must agree to continue using such precautions for 180 days after the final dose of
MEDI4736 and tremelimumab. Cessation of contraception after this point should be
discussed with a responsible physician. Periodic abstinence, the rhythm method, and
the withdrawal method are not acceptable methods of contraception. They must also
refrain from egg cell donation for 180 days after the final dose of MEDI4736 and
tremelimumab: Females of childbearing potential are defined as those who are not
surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy) or those who are not post-menopausal (defined as 12 months with no
menses with postmenopausal gonadotropin levels, luteinizing hormone [LH] and
follicle-stimulating [FSH], or postmenopausal estradiol levels within the
postmenopausal range according to local guidelines without an alternative medical
cause), A highly effective method of contraception is defined as one that results in a
low failure rate (i.e., less than 1% per year) when used consistently and correctly.
The acceptable methods of contraception include barrier methods (male condom plus
spermicide, Copper T intrauterine device, Levonorgesterel-releasing intrauterine
system) or hormonal methods (implants, hormone shot or injection, combined pill,
minipill, patch), Nonsterilized males who are sexually active with a female partner of
childbearing potential must use a highly effective method of contraception (as
outlined above) from Day 1 through 90 days after receipt of the final dose of MEDI4736
and tremelimumab. In addition, they must refrain from sperm donation for 90 days after
the final dose of investigational product.
Exclusion Criteria:
- Concurrent enrollment in another clinical study, unless in a follow-up period or the
study is an observational or non-interventional study
- Prior treatment with anti-CTLA4, anti-PD-1, or anti-PD-L1 (approved or investigational
agent)
- Concurrent treatment with any anticancer agent, including chemotherapy, immunotherapy,
or biologic therapy. In breast cancer patients, concurrent use of hormonal therapy
(but not trastuzumab) is acceptable provided hormonal therapy was initiated more than
30 days prior to treatment on this study.
- Treatment with any other investigational agent within 3 weeks prior to the first dose
of DURVALUMAB (MEDI4736) and tremelimumab
- Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria
- Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the Study
Physician
- Major surgical procedure (as defined by the investigator) within 28 days prior to the
first dose of DURVALUMAB (MEDI4736) and tremelimumab or still recovering from prior
surgery Note: Local surgery of isolated lesions for palliative intent is acceptable
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of DURVALUMAB (MEDI4736) and tremelimumab with the exceptions of intranasal and
inhaled corticosteroids, systemic corticosteroids at physiologic doses not to exceed
10 mg/day of prednisone or equivalent, or steroids used transiently to control
contrast agent allergies for radiographic studies.
- 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:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone.
- History of sensitivity or allergy to monoclonal antibodies or immunoglobulin GActive
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
- Receipt of a live, attenuated vaccine within 30 days prior to the first dose of
DURVALUMAB (MEDI4736) and tremelimumab Note: Patients, if enrolled, should not receive
live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
- Clinical contraindication to stereotactic body radiotherapy as determined by the
investigator (e.g., active systemic sclerosis, active inflammatory bowel disease if
bowel is within radiation field.)
- Prior radiotherapy that precludes the proposed treatment with hypofractionated
radiotherapy
- Females who are pregnant, lactating, or intend to become pregnant during the
participation of the study
- 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 AEs or compromise the ability of the patient to give written
informed consent
- Other active invasive malignancy. History of non-invasive malignancies such as
cervical carcinoma in situ, non-melanomatous carcinoma of the skin, or ductal
carcinoma in situ of the breast is allowed, as is history of other invasive malignancy
that is in remission after treatment with curative intent.
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of the investigational product or interpretation of subject safety or study
results.
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