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Estrogen Receptor Antagonists

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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.

Abexinostat Tosylate

Pamela N Munster, MD

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.

PRIMARY OBJECTIVES:

1. To determine the safety and tolerability of abexinostat tosylate (abexinostat) and palbociclib in combination with fulvestrant.
2. To determine the maximum tolerated dose (MTD) for abexinostat and palbociclib when combined with fulvestrant at standard dose.

SECONDARY OBJECTIVES:

1. To describe the pharmacokinetics associated with abexinostat.
2. To describe the efficacy of abexinostat and palbociclib in combination with fulvestrant in patients with antiestrogen refractory estrogen receptor positive (ER+), HER2 negative(-) breast cancer and gynecological metastatic tumors.
3. To assess the clinical benefit rate (CBR) defined as complete response (CR), partial response (PR), and stable disease (SD) at 6 months and progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.

EXPLORATORY OBJECTIVES:

1. To assess correlations between overall response rate (ORR), CBR at 6 months, and progression free survival (PFS) with genomic aberrations assessed as cell free tumor deoxyribonucleic acid (DNA) and histone acetylation on peripheral blood.
2. To assess correlations between ORR, CBR at 6 months, and PFS endpoints and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) gene expression, PBMC acetylation in vivo and ex vivo.

OUTLINE: This is a dose-escalation study of abexinostat and palbociclib.

Patients receive abexinostat orally (PO) twice daily (BID) on days 1-4, 8-11, and 15-18, palbociclib PO once daily (QD) on days 1-21, and fulvestrant intramuscularly (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.

Patients will be followed for 90 days after completion of treatment or removal from study, or until death, whichever occurs first.

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

Phase I Trial of Abexinostat Combined With Palbociclib and Fulvestrant in Patients With Antiestrogen Refractory ER+, HER2- Breast Cancer and Gynecological Metastatic Tumors

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).

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.

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.

Serum samples will be collected in order to obtain the Cmax of abexinostat over the course of 2 cycles under the following schedule: Pre-dose, immediately post-admin, 4 hrs (+/- 30 min) post-start of drug administration, and after completion of study drug administration on Cycle 1, Day 11 and Cycle 2, Day 11

Serum samples will be collected in order to obtain the Ctrough of abexinostat over the course of 2 cycles under the following schedule: Pre-dose, immediately post-admin, 4 hrs (+/- 30 min) post-start of drug administration, and after completion of study drug administration on Cycle 1, Day 11 and Cycle 2, Day 11

An objective response is defined as Complete Response (CR), Partial Response (PR), assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 from initiation of study therapy until disease progression or study discontinuation, . ORR will be estimated using an exact method based on the binomial distribution (Clopper-Pearson interval) with a 90% confidence interval.

CBR is defined as the proportion of participants who displayed a clinical benefit (CR, PR, or Stable Disease (SD)) per RECIST v 1.1 and without disease progression at 6 months after initiation of study therapy.

PFS will be determined according to RECIST v 1.1 and measured as the time from first objective response after initiation of study therapy until the time of progression or death, which ever occurs first . Will be estimated using Kaplan-Meier analysis.

Pfizer

Xynomic Pharmaceuticals, Inc.

Pamela Munster

Prinicpal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Abexinostat, Palbociclib, and Fulvestrant for the Treatment of Breast or Gynecologic Cancer	NCT04498520	Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Hormone Recepto... Locally Advance... Metastatic Brea... Metastatic Endo... Metastatic Fall... Metastatic HER2... Metastatic Mali... Metastatic Ovar... Metastatic Prim... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Recurrent Fallo... Recurrent Ovari... Recurrent Prima... Refractory Brea... Stage IV Fallop... Stage IV Ovaria... Stage IV Primar... Stage IV Uterin... Stage IVA Fallo... Stage IVA Ovari... Stage IVA Prima... Stage IVA Uteri... Stage IVB Fallo... Stage IVB Ovari... Stage IVB Prima... Stage IVB Uteri...	Abexinostat Tos... Fulvestrant Palbociclib	18 Years -	University of California, San Francisco
Abexinostat, Palbociclib, and Fulvestrant for the Treatment of Breast or Gynecologic Cancer	NCT04498520	Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Hormone Recepto... Locally Advance... Metastatic Brea... Metastatic Endo... Metastatic Fall... Metastatic HER2... Metastatic Mali... Metastatic Ovar... Metastatic Prim... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Recurrent Fallo... Recurrent Ovari... Recurrent Prima... Refractory Brea... Stage IV Fallop... Stage IV Ovaria... Stage IV Primar... Stage IV Uterin... Stage IVA Fallo... Stage IVA Ovari... Stage IVA Prima... Stage IVA Uteri... Stage IVB Fallo... Stage IVB Ovari... Stage IVB Prima... Stage IVB Uteri...	Abexinostat Tos... Fulvestrant Palbociclib	18 Years -	University of California, San Francisco

Spots Global Cancer Trial Database for abexinostat tosylate