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Study of ASTX727 Plus Talazoparib in Patients With Triple Negative or Hormone Resistant/HER2-negative Metastatic Breast Cancer

Primary Purpose

Metastatic Breast Cancer, Triple Negative Breast Cancer, Hormone Receptor Positive Tumor

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Talazoparib
ASTX727
Sponsored by
Kathy Miller
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Breast Cancer focused on measuring Breast Cancer, Phase 1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. ≥ 18 years old at the time of informed consent
  2. Ability to provide written informed consent and HIPAA authorization

  3. Locally recurrent (not amenable to local therapy with curative intent) or metastatic breast cancer

    1. Patients with triple negative breast cancer must have received at least one prior chemotherapy regimen for metastatic disease.
    2. Patients with hormone-positive, HER2-negative disease must have received treatment with and progressed on at least one prior endocrine therapy including a CDK4/6 inhibitor in the metastatic setting.
  4. Measurable or evaluable disease based on RECIST 1.1 criteria.

  5. Only subjects who have disease amenable to biopsy will be asked to consent to serial tumor biopsies. Consent for biopsy is not required for participation.

    a. NOTE: If no amendable disease is present at the time of biopsy, subjects may continue participation in the study and further study specific biopsies will not be required.

  6. Eastern Cooperative Oncology Group Performance Status 0 or 1
  7. Patients with treated, asymptomatic central nervous system (CNS) disease may participate if the patient is > 4 weeks from completion of CNS therapy (radiation and/or surgery), is clinically stable at the time of study entry, and is receiving a stable or decreasing dose of corticosteroid therapy. Brain MRI or head CT is required at screening for patients with known brain metastases.

  8. Adequate organ function as indicated by:

    1. Total bilirubin </= ULN (upper limit of normal) (except in patients with documented Gilbert's disease, who must have a total bilirubin </= 3.0 mg/dL)
    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 3.0 x ULN (</= 1.5-3.0 x baseline if baseline is abnormal)
    3. Calculated creatinine clearance of >/= 60 mL/min using the Cockcroft-Gault formula
    4. Absolute neutrophil count (ANC) >/= 1.5 K/mm3
    5. Platelets >/= 100 K/mm3
    6. Hemoglobin (Hgb) >/= 9.0 g/dL

  9. Women of childbearing potential must have a negative pregnancy test within 14 days of protocol registration. Women are considered to have childbearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) unless they meet one of the following criteria:

    1. Has undergone a hysterectomy or bilateral oophorectomy; or
    2. Has been naturally amenorrheic for at least 24 consecutive months.
  10. Women of childbearing potential and men must agree to use effective contraception throughout the study and for 7 months after the last study treatment. Note: Acceptable methods of birth control include abstinence, partner with previous vasectomy, placement of an intrauterine device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control (pills or injections).

Exclusion Criteria:

  1. Prior treatment with decitabine, guadecitabine or other known DNA Methyltransferase inhibitors (DNMTis)
  2. Prior treatment with talazoparib or other known PARPi (poly(ADP-ribose polymeras inhibitor)
  3. Known deleterious breast cancer susceptibility gene (BRCA) mutation. Patients with BRCA variants of unknown significance (VUS) or who have not had germline genetic testing may participate.
  4. Active or symptomatic CNS disease

  5. Patients with HER2+ disease

    • HER2 will be considered positive if scored 3+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of > 2.0 or > 6 total HER2 gene copies per cell.
  6. Patients with active malignancy other than breast cancer. Patients with prior malignancies without recurrence after standard treatment will not be excluded
  7. Chemotherapy within 3 weeks of registration
  8. Radiation therapy within 2 weeks of registration
  9. Hormone therapy within 2 weeks of registration
  10. Patients requiring ongoing therapy with strong P-gp inhibitors

Sites / Locations

  • Indiana University Melvin & Bren Simon Cancer CenterRecruiting
  • Wake Forest Baptist Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ASTX727 + Talazoparib

Arm Description

Outcomes

Primary Outcome Measures

Safety of ASTX727 plus talazoparib using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0
Rate of dose limiting toxicity
rate of dose limiting toxicity will be assessed during cycle 1 (28 days) in patients enrolled during the dose escalation phase

Secondary Outcome Measures

Overall response rate
Clinical benefit response for triple negative disease subjects
clinical benefit response defined as complete response, partial response, or stable disease
Clinical benefit response for hormone receptor positive/ HER2 negative subjects
clinical benefit response defined as complete response, partial response, or stable disease
Progression free survival in all enrolled subjects

Full Information

First Posted
October 18, 2019
Last Updated
May 2, 2023
Sponsor
Kathy Miller
Collaborators
Pfizer, Astex Pharmaceuticals, Inc., Van Andel Institute Stand Up to Cancer Team
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1. Study Identification

Unique Protocol Identification Number
NCT04134884
Brief Title
Study of ASTX727 Plus Talazoparib in Patients With Triple Negative or Hormone Resistant/HER2-negative Metastatic Breast Cancer
Official Title
A Phase I Study of ASTX727 Plus Talazoparib in Patients With Triple Negative or Hormone Resistant/ Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Metastatic Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2020 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
July 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Kathy Miller
Collaborators
Pfizer, Astex Pharmaceuticals, Inc., Van Andel Institute Stand Up to Cancer Team

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase I study to test the safety of a combination of ASTX727 with talazoparib in patients with triple negative breast cancer or hormone resistant/HER2-negative metastatic breast cancer
Detailed Description
The phase I portion will use a traditional 3 + 3 design and standard definitions of DLT based on toxicity experienced during the first cycle of therapy. Patients with triple negative breast cancer (TNBC) and hormone resistant/HER2 negative (HRBC) metastatic disease will be enrolled and analyzed together during the dose escalation cohorts. Once the maximum tolerated dose is determined, we will enroll a small expansion cohort to further characterize safety and provide preliminary efficacy estimates.The expansion cohort will be limited to 14 patients; 7 with TNBC and 7 with HRBC. The dose level selected for expansion will be based on the totality of the data available including toxicity during the DLT evaluation period, toxicity during subsequent cycles, and correlative results.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Breast Cancer, Triple Negative Breast Cancer, Hormone Receptor Positive Tumor
Keywords
Breast Cancer, Phase 1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Model Description
The dose escalation phase will begin by enrolling 3 patients to the cohort 1 dose level. Patients will be observed for 28 days or one cycle of therapy for dose limiting toxicity (DLT). If 0 of 3 patients experience a DLT, the study will proceed to cohort 2. If 1 patient experiences a DLT, 3 additional patients will be enrolled into cohort 1. If 1 of 6 patients experience a DLT, the study will proceed to the cohort 2 dose level. If > 2/3 or 2/6 patients in cohort 1 experience DLT, we will de-escalate to cohort -1. Identical DLT evaluation and dose escalation/de-escalation decision rules will be used in subsequent cohorts. A total of 6 patients will be treated at the highest dose level achieved to ensure that 6 patients have been treated at the proposed maximum tolerated dose before proceeding to the expansion cohorts.
Masking
None (Open Label)
Allocation
N/A
Enrollment
38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ASTX727 + Talazoparib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Talazoparib
Intervention Description
Talazoparib will be taken on days 4-21, 6-21 or 1-21 at a dose level of 0.25, 0.5, 0.75 or 1.0 mg depending on cohort assignment
Intervention Type
Drug
Intervention Name(s)
ASTX727
Intervention Description
ASTX727 will be taken on days 1 and 3, days 1,3,5 or days 1 through 5 of the 28 day cycle at doses of 10 mg:100 mg or 15 mg:100 mg depending on cohort assignment
Primary Outcome Measure Information:
Title
Safety of ASTX727 plus talazoparib using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0
Time Frame
through study completion i.e up to 1 year
Title
Rate of dose limiting toxicity
Description
rate of dose limiting toxicity will be assessed during cycle 1 (28 days) in patients enrolled during the dose escalation phase
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Overall response rate
Time Frame
through study completion (i.e. up to 1 year)
Title
Clinical benefit response for triple negative disease subjects
Description
clinical benefit response defined as complete response, partial response, or stable disease
Time Frame
18 weeks
Title
Clinical benefit response for hormone receptor positive/ HER2 negative subjects
Description
clinical benefit response defined as complete response, partial response, or stable disease
Time Frame
24 weeks
Title
Progression free survival in all enrolled subjects
Time Frame
through study completion (i.e. up to 1 year)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: ≥ 18 years old at the time of informed consent Ability to provide written informed consent and HIPAA authorization Locally recurrent (not amenable to local therapy with curative intent) or metastatic breast cancer Patients with triple negative breast cancer must have received at least one prior chemotherapy regimen for metastatic disease. Patients with hormone-positive, HER2-negative disease must have received treatment with and progressed on at least one prior endocrine therapy including a CDK4/6 inhibitor in the metastatic setting. Measurable or evaluable disease based on RECIST 1.1 criteria. Only subjects who have disease amenable to biopsy will be asked to consent to serial tumor biopsies. Consent for biopsy is not required for participation. a. NOTE: If no amendable disease is present at the time of biopsy, subjects may continue participation in the study and further study specific biopsies will not be required. Eastern Cooperative Oncology Group Performance Status 0 or 1 Patients with treated, asymptomatic central nervous system (CNS) disease may participate if the patient is > 4 weeks from completion of CNS therapy (radiation and/or surgery), is clinically stable at the time of study entry, and is receiving a stable or decreasing dose of corticosteroid therapy. Brain MRI or head CT is required at screening for patients with known brain metastases. Adequate organ function as indicated by: Total bilirubin </= ULN (upper limit of normal) (except in patients with documented Gilbert's disease, who must have a total bilirubin </= 3.0 mg/dL) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 3.0 x ULN (</= 1.5-3.0 x baseline if baseline is abnormal) Calculated creatinine clearance of >/= 60 mL/min using the Cockcroft-Gault formula Absolute neutrophil count (ANC) >/= 1.5 K/mm3 Platelets >/= 100 K/mm3 Hemoglobin (Hgb) >/= 9.0 g/dL Women of childbearing potential must have a negative pregnancy test within 14 days of protocol registration. Women are considered to have childbearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) unless they meet one of the following criteria: Has undergone a hysterectomy or bilateral oophorectomy; or Has been naturally amenorrheic for at least 24 consecutive months. Women of childbearing potential and men must agree to use effective contraception throughout the study and for 7 months after the last study treatment. Note: Acceptable methods of birth control include abstinence, partner with previous vasectomy, placement of an intrauterine device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control (pills or injections). Exclusion Criteria: Prior treatment with decitabine, guadecitabine or other known DNA Methyltransferase inhibitors (DNMTis) Prior treatment with talazoparib or other known PARPi (poly(ADP-ribose polymeras inhibitor) Known deleterious breast cancer susceptibility gene (BRCA) mutation. Patients with BRCA variants of unknown significance (VUS) or who have not had germline genetic testing may participate. Active or symptomatic CNS disease Patients with HER2+ disease HER2 will be considered positive if scored 3+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of > 2.0 or > 6 total HER2 gene copies per cell. Patients with active malignancy other than breast cancer. Patients with prior malignancies without recurrence after standard treatment will not be excluded Chemotherapy within 3 weeks of registration Radiation therapy within 2 weeks of registration Hormone therapy within 2 weeks of registration Patients requiring ongoing therapy with strong P-gp inhibitors
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Xin Bryan, RN
Phone
317-274-5495
Email
zhongx@iupui.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kathy Miller, MD
Organizational Affiliation
Indiana University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Indiana University Melvin & Bren Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xin Bryan, RN
Email
zhongx@iupui.edu
First Name & Middle Initial & Last Name & Degree
Kathy Miller, MD
Facility Name
Wake Forest Baptist Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Individual Site Status
Suspended

12. IPD Sharing Statement

Learn more about this trial

Study of ASTX727 Plus Talazoparib in Patients With Triple Negative or Hormone Resistant/HER2-negative Metastatic Breast Cancer

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