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Durvalumab and Tremelimumab Before Surgery in Treating Patients With Hormone Receptor Positive, HER2 Negative Stage II-III Breast Cancer

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ClinicalTrials.gov Identifier: NCT03132467
Recruitment Status : Active, not recruiting
First Posted : April 27, 2017
Last Update Posted : August 2, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This early phase I trial studies the side effects of durvalumab and tremelimumab before surgery in treating patients with hormone receptor positive, HER2 negative stage II-III breast cancer. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
Anatomic Stage II Breast Cancer AJCC v8 Anatomic Stage IIA Breast Cancer AJCC v8 Anatomic Stage IIB Breast Cancer AJCC v8 Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IIIA Breast Cancer AJCC v8 Anatomic Stage IIIB Breast Cancer AJCC v8 Anatomic Stage IIIC Breast Cancer AJCC v8 Estrogen Receptor Positive HER2/Neu Negative Progesterone Receptor Positive Prognostic Stage II Breast Cancer AJCC v8 Prognostic Stage IIA Breast Cancer AJCC v8 Prognostic Stage IIB Breast Cancer AJCC v8 Prognostic Stage III Breast Cancer AJCC v8 Prognostic Stage IIIA Breast Cancer AJCC v8 Prognostic Stage IIIB Breast Cancer AJCC v8 Prognostic Stage IIIC Breast Cancer AJCC v8 Biological: Durvalumab Biological: Tremelimumab Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the feasibility of enrolling patients with hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2-) breast cancer onto a trial evaluating investigational agents prior to initiating standard neoadjuvant chemotherapy.

II. To evaluate the safety and tolerability of tremelimumab plus durvalumab in patients with HR+/HER2- breast cancer.

SECONDARY OBJECTIVES:

I. To assess immunologic/molecular responses to tremelimumab and durvalumab in patients with HR+/HER2- breast cancer who receive the combination therapy.

EXPLORATORY OBJECTIVES:

I. To evaluate the pathologic response in patients with HR+/HER2- breast cancer receiving tremelimumab plus durvalumab prior to initiating standard neoadjuvant chemotherapy.

OUTLINE:

Patients receive tremelimumab intravenously (IV) over 1 hour and durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo a biopsy and receive standard of care neoadjuvant chemotherapy before undergoing surgery.

After completion of study treatment, patients are followed up until the time of surgery.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Pre-Surgical Study Evaluating Anti-PD-L1 Antibody (Durvalumab [MEDI4736]) Plus Anti-CTLA-4 Antibody (Tremelimumab) in Patients With Hormone Receptor Positive, HER2 Negative Breast Cancer
Actual Study Start Date : June 13, 2017
Estimated Primary Completion Date : June 13, 2020
Estimated Study Completion Date : June 13, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Treatment (tremelimumab, durvalumab)
Patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment repeats every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo a biopsy and receive standard of care neoadjuvant chemotherapy before undergoing surgery.
Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Biological: Tremelimumab
Given IV
Other Names:
  • Anti-CTLA4 Human Monoclonal Antibody CP-675,206
  • CP-675
  • CP-675,206
  • CP-675206
  • Ticilimumab




Primary Outcome Measures :
  1. Feasibility defined by number of patients willing to enroll [ Time Frame: Up to 2 years ]
    Feasibility established if all 15 patients enroll within 12 months of starting the study. The start date for measuring feasibility will be the date the first patient is screened.

  2. Feasibility defined by number of patients to complete the protocol [ Time Frame: Up to 2 years ]
    Feasibility established if at least 10 patients complete the study and have available immune data.

  3. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Will be recorded according to Common Terminology Criteria for Adverse Events (CTCAE) 4.03.


Secondary Outcome Measures :
  1. Change in immune and molecular measures in peripheral blood [ Time Frame: Baseline up to 2 months ]
    Descriptive statistics including plots, tabulations, mean, median and standard deviations will be used to summarize data. Differences and/or percent changes will be calculated between pre- and post-therapy samples from each patient and described as continuous measures.

  2. Change in immune and molecular measures in tumor tissue [ Time Frame: Baseline up to 2 months ]
    Descriptive statistics including plots, tabulations, mean, median and standard deviations will be used to summarize data. Differences and/or percent changes will be calculated between pre- and post-therapy samples from each patient and described as continuous measures.


Other Outcome Measures:
  1. Pathologic response [ Time Frame: At time of surgery ]
    Pathologic response at surgery will be recorded for each patient.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA]) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Hormone receptor positive (defined as estrogen receptor [ER] and/or progesterone receptor [PR] positive), HER2 negative breast cancer that is clinically staged II-III with no known metastatic disease. ER and/or PR defined as positive if expression > 10% by immunohistochemistry (IHC). HER2 negative or non-amplified as determined by the current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria which are as follows: HER2 testing by immunohistochemistry (IHC) as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive if: IHC 3+ based on circumferential membrane staining that is complete, intense ISH positive based on: 1) Single-probe average HER2 copy number >= 6.0 signals/cell, 2) Dual-probe HER2/CEP17 ratio >= 2.0; c,e with an average HER2 copy number >= 4.0 signals/cell, 3) Dual-probe HER2/CEP17 ratio >= 2.0; c,e with an average HER2 copy number < 4.0 signals/cell, 4) Dual-probe HER2/CEP17 ratio < 2.0; c,e with an average HER2 copy number >= 6.0 signals/cell
  • Chemotherapy is planned for the patient in the neoadjuvant setting
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >=1.5 x 10^9/L (>= 1500 per mm^3)
  • Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only upon treating physician, principal investigators (PI) or co-PIs approval
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
  • Creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
  • Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative urine pregnancy test upon study entry
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Participation in another clinical study with an investigational product during the last 1 month prior to initiation of therapy
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
  • 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 study drug 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 e.g., cervical cancer in situ
  • Has received therapy for this current diagnosis of breast cancer including endocrine therapy or chemotherapy
  • A single QT interval corrected for heart rate (QTc) >= 470 ms. If an electrocardiogram (ECG) is interpreted to be a prolonged QT interval, 2 additional ECGs will be obtained and the PI will then evaluate all three ECGs and determine whether the patient should be excluded. Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Active or prior documented autoimmune disease within the past 2 years

    • NOTE: Subjects with vitiligo, Graves disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
  • Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
  • History of primary immunodeficiency
  • History of allogeneic organ transplant
  • History of hypersensitivity to durvalumab or tremelimumab or any excipient
  • History of hypersensitivity to the combination or comparator agent (if applicable)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Known history of previous clinical diagnosis of tuberculosis
  • History of leptomeningeal carcinomatosis
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
  • Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Subjects with uncontrolled seizures

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03132467


Locations
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United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jennifer K Litton M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03132467     History of Changes
Other Study ID Numbers: 2016-0902
NCI-2018-01189 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2016-0902 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: April 27, 2017    Key Record Dates
Last Update Posted: August 2, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Durvalumab
Ipilimumab
Tremelimumab
Antibodies
Antibodies, Monoclonal
Hormones
Immunologic Factors
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Immunological
Antineoplastic Agents