Testing the Addition of an Investigational Anti-Cancer Drug, ASTX660 (Tolinapant), to a Usual Chemotherapy Treatment (Eribulin) for Treatment of Advanced Triple Negative Breast Cancer

NCT06590558 | Withdrawn Phase 1 FDA Drug

• 3 other identifiers: NCI-2024-0566610647UM1CA186712
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I/Ib trial tests the safety, side effects, best dose, and effectiveness of ASTX660 (tolinapant) in combination with eribulin mesylate (eribulin) in treating patients with triple negative breast cancer that cannot be removed by surgery (unresectable) or that has spread to nearby tissues or lymph nodes (locally advanced) or to other places in the body (metastatic). Tolinapant may stop the growth of tumor cells by blocking proteins, such as XIAP and cIAP1, needed for tumor cell survival. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tolinapant in combination with eribulin may be safe, tolerable, and/or effective in treating patients with unresectable, locally advanced, or metastatic triple negative breast cancer.

Conditions

Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IV Breast Cancer AJCC v8; Invasive Breast Carcinoma; Locally Advanced HER2-Negative Breast Carcinoma; Locally Advanced Hormone Receptor-Positive Breast Carcinoma; Locally Advanced Triple-Negative Breast Carcinoma; Metastatic HER2-Negative Breast Carcinoma; Metastatic Hormone Receptor-Positive Breast Carcinoma; Metastatic Triple-Negative Breast Carcinoma; Unresectable HER2-Negative Breast Carcinoma; Unresectable Hormone Receptor-Positive Breast Carcinoma; Unresectable Triple-Negative Breast Carcinoma

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events (AEs)

  Medical Dictionary for Regulatory Activities (MedDRA) terms will be used to characterized AEs which will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Descriptive statistics will be used to report the frequency according to severity of the AEs.

  Up to 3 months after last dose of study drug

• Dose-limiting toxicities (DLT)

  MedDRA terms will be used to characterized the AEs which will be graded according to the NCI CTCAE v5.0. Descriptive statistics will be used to report the frequency according to the severity of the AEs.

  Up to 4 weeks following the first administration (cycle 1 day 1) of the investigational therapy

• Maximum tolerated dose (MTD)

  The MTD will be defined as the highest dose at which 0 out of first 3 or 1 out of total of 6 patients experience a DLT during the first cycle of therapy, collectively 4 weeks of the investigational therapy.

  Up to 4 weeks

Secondary Outcomes (10)

• Overall response rate (ORR)

  At start of treatment until disease progression/recurrent, assessed up to 3 years

• Duration of response (DOR)

  At complete response (CR) or partial response (PR) to recurrent or progressive disease, assessed up to 3 years

• Progression-free survival (PFS)

  At start of treatment to progression or death, assessed up to 3 years

• Overall survival (OS)

  At start of treatment to death, assessed up to 3 years

• Maximum concentration (Cmax) of ASTX660 (tolinapant) and eribulin

  Up to day 8

Other Outcomes (6)

• Positive and negative predictive value of RIPK1 and RIPK1 in pretreatment tumor biopsies in predicting response to the investigational therapy

  At pre-study and up to 3 years

• Sensitivity and specificity of RIPK1 and RIPK1 in pretreatment tumor biopsies in predicting response to the investigational therapy

  At pre-study and up to 3 years

• Area under the receiver operating characteristic curve of RIPK1 and RIPK1 in pretreatment tumor biopsies in predicting response to the investigational therapy

  At pre-study and up to 3 years

Study Arms (1)

Treatment (tolinapant, eribulin)

EXPERIMENTAL

Patients receive tolinapant PO QD on days 1-7 and 15-21 and eribulin IV over 2-5 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tissue biopsy, chest X-ray, and CT or MRI throughout the study.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Eribulin Mesylate; Procedure: Magnetic Resonance Imaging; Drug: Tolinapant; Procedure: X-Ray Imaging

Interventions

Biopsy Procedure PROCEDURE

Undergo tissue biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Treatment (tolinapant, eribulin)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (tolinapant, eribulin)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (tolinapant, eribulin)

Eribulin Mesylate DRUG

Given IV

Also known as: B1939 Mesylate, E7389, ER-086526 Mesylate, Halaven, Halichondrin B Analog

Treatment (tolinapant, eribulin)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (tolinapant, eribulin)

Tolinapant DRUG

Given PO

Also known as: ASTX 660, ASTX660, XIAP/cIAP1 Antagonist ASTX660

Treatment (tolinapant, eribulin)

X-Ray Imaging PROCEDURE

Undergo chest X-ray

Also known as: Conventional X-Ray, Diagnostic Radiology, Medical Imaging, X-Ray, Plain film radiographs, Radiographic Imaging, Radiographic imaging procedure (procedure), Radiography, RG, Static X-Ray, X-Ray

Treatment (tolinapant, eribulin)

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically or cytologically confirmed invasive breast carcinoma.
• We limit the molecular subtype to triple negative (TNBC) and hormone receptor-low and Her2 negative (hormone receptor \[HR\]-low/Her2\[-\]) breast cancer. TNBC is defined as: HER2 expression 0 or 1+ on immunohistochemistry (IHC) or non-amplified (defined as HER2/CEP17 ratio \< 2 or copy number \< 6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, negative HER2 expression must be confirmed by FISH. Pathologic diagnosis of TNBC (negative HER2 status by cytogenetics, \< 1% of cells stained positive for estrogen receptor \[ER\] by IHC, and \< 1% of cells stained positive for progesterone receptor \[PR\] by IHC) (Allison et al., 2020, Wolff et al., 2013). HR-low/Her2(-) is defined as: HER2 expression 0 or 1+ on IHC or non-amplified (defined as HER2/CEP17 ratio \< 2 or copy number \< 6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, negative HER2 expression must be confirmed by FISH. 1-10% of cells stained positive for ER by IHC, and/or 1-10% of cells stained positive for PR by IHC) (Allison et al., 2020, Wolff et al., 2013)
• Patients must have confirmed locally advanced and unresectable or metastatic disease by either imaging or tissue diagnosis
• Patients must have received at least 2 lines of systemic treatment for metastatic disease
• Patients must have measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) criteria
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ASTX660 (tolinapant) in combination with eribulin mesylate in patients \< 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.8 mg/dL
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional upper limit of normal (ULN) or ≤ 5 x institutional ULN if known liver metastases
• Alkaline phosphatase ≤ 3 x institutional ULN or ≤ 5 x institutional ULN if known liver and/or skeletal metastases
• Lipase ≤ 1.5 x ULN

You may not qualify if:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
• Patients who are receiving any other investigational agents or concurrent anticancer therapy
• Patients who have had prior treatment with eribulin mesylate
• Patients with pre-existing neuropathy of grade 2 or higher
• Myeloid growth factors within 7 days prior to treatment start
• Platelet transfusion within 7 days prior to treatment start
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ASTX660 (tolinapant) or other agents used in study
• Immunosuppressive therapy is not allowed while on study
• Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not permitted while on study. Previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days prior to the CT/MRI screening. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the screening. Patients may be using topical or inhaled corticosteroids. Short-term (up to 7 days) systemic corticosteroids above 15 mg prednisolone or equivalent will be allowed for the management of acute conditions (e.g., treatment non-infectious pneumonitis)
• Patients with non-healing wound, ulcer, or bone fracture. Patients with compression or pathologic fractures that are stable in the opinion of the investigator may be enrolled, as long as the bone fracture is not felt to pose a high likelihood of treatment delay or difficulties in treatment adherence as per the judgement of the investigator
• Patients with active, clinically serious infections \> grade 2 (Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5.0) (viral, bacterial or fungal infection)
• History of known pneumocystis jiroveci pneumonia (PJP) infection or documented non-infectious pneumonitis/interstitial lung disease (ILD)
• Patients with arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication
• Uncontrolled hypertension (defined as blood pressure ≥ 150/90 mm/Hg) despite optimal medical management (per investigator's opinion)
• Proteinuria as estimated by urine protein/creatinine ratio \> 3.5 g/g on random urine sample or grade ≥ 3 as assessed by 24-hour urine protein collection

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

Biopsy; Specimen Handling; eribulin; Magnetic Resonance Spectroscopy; ASTX-660; X-Rays; Phantoms, Imaging

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing; Equipment and Supplies

Study Officials

• Kristen Kelley

  Ohio State University Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2024
• First Posted: September 19, 2024
• Study Start: August 4, 2025
• Primary Completion (Estimated): May 17, 2027
• Study Completion (Estimated): May 17, 2027
• Last Updated: July 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share