| Eligibility |
Inclusion Criteria:
Untreated metastatic melanoma
- A metastatic lesion at least 1.5 cm in diameter that can be removed surgically
- Measurable or evaluable disease not including the resected lesion; at least 1 lesion,
not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at
baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance
imaging (MRI) must be performed within 28 days prior to enrollment
- Capable of giving signed informed consent
- Age >18 years at time of screening
- Eastern Cooperative Oncology Group (ECOG) 0-1
- Body weight >30 kg
- Hemoglobin =9.0 g/dL
- Absolute neutrophil count (ANC =1.0 x 109/L (> 1000 per mm3)
- Absolute lymphocyte count (ALC =0.5 x 109/L (> 500 per mm3) Platelet count =100 (or
75) x 109/L (>75,000 per mm3)
- Serum bilirubin =1.5 x institutional upper limit of normal (ULN). (This will not apply
to patients with confirmed Gilbert's syndrome)
- Aspartate aminotransferase (AST) (SGOT)/Alanine aminotransferase (ALT) (SGPT) =2.5 x
institutional upper limit of normal unless liver metastases are present, in which case
it must be =5x ULN
- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 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
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).
- Patient 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.
- Must have a life expectancy of at least 12 weeks.
Exclusion Criteria:
Received prior treatment for metastatic melanoma
- Received prior cell transfer therapy that included non-myeloablative or ablative
chemotherapy
- Received anti PD-1 immune therapy within prior 6 months
- Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active
major infection, no site of active, clinically significant bleeding)
- Concurrent major medical illnesses
- Any form of immunodeficiency
- Severe hypersensitivity to any of the agents used in this study
- Contraindications for IL-2 administration
- 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 product during the
last 4 weeks
- 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
- 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, tremelimumab, ipilimumab or nivolumab may be included
only after consultation with the Study Physician.
- Any concurrent chemotherapy, investigational 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:
- 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
- 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
- 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
- History of active primary immunodeficiency
- Active infection including tuberculosis (TB) (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in
line with local practice), hepatitis B (HBV) (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.
- 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:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.
- Female patients who are pregnant or breastfeeding or male or female patients 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 randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.
- Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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