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Breast CancerPhase 1NCT01975831

A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab

A Phase 1 study testing Durvalumab and Tremelimumab in people with Breast Cancer and Ovarian Cancer, run by Ludwig Institute for Cancer Research at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Breast Cancer, Ovarian Cancer, Colorectal Cancer
What is being tested?
Durvalumab and Tremelimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
104 participants
Where
6 sitesUnited States
Study dates
19 Dec 2013to 2 Jul 2021
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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;
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  • 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
  • Have been informed of other treatment options.
  • Age ≥ 18 years.
  • Able and willing to give valid written informed consent.
  • Able and willing to give valid written consent for archival tumor samples.
  • Able and willing to give valid written consent for biopsy samples (subjects with biopsiable tumors, and if clinically appropriate, in the expansion phase only).

Who cannot join

  • 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.
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  • 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]).
  • 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).
  • 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.
  • 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.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Roswell Park Cancer Institute

    Buffalo, New York, 14203

  • University of Virginia Division of Hematology and Oncology

    Charlottesville, Virginia, 22903

  • Mary Crowley Cancer Research Center

    Dallas, Texas, 75230

  • Yale Cancer Center

    New Haven, Connecticut, 06510

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

Other trials in United States

About this study

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

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.

Read the 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).

Being tested
Durvalumab, Tremelimumab
Medical subject headings
Breast Neoplasms, Ovarian Neoplasms, Colorectal Neoplasms, Uterine Cervical Neoplasms, Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called MEDI4736, Durva

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

  • TremelimumabDrug

    Also called Treme

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

Study groups in NCT01975831
Study groupRoleWhat they receive
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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: 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.
Receives: Drug: Durvalumab; Drug: Tremelimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 36 months

Secondary outcomes (5)

  1. Number of Subjects With Best Overall Immune-related Tumor Response

    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.

    Measured: Up to 24 months

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

    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.

    Measured: Up to 24 months

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

    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.

    Measured: Up to 36 months

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

    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.

    Measured: Up to 36 months

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

    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.

    Measured: Up to 48 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Nov 2013 (estimated)
  2. Study start19 Dec 2013
  3. Primary completionDec 2019
  4. Study completion2 Jul 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
104 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01975831
Sponsor's protocol ID
LUD2013-003
Status last verified
Oct 2022
First submitted
29 Oct 2013
Last updated
12 Oct 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 19934295

  • 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.

    PubMed 19097774

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Durvalumab and Tremelimumab in people with Breast Cancer and Ovarian Cancer, run by Ludwig Institute for Cancer Research at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) (time frame: Up to 36 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01975831, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Oct 2022.

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