An Open-Label, Multi-Centre, Study to Assess the Safety of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
Condition: Advanced Solid Malignancies
MeSH terms: Neoplasms
Intervention: MEDI4736 (Durvalumab); MEDI4736 (Durvalumab) + Tremelimumab
Intervention description: A human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on immune cells (IC).; Durvalumab: A human mAb of IgG 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on IC.
Tremelimumab: A human Ig G2 mAb that completely blocks the interaction of human CTLA-4 (cluster of differentiation [CD]152) with CD80 and CD86 and increase release of cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood mononuclear cells and whole blood.
Intervention MeSH terms: Durvalumab; Tremelimumab; Antibodies, Monoclonal
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 867.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Programmed death ligand 1 (PD-L1); Cytotoxic T-lymphocyte antigen-4 (CTLA-4); Durvalumab in combination with tremelimumab

Summary:

      To evaluate the safety, tolerability, and anti-tumor activity of the combination of
      durvalumab + tremelimumab or durvalumab alone in different solid tumors.
    

Eligibility criteria:

        Inclusion criteria:

          1. Must have a life expectancy of at least 12 weeks.

          2. Age ≥18 years at the time of screening. For patients aged <20 years and enrolled in
             Japan, a written informed consent should be obtained from the patient and his or her
             legally acceptable representative

          3. 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. Written informed consent and any locally required authorization (eg, Health
             Insurance Portability and Accountability Act in the US, European Union [EU] Data
             Privacy Directive in the EU) obtained from the patient/legal representative prior to
             performing any protocol-related procedures, including screening evaluations. For
             patients aged <20 years and enrolling in Japan, a written informed consent should be
             obtained from the patient and his or her legally acceptable representative.

          4. Disease not amenable to curative surgery

          5. Eastern Cooperative Oncology Group (ECOG) performance status as defined in the
             specific module.

          6. Body weight >30 kg.

          7. No prior exposure to anti-PD-1 or anti-PD-L1, including on another AstraZeneca study.
             Exposure to other investigational agents may be permitted after discussion with the
             Sponsor.

          8. Adequate organ and marrow function as defined below

               -  Hemoglobin ≥9.0 g/dL

               -  Absolute neutrophil count ≥1.0 × 109 /L

               -  Platelet count ≥75 × 109/L

               -  Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to
                  patients with confirmed Gilbert's syndrome, who will be allowed in consultation
                  with their physician.

               -  ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 ×
                  ULN

               -  Measured creatinine clearance (CL) >40 mL/min or calculated creatinine clearance
                  (CL) >40 mL/min as determined by Cockcroft-Gault (using actual body weight)

             Males:

             Creatinine CL = Weight (kg) × (140 - Age) (mL/min) 72 × serum creatinine (mg/dL)

             Females:

             Creatinine CL = Weight (kg) × (140 - Age) x 0.85 (mL/min) 72 × serum creatinine
             (mg/dL)

          9. Female patients of childbearing potential (ie, not surgically sterile or post
             menopausal) who are sexually active with a non sterilized male partner must use at
             least one highly effective method of contraception from the time of screening and must
             agree to continue using such precautions for 180 days after the last dose of
             durvalumab + tremelimumab combination therapy or 90 days after the last dose of
             durvalumab monotherapy (see Section 3.8 and specifically Table 1).

         10. Evidence of post-menopausal status or negative urinary or serum pregnancy test (per
             Section 4) 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:

         11. 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).

        Non sterilized male patients 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.

        Exclusion criteria:

          1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site).

          2. Previous IP assignment in the present study.

          3. Concurrent enrollment in another clinical study, or another sub-study of this
             protocol, unless it is an observational (non-interventional) clinical study or during
             the follow up period of an interventional study.

          4. Participation in another clinical study with an investigational product during the
             last 28 days or 5 half-lives, whichever is longer, prior to the first dose of study
             treatment.

          5. Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for
             cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
             (eg, hormone replacement therapy) is acceptable.

          6. Local treatment of isolated lesions for palliative intent is acceptable (eg, local
             surgery or radiotherapy).

          7. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives,
             whichever is longer, prior to the first dose of study treatment.

          8. Radiotherapy 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. Note: Local treatment of
             isolated lesions, excluding target lesions, for palliative intent is acceptable.

          9. 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.

         10. History of allogenic organ transplantation.

         11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, ILD, serious chronic GI 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

         12. 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 investigational product (durvalumab + tremelimumab) 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

         13. History of leptomeningeal carcinomatosis

         14. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
             identified either on baseline brain imaging (please refer to RECIST for details on the
             imaging modality) obtained during the screening period or identified prior to signing
             the ICF. Patients 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 4 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 and anti-convulsants for at least 14 days prior to the start of treatment.
             Brain metastases will not be recorded as RECIST Target Lesions at baseline.

         15. History of active primary immunodeficiency.

         16. Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and tuberculosis 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). 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 virus (HCV) antibody are eligible only if polymerase
             chain reaction is negative for HCV RNA.

         17. 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 (eg, intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

         18. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, 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 (eg, 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

         19. 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.

         20. Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic
             composition to the study drug(s), or any of the study drug excipients.

         21. Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti cancer therapy with the
             exception of vitiligo, alopecia, 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 or tremelimumab may be included only after consultation
                  with the Study Physician

         22. For women only, currently pregnant (confirmed with positive pregnancy test) or breast
             feeding.

         23. 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 180 days after the last dose of durvalumab + tremelimumab combination
             therapy or 90 days after the last dose of durvalumab monotherapy.

         24. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
             study regardless of treatment arm assignment.