A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab
Condition: Breast Cancer; Ovarian Cancer; Colorectal Cancer; Cervical Cancer; Renal Cell Carcinoma
MeSH terms: Carcinoma, Renal Cell
Intervention: Durvalumab; Tremelimumab
Intervention description: Durvalumab was administered as an intravenous (IV) infusion over 60 (± 5) minutes.; Tremelimumab was administered as an intravenous (IV) infusion over 60 (± 5) minutes.
Intervention MeSH terms: Durvalumab; Tremelimumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 104.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This was a Phase 1, open-label, nonrandomized, multicenter study of durvalumab and
      tremelimumab in subjects with advanced cancers who were not eligible for, declined, or failed
      standard treatment. The primary study objective was to determine the maximum tolerated dose
      (MTD) and safety profile of the durvalumab and tremelimumab combination. Secondary objectives
      were to evaluate the pharmacokinetics (PK) and immunogenicity of durvalumab and tremelimumab,
      and the antitumor activity (tumor response, progression-free survival [PFS], and overall
      survival [OS]) of the durvalumab and tremelimumab combination. (Note: Collection of PK and
      immunogenicity samples was removed by amendment; analysis was not done.) Exploratory
      objectives were to evaluate the biological activity of the durvalumab and tremelimumab
      combination.
    

Eligibility criteria:

        Inclusion Criteria

          1. Histologically- or cytologically-confirmed ovarian cancer, colorectal cancer,
             non-triple negative breast cancer, renal cell carcinoma and cervical cancer, with at
             least one lesion measurable by the immune-related Response Criteria (irRC) not
             previously irradiated. NOTE: Per Amendment 5, the disease states of non-small cell
             lung cancer and head and neck cancer were removed from the study and were replaced by
             non-triple negative breast cancer.

          2. Failed to respond to or relapsed following standard treatment or declined or was not
             eligible for standard treatment.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

          4. Anticipated lifespan greater than 6 months.

          5. At the time of Day 1 of the study, subjects with brain metastases must have been
             asymptomatic for at least 4 weeks and:

               -  at least 8 weeks without tumor progression after any whole brain radiotherapy;

               -  at least 4 weeks since craniotomy and resection or stereotactic radiosurgery;

               -  at least 3 weeks without new brain metastases as evidenced by magnetic resonance
                  imaging (MRI)/computed tomography (CT).

          6. Adequate organ and marrow function, as defined below:

               -  hemoglobin ≥ 9 g/dL

               -  absolute neutrophil count ≥ 1500/mm^3

               -  platelet count ≥ 100,000/mm^3

               -  total bilirubin within normal ranges unless associated with hepatobiliary
                  metastases or Gilbert syndrome, then total bilirubin ≤ 2 × the upper limit of
                  normal (ULN)

               -  alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN
                  unless associated with hepatic metastases, then ALT and AST ≤ 5 × ULN

               -  creatinine ≤ 2.0 mg/dL

          7. Have been informed of other treatment options.

          8. Age ≥ 18 years.

          9. Able and willing to give valid written informed consent.

         10. Able and willing to give valid written consent for archival tumor samples.

         11. Able and willing to give valid written consent for biopsy samples (subjects with
             biopsiable tumors, and if clinically appropriate, in the expansion phase only).

        Exclusion Criteria

          1. Prior exposure to tremelimumab or durvalumab or other anti-cytotoxic
             T-lymphocyte-associated antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1),
             anti-programmed cell death ligand-1 (PD-L1) antibodies.

          2. History of severe allergic reactions to any unknown allergens or any components of the
             study drugs.

          3. Active or prior autoimmune disease except for autoimmune thyroiditis or vitiligo.

          4. Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior
             corticosteroid-refractory irAE.

          5. Known active or chronic viral hepatitis or history of any type of hepatitis within the
             last 6 months.

          6. History of sarcoidosis syndrome.

          7. Active or history of inflammatory bowel disease (colitis, Crohn's), diverticulitis,
             irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal
             conditions associated with diarrhea. Active or history of systemic lupus erythematosus
             or Wegener's granulomatosis.

          8. Metastatic disease to the central nervous system for which other therapeutic options,
             including radiotherapy, may have been available.

          9. Known immunodeficiency or active human immunodeficiency virus (HIV).

         10. Other active serious illnesses (e.g., serious infections requiring antibiotics).

         11. If a subject previously received investigational treatment, the last dose of
             investigational treatment was administered within 4 weeks of Day 1 of the study or
             AE(s) attributable to investigational treatment had not resolved to Grade 1 or better.

         12. Major surgical procedure (as defined by the Investigator) within 30 days prior to Day
             1 or still recovering from prior surgery.

         13. Mental impairment that may have compromised the ability to give informed consent and
             comply with the requirements of the study.

         14. Lack of availability for immunological and clinical follow-up assessments.

         15. Women who were breast feeding or pregnant as evidenced by positive serum pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]).

         16. Female subjects of childbearing potential who were sexually active with a
             non-sterilized male partner must have used at least one highly effective method of
             contraception from the time of screening and must have agreed to continue using such
             precautions for 90 days after the last dose of durvalumab or for 6 months after the
             final dose of durvalumab + tremelimumab (whichever was longer). Non-sterilized male
             partners of a female subject must have used male condoms plus spermicide throughout
             this period. Cessation of birth control after this point should have been discussed
             with a responsible physician. Not engaging in sexual activity for the total duration
             of the trial and the drug washout period was an acceptable practice; however, periodic
             abstinence, the rhythm method, and the withdrawal method were not acceptable methods
             of birth control.

             Female subjects should have also refrained from breastfeeding throughout the period
             described above.

             Females of childbearing potential were defined as those who were not surgically
             sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
             hysterectomy) or post-menopausal.

             Females were considered post-menopausal if they had been amenorrheic for 12 months
             without an alternative medical cause. The following age-specific requirements applied:

               -  Females <50 years of age were considered post-menopausal if they had been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they had luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Females ≥ 50 years of age were considered post-menopausal if they had 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 subjects who were sexually active with a female partner of
             childbearing potential must have used male condoms plus spermicide from screening
             through 90 days after the last dose of durvalumab or through 6 months after receipt of
             the final dose of durvalumab + tremelimumab (whichever was longer). Female partners
             (of childbearing potential) of a male subject must have used a highly effective method
             of contraception throughout this period. Cessation of birth control after this point
             should have been discussed with a responsible physician. Not engaging in sexual
             activity for the total duration of the trial and the drug washout period was an
             acceptable practice; however, periodic abstinence, the rhythm method, and the
             withdrawal method were not acceptable methods of contraception.

             Male subjects should have refrained from sperm donation throughout the period
             described above.

             A highly effective method of contraception was defined as one that resulted in a low
             failure rate (i.e. less than 1% per year) when used consistently and correctly. Note
             that some contraception methods were not considered highly effective (e.g., male or
             female condom with or without spermicide; female cap, diaphragm, or sponge with or
             without spermicide; non-copper containing intrauterine device; progestogen-only oral
             hormonal contraceptive pills where inhibition of ovulation is not the primary mode of
             action [excluding Cerazette/desogestrel which was considered highly effective]; and
             triphasic combined oral contraceptive pills).

         17. Any condition that, in the clinical judgment of the treating physician, was likely to
             prevent the subject from complying with any aspect of the protocol or that may have
             put the subject at unacceptable risk.

         18. Subjects must not have donated blood while on study and for at least 90 days following
             the last durvalumab treatment or 6 months after the last tremelimumab treatment,
             whichever was longer.