Clinical Trials /

A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab

NCT01975831

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Cervical Carcinoma
  • Colorectal Carcinoma
  • Ovarian Carcinoma
  • Renal Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab
  • Official Title: A Phase 1 Study to Evaluate the Safety and Tolerability of Anti-PD-L1, MEDI4736, in Combination With Tremelimumab in Subjects With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: LUD2013-003
  • NCT ID: NCT01975831

Conditions

  • Breast Cancer
  • Ovarian Cancer
  • Colorectal Cancer
  • Cervical Cancer
  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
DurvalumabMEDI4736, DurvaEscalation: 0.3 mg/kg Durva + 3 mg/kg Treme
TremelimumabTremeEscalation: 0.3 mg/kg Durva + 3 mg/kg Treme

Purpose

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.

Detailed Description

      The study comprised a 3 + 3 dose escalation phase in which 3 to 6 subjects were enrolled into
      sequential cohorts until determination of the MTD, followed by an expansion phase in 5 tumor
      type-specific cohorts (i.e., ovarian cancer, colorectal cancer, non-triple negative breast
      cancer, renal cell carcinoma, and cervical cancer). Each expansion cohort was to include 15
      subjects treated with the identified MTD or maximum dose tested in the dose-escalation phase.

      Subjects received durvalumab and tremelimumab over 12 to 13 four-week cycles during the Core
      Study, with continuous monitoring for safety, clinical efficacy, and biological activity,
      followed by optional treatment extension with durvalumab for subjects maintaining at least
      stable disease if agreed upon by the Investigator and Sponsor. After study treatment
      completion, study assessments were continued for up to 90 days after the last administration
      of study treatment or until start of alternate therapy, with long-term follow up after study
      completion for clinical outcomes at least every 6 months for up to 3 years following
      initiation of treatment.

      Study treatment in the Core Study continued for up to 12 months or until confirmed
      progressive disease (PD), initiation of alternative cancer therapy, observation of
      unacceptable toxicity, or any other criteria for treatment discontinuation.

      Optional treatment extension beyond the Core Study was permitted for subjects who completed
      the Core Study with a tumor response of stable disease or better and upon agreement by the
      Sponsor and Investigator. Extended treatment comprised durvalumab monotherapy administered at
      the recommended fixed dose of 1500 mg administered every 4 weeks (Q4W).
    

Trial Arms

NameTypeDescriptionInterventions
Escalation: 0.3 mg/kg Durva + 3 mg/kg TremeExperimentalSubjects received durvalumab (0.3 mg/kg every 2 weeks [Q2W] for 13 cycles) and tremelimumab (3 mg/kg every 4 weeks [Q4W] for 6 cycles, then every 12 weeks [Q12W]). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Escalation: 1 mg/kg Durva + 3 mg/kg TremeExperimentalSubjects received durvalumab (1 mg/kg Q2W for 13 cycles) and tremelimumab (3 mg/kg Q4W for 6 cycles, then Q12W). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Escalation: 3 mg/kg Durva + 3 mg/kg TremeExperimentalSubjects received durvalumab (3 mg/kg Q2W for 13 cycles) and tremelimumab (3 mg/kg Q4W for 6 cycles, then Q12W). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Escalation: 3 mg/kg Durva + 1 mg/kg TremeExperimentalSubjects received durvalumab (3 mg/kg Q2W for 12 or 13 cycles) and tremelimumab (1 mg/kg Q4W for 6 cycles, then Q12W or Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Expansion: Ovarian CancerExperimentalSubjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Expansion: Colorectal CancerExperimentalSubjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Expansion: Non-triple Negative Breast CancerExperimentalSubjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Expansion: Renal Cell CarcinomaExperimentalSubjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab
Expansion: Cervical CancerExperimentalSubjects received durvalumab (10 mg/kg Q2W for 13 cycles or 1500 mg Q4W for 12 cycles) and tremelimumab (1 mg/kg or 75 mg Q4W for 4 cycles). Optional extended treatment comprised durvalumab monotherapy administered at the recommended fixed dose of 1500 mg Q4W.
  • Durvalumab
  • Tremelimumab

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
Time Frame:Up to 36 months
Safety Issue:
Description:Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, electrocardiograms, magnetic resonance imaging, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of study treatment. AEs were considered to be treatment emergent (TEAE) if they occurred or worsened in severity after the first dose of study treatment.

Secondary Outcome Measures

Measure:Number of Subjects With Best Overall Immune-related Tumor Response
Time Frame:Up to 24 months
Safety Issue:
Description:Immune-related tumor response was evaluated by computed tomography at Baseline and every 4 to 8 or 12 weeks on study. Tumor response was designated according to the immune-related Response Criteria (irRC) (Wolchok et al 2009) into the following categories: immune-related complete response (irCR) requires disappearance of all lesions in two consecutive observations not less than 4 weeks apart; immune-related partial response (irPR) requires ≥ 50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart; immune-related stable disease (irSD) is assigned when neither a 50% decrease from baseline tumor burden nor a 25% increase in tumor burden from nadir can be established; immune-related progressive disease (irPD) requires a ≥ 25% increase from nadir in tumor burden at any single time point in two consecutive observations at least 4 weeks apart.
Measure:Number of Subjects With Best Overall Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time Frame:Up to 24 months
Safety Issue:
Description:Tumor response was evaluated using computed tomography and categorized according to RECIST (version 1.1) at Baseline and every 4 to 8 or 12 weeks on study. Per RECIST 1.1 (Eisenhauer et al 2009), target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.
Measure:Median Progression-free Survival Per irRC Based on Kaplan-Meier Product Limit Estimates
Time Frame:Up to 36 months
Safety Issue:
Description:PFS was measured from the date of the first dose of study treatment to the date of the first confirmed progression (including clinical progression) or the date of death if a subject died before progression. Per irRC, irPD requires a ≥ 25% increase from nadir in tumor burden at any single time point in two consecutive observations at least 4 weeks apart (Wolchok et al 2009). Subjects who did not experience a PFS event (progression or death) were censored at the date of the last tumor assessment. Subjects with no relevant tumor response assessment were censored at the start date of study treatment.
Measure:Median Progression-free Survival Per RECIST 1.1 Based on Kaplan-Meier Product Limit Estimates
Time Frame:Up to 36 months
Safety Issue:
Description:PFS was measured from the date of the first dose of study treatment to the date of the first confirmed progression (including clinical progression) or the date of death if a subject died before progression. Per RECIST 1.1, PD requires a ≥ 20% increase in the sum of the longest diameter of target lesions (Eisenhauer et al 2009). Subjects who did not experience a PFS event (progression or death) were censored at the date of the last tumor assessment. Subjects with no relevant tumor response assessment were censored at the start date of study treatment.
Measure:Median Overall Survival (OS) Based on Kaplan-Meier Product Limit Estimates
Time Frame:Up to 48 months
Safety Issue:
Description:All subjects were monitored for survival follow-up at least every 6 months after study completion for up to 3 years after initiation of treatment. Subjects who continued into the Extension part of the study may have been followed for longer than 3 years if they were still receiving treatment. OS was measured from the date of the first dose of study treatment until the recorded date of death. Subjects without a recorded outcome of death were censored at the date of last contact.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Ludwig Institute for Cancer Research

Last Updated

March 17, 2021