Evaluating Anti-PD-L1 Antibody (Durvalumab) Plus Anti-CTLA-4 Antibody (Tremelimumab) in HR+/HER2- Breast Cancer

• Status: Not yet recruiting
• Trial end date: 0000-00-00
• Target enrollment: 15
• Participant gender: Female

Summary

The goal of this clinical research study is to find the highest dose combination of tremelimumab and durvalumab [also called MEDI4736]) that can be given before standard of care pre-surgery chemotherapy to patients with HR+, HER2- breast cancer. Researchers also want to learn more about how certain immune cells may change in the body when they are given the drug combination. Researchers also want to find out how patients with HR+, HER2- breast cancer respond to the study drugs before they receive standard chemotherapy treatment.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: M.D. Anderson Cancer Center
• Collaborator: AstraZeneca
• Treatments: Antibodies; Antibodies, Monoclonal; Tremelimumab
• Last Updated: 2017-04-26

Criteria

Inclusion Criteria:

1. Written informed consent and any locally-required authorization (e.g., HIPAA) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations

2. Age >/= 18 years at time of study entry

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

4. Hormone receptor positive (defined as estrogen receptor [ER] and/or progesterone receptor [PR] positive), HER2 negative breast cancer that is clinically staged I-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 ASCO-CAP criteria which are as follows: HER2 testing by 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

5. Chemotherapy is planned for the patient in the neoadjuvant setting

6. Adequate normal organ and marrow function as defined below: 1) Hemoglobin >/=9.0 g/dL, 2) Absolute neutrophil count (ANC) >/=1.5 x 109/L (>/=1500 per mm3), 3) Platelet count >/=100 x 109/L (>/=100,000 per mm3), 4) Serum bilirubininstitutional 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. 5) AST (SGOT)/ALT (SGPT)unless liver metastases are present, in which case it must becreatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

7. 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.

8. 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:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

2. Participation in another clinical study with an investigational product during the last 1 month prior to initiation of therapy

3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab

4. History of another primary malignancy except for: 1) 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, 2) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, 3) Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ

5. Has not received therapy for this current diagnosis of breast cancer including endocrine therapy or chemotherapy

6. A single QT interval corrected for heart rate (QTc) >/= 470 ms. If an 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 Fredericia's Correction

7. 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

8. Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.

9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

10. History of primary immunodeficiency

11. History of allogeneic organ transplant

12. History of hypersensitivity to durvalumab or tremelimumab or any excipient

13. History of hypersensitivity to the combination or comparator agent (if applicable)

14. 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

15. Known history of previous clinical diagnosis of tuberculosis

16. History of leptomeningeal carcinomatosis

17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab

18. 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

19. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

20. Subjects with uncontrolled seizures