Abexinostat, Palbociclib, and Fulvestrant for the Treatment of Breast or Gynecologic Cancer

NCT04498520 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 20953NCI-2020-05026
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I trial investigates the side effects and best dose of abexinostat and palbociclib when given together with fulvestrant in treating patients with breast or gynecologic cancer. Abexinostat may prevent tumor cells from growing and multiplying and may kill tumor cells. Palbociclib may prevent or slow the growth of tumor cells when used with other anti-hormonal therapy. Estrogen can cause the growth of breast and gynecologic tumor cells. Fulvestrant may help fight breast or gynecologic cancer by blocking the use of estrogen by the tumor cells. Giving abexinostat, palbociclib, and fulvestrant may work better in treating patients with breast or gynecologic cancer.

Conditions

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; Anatomic Stage IV Breast Cancer AJCC v8; Hormone Receptor Positive Breast Carcinoma; Locally Advanced Breast Carcinoma; Metastatic Breast Carcinoma; Metastatic Endometrioid Adenocarcinoma; Metastatic Fallopian Tube Carcinoma; Metastatic HER2 Negative Breast Carcinoma; Metastatic Malignant Solid Neoplasm; Metastatic Ovarian Carcinoma; Metastatic Primary Peritoneal Carcinoma; 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; Prognostic Stage IV Breast Cancer AJCC v8; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Refractory Breast Carcinoma; Stage IV Fallopian Tube Cancer AJCC v8; Stage IV Ovarian Cancer AJCC v8; Stage IV Primary Peritoneal Cancer AJCC v8; Stage IV Uterine Corpus Cancer AJCC v8; Stage IVA Fallopian Tube Cancer AJCC v8; Stage IVA Ovarian Cancer AJCC v8; Stage IVA Primary Peritoneal Cancer AJCC v8; Stage IVA Uterine Corpus Cancer AJCC v8; Stage IVB Fallopian Tube Cancer AJCC v8; Stage IVB Ovarian Cancer AJCC v8; Stage IVB Primary Peritoneal Cancer AJCC v8; Stage IVB Uterine Corpus Cancer AJCC v8

Keywords

Metastatic Breast Cancer; Gynecological Cancer; HER2 Negative; Antiestrogen Refractory ER+

Outcome Measures

Primary Outcomes (3)

• Dose limiting toxicities (DLTs)

  An occurrence of any of the protocol specified toxicities occurring during cycle 1: (1) Hematologic - Grade 4 neutropenia lasting \> 5 consecutive days, Grade 3/4 febrile neutropenia, Grade 4 thrombocytopenia lasting \>=7 days, or Grade 3 or 4 thrombocytopenia w/ clinically significant bleeding or requirement for platelet transfusion, (2) Non-hematologic: Any adverse event (AE) \>= Grade 3, with the exceptions of Grade 3 nausea, vomiting, diarrhea, clinically insignificant laboratory abnormality, or fatigue resolving to Grade \<=2 w/in 72 hours (3) Any AE that results in delay in administration of abexinostat or palbociclib of less than 75% and a delay of more than 7 days before starting cycle 2 unless the AE can be clearly attributed to an extraneous cause. DLTs are classified according to Medical Dictionary for Regulatory Activities (MedDRA) version 20 and graded for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE).

  At the end of Cycle 1 (each cycle is 28 days)

• Maximum tolerated dose (MTD)

  Defined as the dose at which fewer than one-third of participants experience a DLT or the highest dose at which no more than one instance of DLT is observed among 6 participants treated.

  At the end of Cycle 1 (each cycle is 28 days)

• Incidence of treatment-related adverse events (AE)

  Adverse events will be classified using MedDRA version 20.0 and graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Will be summarized with descriptive statistics.

  From initiation of study treatment until 30 days after completion of study treatment, up to 1 year

Secondary Outcomes (5)

• Abexinostat: Maximum concentration (Cmax)

  Cycle 1, Days 1 and 11; Cycle 2, Day 11 (each cycle is 28 days)

• Abexinostat: Trough concentration (Ctrough)

  Cycle 1, Days 1 and 11; Cycle 2, Day 11 (each cycle is 28 days)

• Objective response rates (ORR)

  Up to 1 year

• Clinical benefit rate (CBR)

  Up to 6 months

• Median progression-free survival (PFS)

  Up to 1 year

Study Arms (1)

Treatment (abexinostat tosylate, palbociclib, fulvestrant)

EXPERIMENTAL

Patients receive abexinostat PO BID on days 1-4, 8-11, and 15-18, palbociclib PO QD on days 1-21, and fulvestrant IM on days 1 and 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Abexinostat Tosylate; Drug: Fulvestrant; Drug: Palbociclib

Interventions

Abexinostat Tosylate DRUG

Given PO

Also known as: PCI-24781 Tosylate

Treatment (abexinostat tosylate, palbociclib, fulvestrant)

Fulvestrant DRUG

Given IM

Also known as: Faslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780, ZD9238

Treatment (abexinostat tosylate, palbociclib, fulvestrant)

Palbociclib DRUG

Given PO

Also known as: 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one, Ibrance, PD 0332991, PD 332991, PD 991, PD-0332991

Treatment (abexinostat tosylate, palbociclib, fulvestrant)

Eligibility Criteria

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

You may qualify if:

• BREAST CANCER: Participants must have histologically confirmed hormone receptor (HR)+, HER2- locally advanced or metastatic stage IV breast cancer. HER2- should be defined as 0 or 1 by immunohistochemistry, or HER2 gene amplification by fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), or in situ hybridization (ISH) performed upon the primary tumor or metastatic lesion (ration \< 2 and HER2 copy \< 4). Estrogen receptor (ER) and progesterone receptor (PR) expression positivity is defined as more than 5% of tumor cells nuclei positive by immunohistochemistry in the sample on testing
• BREAST CANCER: Patients must have had disease progression after treatment with anti-estrogen therapy combined with Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor after a minimum of at least 3 months therapy in the metastatic setting and no more than 3 prior lines of systemic therapy for metastatic breast cancer (MBC), unrestricted prior therapy in the dose escalation
• Note: Patients with breast cancer who were not previously treated with CDK4/6 inhibitors or have not tolerated full doses of prior ribociclib or palbociclib or abemaciclib are not eligible
• ENDOMETRIAL CANCER: Patients must have histologically confirmed metastatic endometrial cancer of endometrioid type
• ENDOMETRIAL CANCER: Tumors must have ER expression
• ENDOMETRIAL CANCER: Patients must have received a maximum of one line of hormonal therapy for the treatment of endometrial cancer and may have received any lines of chemotherapy treatment
• Note: Mixed tumor histology is allowed if the non-endometrioid component is less than 1%. Tumor must be estrogen receptor positive
• OVARIAN, FALLOPIAN TUBE, OR PERITONEAL EPITHELIAL CANCER: Patients must have histologically confirmed recurrent or metastatic ovarian, fallopian, or peritoneal epithelial carcinoma
• OVARIAN, FALLOPIAN TUBE, OR PERITONEAL EPITHELIAL CANCER: Tumors must have ER expression
• OVARIAN, FALLOPIAN TUBE, OR PERITONEAL EPITHELIAL CANCER: Patients must have received a maximum of one line of hormonal therapy for the treatment of ovarian cancer and may have received any lines of chemotherapy treatment
• Note: pure clear cell and pure mucinous ovarian carcinomas are not eligible
• ALL PATIENTS
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1
• Leukocytes \>= 2,500/microliter (mcL)

You may not qualify if:

• Patient with symptomatic visceral disease or any disease burden that renders the patient ineligible for endocrine therapy per the investigator's best judgment
• Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse event to grade 1 or less from agents administered more than 2 weeks earlier
• Patient has received treatment with any investigational drug within 21 days prior to study treatment administration. For classes of investigational agents that are not known to have prolonged toxicities, the washout time may be decreased to 14 days at the discretion of the principal investigator
• Patients may not have any known intolerability to any of the involved agents or established cytopenias to CDK4/6 inhibitors that require dose modifications or dose delays of greater than 2 weeks
• Patient with a known hypersensitivity to any of the excipients of palbociclib, abexinostat, or fulvestrant, including to peanut and soy
• Patient has a concurrent malignancy or malignancy within 3 years of study entry, with the exception of adequately treated, basal or squamous cell skin carcinoma, nonmelanomatous skin cancer or curatively resected cervical cancer
• Patient who has a history of untreated brain, or leptomeningeal, metastases (central nervous system (CNS) imaging is not required before study entry unless there is a clinical suspicion of CNS involvement)
• Participants with previously treated brain metastases may participate, provided:
• They are stable (without evidence of progression by imaging for at least four weeks and any neurologic symptoms have returned to baseline)
• They have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days of the first dose of study drug)
• They are not using steroids for at least 7 days before the first dose of study drug
• Have isolated lesions that were treated with localized radiation therapy
• This exception does not include leptomeningeal metastases, which is excluded regardless of clinical stability
• Patient must not have been previously treated with histone deacetylase inhibitor (HDACi), with the exception of low dose of divalproex sodium (Depakote) or valproic acid
• Patient has any medical, psychiatric or social condition, which in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities or affects compliance to study procedures

Sponsors & Collaborators

• Pamela Munster: lead
• Pfizer: collaborator
• Xynomic Pharmaceuticals, Inc.: collaborator

MeSH Terms

Conditions

Breast Neoplasms; Carcinoma, Endometrioid; Fallopian Tube Neoplasms; Neoplasm Metastasis; Ovarian Neoplasms

Interventions

Fulvestrant; palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Endometrial Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Fallopian Tube Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Endocrine Gland Neoplasms

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Pamela N Munster, MD

  University of California, San Francisco

  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: SPONSOR INVESTIGATOR
• PI Title: Prinicpal Investigator

Study Record Dates

• First Submitted: July 29, 2020
• First Posted: August 4, 2020
• Study Start: March 31, 2021
• Primary Completion: June 30, 2025
• Study Completion: June 30, 2025
• Last Updated: May 18, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share