Neoadjuvant Study of Abemaciclib, Durvalumab, and an Aromatase Inhibitor Early Stage Breast Cancer

A Pilot Neoadjuvant Clinical Trial of Combination Therapy With Abemaciclib, Durvalumab (MEDI4736), and an Aromatase Inhibitor in Locally Advanced Hormone Receptor Positive Breast Cancer

The purpose of this study is to test the efficacy, safety and tolerability of a combination of immunotherapy and anticancer drugs presurgery in patients with hormone-receptor positive breast cancer.

Study Overview

• Status: Withdrawn
• Conditions: Locally Advanced Breast Cancer; Hormone Receptor Positive Malignant Neoplasm of Breast; Breast Cancer Female
• Intervention / Treatment: Drug: Abemaciclib, durvalumab and aromatase inhibitor

Detailed Description

The primary hypothesis is that a Programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor combined with a Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor will be well tolerated in early stage, hormone receptor positive (HR+) breast cancer patients treated with neoadjuvant endocrine therapy (NET). The secondary hypothesis and biomarker based endpoint is that patients with HR positive locally advanced breast cancer with low to intermediate stromal tumor-infiltrating lymphocytes (TILs) will demonstrate an increase in stromal TILs following NET when combined with abemaciclib and durvalumab for 4 cycles (16 weeks).

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. A signed, written informed consent will be obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.

2. Postmenopausal women age ≥ 18 years at time of study entry. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

   • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
   • Women <50 years of age receiving luteinising hormone-releasing hormone (LHRH) agonist for ovarian suppression are also eligible for the study but must initiate LHRH agonist therapy at least 2 weeks prior to starting on study intervention.
   • Women ≥ 50 years of age would be considered post-menopausal if they have 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).
3. Histologically confirmed estrogen and/or progesterone positive invasive breast cancer, defined as either estrogen and/or progesterone receptor (ER/PR) staining >10%, AND Human Epidermal Growth Factor Receptor 2 (HER2) negative by either Immunohistochemistry (IHC) or Fluorescent in situ Hybridization (FISH).
4. Clinical stage II-III disease with no clinical or radiologic evidence of metastatic disease. Patients must have a measurable primary breast lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines.
5. Eastern Cooperative Oncology Group (ECOG) status < 1.
6. Patient must be able to swallow pills.

7. Adequate organ and marrow function as defined below and in Table 1:

   • Hemoglobin ≥ 9 g/deciliter
   • Absolute neutrophil count ≥ 1,500/mm3
   • Platelet count ≥ 100,000/mm3
   • Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2 × institutional upper limit of normal (ULN)
   • Bilirubin ≤ 1.5 × ULN; for subjects with documented/suspected Gilbert's disease, bilirubin ≤ 2 × ULN
   • Creatinine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation, or creatinine ≤1.5 x ULN
8. Patient 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.
9. Must have a life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Any serious preexisting medical condition(s) that would place the patient at increased risk for toxicities including interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel.
2. Body weight < 30 kg (or 66.5 lbs.). If during the study, the patient's weight drops to < 30 Kg (or 66.5 lbs), they will be withdrawn from the study.
3. Females who are pregnant or lactating.
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, severe active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirement or compromise the ability of the subject to give written informed consent
5. Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, Grave's disease, Hashimoto's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are eligible
6. History of significant cardiac disease including heart failure, ventricular arrhythmia, or prolonged QT syndrome.
7. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or a preexisting chronic condition resulting in baseline ≥ Grade 2 diarrhea.)
8. History of primary immunodeficiency, or subjects who are known to be HIV (Human Immunodeficiency Virus ) positive
9. History of organ transplant that requires use of immunosuppressives
10. Known allergy or reaction to any of the study drugs.
11. Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured
12. Major surgical procedure (as defined by the investigator) within 30 days prior to the first dose of study drugs or still recovering from prior surgery
13. Known history of tuberculosis
14. Subjects who are known to be hepatitis B or C positive
15. History of prior therapy with a checkpoint (PD-L1/PD-1) including durvalumab or CDK4/6 inhibitor
16. History of prior ipsilateral radiation therapy to the cancer-affected breast
17. History of prior therapy with an investigational anticancer therapy within 6 weeks prior to the first dose of study drugs
18. Prior chemotherapy or aromatase inhibitor therapy for breast cancer
19. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
20. Patients who must take strong cytochrome cytochrome P450 (CYP3A) inhibitors such as clarithromycin, diltiazem, verapamil, itraconazole, or ketoconazole
21. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
22. Concurrent enrollment in another therapeutic clinical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Active; Experimental treatment	Drug: Abemaciclib, durvalumab and aromatase inhibitor; Subjects will receive standard therapy with an aromatase inhibitor (exemestane, anastrozole, or letrozole), combined with the experimental treatment of abemaciclib and durvalumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	The primary endpoints will be safety and tolerability of the study intervention	Through study completion, up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic response at surgery	Pathologic response at surgery by Preoperative Endocrine Prognostic Index (PEPI) score	At the time of definitive surgery
Pathologic response at surgery	Pathologic response at surgery by change in Ki-67% from pre and surgical biopsies	At the time of definitive surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the number of T cells	Change in subtype of T cell infiltrates and spatial relationship of T cells to tumor cells (number of T cells withing the tumor)	At the time of definitive surgery
Change in the number of T regs cells	Change in number of T regs per tumor spatial unit	At the time of definitive surgery
Change in the number of macrophages	Change in number of myeloid derived immunosuppressive cells (M1 vs M2 macrophages) per tumor spatial unit	At the time of definitive surgery
Changes in immune markers in the tumor specimens and/or peripheral blood	Change in gene expression immune signatures (RNA quantification)	At the time of definitive surgery

Collaborators and Investigators

• Sponsor: Alison Stopeck
• Collaborators: Eli Lilly and Company; AstraZeneca
• Investigators: Study Director: Alison Stopeck, MD, Stony Brook University; Principal Investigator: Lea Baer, MD, Stony Brook University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): October 1, 2019
• Primary Completion (ANTICIPATED): December 31, 2020
• Study Completion (ANTICIPATED): December 31, 2020

Study Registration Dates

• First Submitted: September 10, 2019
• First Submitted That Met QC Criteria: September 11, 2019
• First Posted (ACTUAL): September 12, 2019

Study Record Updates

• Last Update Posted (ACTUAL): July 16, 2020
• Last Update Submitted That Met QC Criteria: July 14, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Site; Breast Diseases; Neoplasms; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Immunological; Hormone Antagonists; Steroid Synthesis Inhibitors; Estrogen Antagonists; Durvalumab; Aromatase Inhibitors
• Other Study ID Numbers: 2019-00174 Neoadj Breast Pilot

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No