A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab

NCT01975831 | Completed Phase 1 Results FDA Drug

• 1 other identifier: LUD2013-003
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 6

Brief 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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

  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.

  Up to 36 months

Secondary Outcomes (5)

• Number of Subjects With Best Overall Immune-related Tumor Response

  Up to 24 months

• Number of Subjects With Best Overall Tumor Response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  Up to 24 months

• Median Progression-free Survival Per irRC Based on Kaplan-Meier Product Limit Estimates

  Up to 36 months

• Median Progression-free Survival Per RECIST 1.1 Based on Kaplan-Meier Product Limit Estimates

  Up to 36 months

• Median Overall Survival (OS) Based on Kaplan-Meier Product Limit Estimates

  Up to 48 months

Study Arms (9)

Escalation: 0.3 mg/kg Durva + 3 mg/kg Treme

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Escalation: 1 mg/kg Durva + 3 mg/kg Treme

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Escalation: 3 mg/kg Durva + 3 mg/kg Treme

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Escalation: 3 mg/kg Durva + 1 mg/kg Treme

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Expansion: Ovarian Cancer

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Expansion: Colorectal Cancer

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Expansion: Non-triple Negative Breast Cancer

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Expansion: Renal Cell Carcinoma

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Expansion: Cervical Cancer

EXPERIMENTAL

Subjects 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.

Drug: Durvalumab; Drug: Tremelimumab

Interventions

Durvalumab DRUG

Durvalumab was administered as an intravenous (IV) infusion over 60 (± 5) minutes.

Also known as: MEDI4736, Durva

Escalation: 0.3 mg/kg Durva + 3 mg/kg Treme; Escalation: 1 mg/kg Durva + 3 mg/kg Treme; Escalation: 3 mg/kg Durva + 1 mg/kg Treme; Escalation: 3 mg/kg Durva + 3 mg/kg Treme; Expansion: Cervical Cancer; Expansion: Colorectal Cancer; Expansion: Non-triple Negative Breast Cancer; Expansion: Ovarian Cancer; Expansion: Renal Cell Carcinoma

Tremelimumab DRUG

Tremelimumab was administered as an intravenous (IV) infusion over 60 (± 5) minutes.

Also known as: Treme

Escalation: 0.3 mg/kg Durva + 3 mg/kg Treme; Escalation: 1 mg/kg Durva + 3 mg/kg Treme; Escalation: 3 mg/kg Durva + 1 mg/kg Treme; Escalation: 3 mg/kg Durva + 3 mg/kg Treme; Expansion: Cervical Cancer; Expansion: Colorectal Cancer; Expansion: Non-triple Negative Breast Cancer; Expansion: Ovarian Cancer; Expansion: Renal Cell Carcinoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Failed to respond to or relapsed following standard treatment or declined or was not eligible for standard treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Anticipated lifespan greater than 6 months.
• 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).
• 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

You may not qualify if:

• 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.
• History of severe allergic reactions to any unknown allergens or any components of the study drugs.
• Active or prior autoimmune disease except for autoimmune thyroiditis or vitiligo.
• Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE.
• Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months.
• History of sarcoidosis syndrome.
• 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.
• Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may have been available.
• Known immunodeficiency or active human immunodeficiency virus (HIV).
• Other active serious illnesses (e.g., serious infections requiring antibiotics).
• 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.
• Major surgical procedure (as defined by the Investigator) within 30 days prior to Day 1 or still recovering from prior surgery.
• Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
• Lack of availability for immunological and clinical follow-up assessments.
• 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 \[HCG\]).

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• MedImmune LLC: collaborator
• Cancer Research Institute, New York City: collaborator

Study Sites (6)

Yale Cancer Center

New Haven, Connecticut, 06510, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14203, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Mary Crowley Cancer Research Center

Dallas, Texas, 75230, United States

Location

University of Virginia Division of Hematology and Oncology

Charlottesville, Virginia, 22903, United States

Location

Related Publications (2)

• Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20. doi: 10.1158/1078-0432.CCR-09-1624. Epub 2009 Nov 24.

  PMID: 19934295 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Ovarian Neoplasms; Colorectal Neoplasms; Uterine Cervical Neoplasms; Carcinoma, Renal Cell

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Uterine Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• Jedd D Wolchok, MD, PhD

  Memorial Sloan Kettering Cancer Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2013
• First Posted: November 5, 2013
• Study Start: December 19, 2013
• Primary Completion: December 1, 2019
• Study Completion: July 2, 2021
• Last Updated: October 12, 2022
• Results First Posted: June 22, 2020

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)