A Pilot Study of the Combination of Entinostat With Capecitabine in High Risk Breast Cancer After Neo-adjuvant Therapy

NCT03473639 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 20218
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to learn about the safety and side effects of combining entinostat, an investigational drug, with capecitabine, a drug commonly used in breast cancer (BC), in both participants with metastatic breast cancer (MBC) and then participants with high-risk breast cancer after neo-adjuvant therapy.

Conditions

Metastatic Breast Cancer; Breast Cancer

Keywords

Residual invasive breast cancer; Metastatic breast cancer

Outcome Measures

Primary Outcomes (3)

• Identification of a maximum tolerated dose combination (MTDC) of entinostat and capecitabine

  This will be defined based on the number of "dose limiting toxicities" in participants at each dose level.

  During the first cycle of treatment (each cycle is 21 days) for each participant

• Frequency of adverse events (AEs) in participants with high-risk breast cancer after neo-adjuvant therapy

  Frequency of adverse events (AEs) in participants with high-risk BC after neo-adjuvant therapy at the determined MTDC.

  AEs from consent through 30 days following stopping study treatment. Study treatment-related serious adverse events (SAEs) anytime

• Severity (as graded with the Common Terminology Criteria for Adverse Events (CTCAE)) of adverse events (AEs) in participants with high-risk breast cancer after neo-adjuvant therapy

  Severity of adverse events (AEs) in participants with high-risk BC after neo-adjuvant therapy at the determined MTDC.

  AEs from consent through 30 days following stopping study treatment. Study treatment-related serious adverse events (SAEs) anytime

Secondary Outcomes (5)

• Frequency of adverse events (AEs) in MBC participants at the determined MTDC.

  AEs from consent through 30 days following stopping study treatment. Study treatment-related serious adverse events (SAEs) anytime

• Disease-free survival (DFS)

  Participants will be followed for up to 10 years following completion of study therapy

• Severity (as graded with the Common Terminology Criteria for Adverse Events (CTCAE)) of adverse events (AEs) in MBC participants

  AEs from consent through 30 days following stopping study treatment. Study treatment-related serious adverse events (SAEs) will be collected starting at consent and continuing for the life of the study.

• Frequency of adverse events (AEs) and dose-limiting toxicities (DLTs) in participants on both arms of the study at the determined MTDC.

  DLTs will be identified during the 1st cycle (each cycle is 21 days) of study treatment. AEs from consent through 30 days following completion of treatment. Study treatment-related SAEs will be collected starting at consent through end of study

• Severity (as graded with the CTCAE) of adverse events (AEs) in participants on both arms of the study at the determined MTDC

  DLTs will be identified during the 1st cycle (each cycle is 21 days) of study treatment. AEs from consent through 30 days following completion of treatment. Study treatment-related SAEs will be collected starting at consent through end of study

Other Outcomes (6)

• Overall survival

  Up to 10 years following completion of study treatment for each participant

• Relationship of circulating tumor DNA and residual disease

  Before and after study treatment (unless treatment is stopped early for safety, disease progression/recurrence, or subject or investigator decision, treatment will last 8 cycles of 21 days each) for each participant with high-risk BC following surgery

• Relationship of circulating tumor cells and residual disease

  Before and after study treatment (unless treatment is stopped early for safety, disease progression/recurrence, or subject or investigator decision, treatment will last 8 cycles of 21 days each) for each participant with high-risk BC following surgery.

Study Arms (1)

Entinostat and Capecitabine

EXPERIMENTAL

Dose escalation of the combination of entinostat and capecitabine in MBC patients. This dose will be given to MBC patients and to BC patients with residual invasive disease after neoadjuvant chemotherapy and surgery. The dose combinations include: Combination 1: 3 mg/week entinostat, 800 mg/m2 twice a day for 14 days of capecitabine Combination 2: 5 mg/week entinostat, 800 mg/m2 twice a day for 14 days of capecitabine Combination 3: 3 mg/week entinostat, 1000 mg/m2 twice a day for 14 days of capecitabine Combination 4: 5 mg/week entinostat, 1000 mg/m2 twice a day for 14 days of capecitabine If a participant experiences unacceptable side effects, he or she will receive the next lowest dose combination. If he or she is on Combination 1, he or she will stop study treatment.

Drug: Entinostat; Drug: Capecitabine

Interventions

Entinostat DRUG

In metastatic breast cancer patients, entinostat will be taken orally starting at 3 mg per week and will increase to 5 mg per week in the absence of unacceptable side effects. The safe dose (when combined with capecitabine) will be confirmed in additional metastatic breast cancer patients and breast cancer patients with residual invasive disease following neoadjuvant chemotherapy and surgery.

Also known as: SNDX-275

Entinostat and Capecitabine

Capecitabine DRUG

In metastatic breast cancer patients, capecitabine will be taken by mouth starting at 800 mg/m2 twice a day for 14 days per cycle and increase to 1000 mg/m2 (for 14 days per cycle) in the absence of unacceptable side effects. The safe dose (when combined with capecitabine) will be confirmed in additional metastatic breast cancer patients and breast cancer patients with residual invasive disease following neoadjuvant chemotherapy and surgery.

Also known as: Xeloda

Entinostat and Capecitabine

Eligibility Criteria

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

You may qualify if:

• Disease Characteristics by Dose Escalation Phase and Expansion Phase:
• Part A: Dose Escalation Phase:
• Patients must have a histologically confirmed diagnosis of stage IV invasive breast cancer.
• Patients can have breast cancer with positive OR negative estrogen and progesterone receptor status. Patients must have negative HER-2 receptor status. Estrogen, progesterone, and HER2 receptor status must be assessed according to ASCO/CAP guidelines. ER or PR positivity is defined as ≥ 1% positive nuclear staining. HER-2 is negative if tumor testing shows: a) IHC negative (0 or 1+) or b) ISH negative using single probe or dual probe. If HER-2 IHC is 2+, ISH must be performed and negative. HER-2 equivocal is not eligible.
• Part B: Expansion Phase:
• Patients must have a histologically confirmed diagnosis of stage I-III invasive breast cancer.
• Patients with multifocal, multicentric, synchronous bilateral and primary inflammatory breast cancers are allowed.
• Multifocal disease is defined as more than one invasive cancer \< 2 cm from the largest lesion within the same breast quadrant.
• Multicentric disease is defined as more than one invasive cancer ≥ 2 cm from the largest lesion within the same breast quadrant or more than one lesion in different quadrants.
• Synchronous bilateral disease is defined as invasive breast cancer with positive lymph nodes (axillary or intramammary) in at least one breast, diagnosed within 30 days of each other. NOTE: The tumor with the highest recurrence score should be used.
• Patients can have breast cancer with positive OR negative estrogen and progesterone receptor status. Patients must have negative HER-2 receptor status. Estrogen, progesterone, and HER2 receptor status must be assessed according to ASCO/CAP guidelines. ER or PR positivity is defined as ≥ 1% positive nuclear staining. HER-2 is negative if tumor testing shows: a) IHC negative (0 or 1+) or b) ISH negative using single probe or dual probe. If HER-2 IHC is 2+, ISH must be performed and negative. HER-2 equivocal is not eligible.
• Patients must have been treated with standard neoadjuvant chemotherapy with at least three cycles of taxane or anthracycline based regimen. Patients must be registered within 36 weeks after last dose of chemotherapy.
• Patients must have histologically confirmed residual invasive carcinoma at the time of surgery (ypT1mi or greater) or positive lymph nodes (ypN0(itc) or greater).
• Both Phases:
• Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the investigator.

You may not qualify if:

• Subjects who have had chemotherapy, biological therapy, immunological therapy, radiation therapy, or hormonal therapy within 3 weeks prior to first dose of study treatment.
• Subjects who are unable or unwilling to discontinue use of prohibited medications.
• Subject is unable or unwilling to participate in a study related procedure.
• Subject is a prisoner.
• Subject has evidence or history of an uncontrolled bleeding disorder. Patients with chronic bleeding disorders that are controlled with treatment or not clinically relevant are allowed.
• Subjects with history of CNS disease including primary brain tumor, seizures not controlled with standard medical therapy, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within six months of first dose of study treatment.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment AND enrolling in the metastatic dose escalation phase of present study only.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:
• Myocardial infarction or arterial thromboembolic events within 6 months prior to first dose of study treatment or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval \> 470 msec.
• Uncontrolled hypertension (defined as BP \>160/100) or diabetes mellitus.
• Another known malignancy that is progressing or requires active treatment.
• Any prior history of other cancer within the 2 years prior to first dose of study treatment with the exception of adequately treated non-melanoma skin cancer or cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ or melanoma in situ).
• Active infection requiring systemic therapy.
• Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
• Allergy to benzamide or inactive components of entinostat.

Sponsors & Collaborators

• University of Virginia: lead
• Syndax Pharmaceuticals: collaborator

Study Sites (2)

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Related Publications (1)

• Millard T, Brenin C, Humphrey C, Dhakal A, Falkson C, Petroni G, Wages NA, Dillon P. A Pilot Study of the Combination of Entinostat with Capecitabine in Advanced Breast Cancer. Int J Breast Cancer. 2024 Feb 7;2024:5515966. doi: 10.1155/2024/5515966. eCollection 2024.

  PMID: 38356965 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

entinostat; Capecitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Patrick Dillon, MD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 14, 2018
• First Posted: March 22, 2018
• Study Start: January 29, 2019
• Primary Completion: September 2, 2021
• Study Completion: November 1, 2022
• Last Updated: November 1, 2022

Record last verified: 2022-10

Locations

US (2)