Trial Title:
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
NCT ID:
NCT06590558
Condition:
Anatomic Stage III Breast Cancer AJCC v8
Anatomic Stage IV Breast Cancer AJCC v8
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
Conditions: Official terms:
Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Halichondrin B
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tissue biopsy
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Eribulin Mesylate
Description:
Given IV
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
B1939 Mesylate
Other name:
E7389
Other name:
ER-086526 Mesylate
Other name:
Halaven
Other name:
Halichondrin B Analog
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Drug
Intervention name:
Tolinapant
Description:
Given PO
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
ASTX 660
Other name:
ASTX660
Other name:
XIAP/cIAP1 Antagonist ASTX660
Intervention type:
Procedure
Intervention name:
X-Ray Imaging
Description:
Undergo chest X-ray
Arm group label:
Treatment (tolinapant, eribulin)
Other name:
Conventional X-Ray
Other name:
Diagnostic Radiology
Other name:
Medical Imaging, X-Ray
Other name:
Plain film radiographs
Other name:
Radiographic Imaging
Other name:
Radiographic imaging procedure (procedure)
Other name:
Radiography
Other name:
RG
Other name:
Static X-Ray
Other name:
X-Ray
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.
Detailed description:
PRIMARY OBJECTIVES:
I. Determine the safety and tolerability of ASTX660 (tolinapant) in combination with
eribulin in patients with metastatic breast cancer.
II. Determine the maximum tolerated dose (MTD) of ASTX660 (tolinapant) in combination
with eribulin.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. Determine the pharmacokinetic
parameters of ASTX660 (tolinapant) and eribulin when used in combination.
III. Determine the pharmacodynamic parameters of antitumor activity of ASTX660
(tolinapant) and eribulin combination.
EXPLORATORY OBJECTIVES:
I. Develop biomarkers predictive of response and resistance to ASTX660 (tolinapant) in
combination with eribulin in metastatic triple negative breast cancer.
II. Investigate biomarkers and mechanisms of primary and secondary resistance to ASTX660
(tolinapant) in combination with eribulin in metastatic triple negative breast cancer.
OUTLINE: This is a dose-escalation study of tolinapant in combination with eribulin
followed by a dose-expansion study.
Patients receive tolinapant orally (PO) once daily (QD) on days 1-7 and 15-21 and
eribulin intravenously (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 computed
tomography (CT) or magnetic resonance imaging (MR) during screening and on study.
After completion of study treatment, patients are followed for up to 3 months.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- 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
- Creatinine ≤ 1.5 x institutional ULN OR glomerular filtration rate (GFR) ≥ 60
mL/min/1.73 m^2
- International normalized ratio (INR) ≤ 1.5 x ULN
- Partial thromboplastin time (PTT) ≤ 1.5 x ULN
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
provided they are on a stable regimen of anti-retroviral therapy (ART) with no
medications otherwise prohibited by this protocol (e.g., drug-drug interactions)
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if there is no evidence of
progression for at least 4 weeks after central nervous system (CNS)-directed
treatment, as ascertained by clinical examination and brain imaging (MRI or CT)
during the screening period
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS specific treatment is not required and is unlikely to be required
during the first cycle of therapy
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better. Patients with
history of known congestive heart failure (left ventricular ejection fraction [LVEF]
< 50%) must have documented LVEF ≥ 50% within 12 months of study enrollment
- Patients with history of known type I or type II diabetes must have a fasting
glucose level of < 120 mg/dL on at least 2 separate occasions or glycosylated
hemoglobin (HbA1c) < 8.5% at screening within 14 days prior to registration
- Patients who are therapeutically treated with an agent such as warfarin or heparin
will be allowed to participate provided that their medication dose and INR/PTT is
stable
- Prophylactic antiemetics may be administered according to standard practice. The
routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron,
ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT
(QTc) interval on baseline electrocardiogram (ECG) < 480 msec
- Patients must be willing to have biopsies for this study in order to be enrolled in
the dose expansion
- The effects of ASTX660 (tolinapant) on the developing human fetus are unknown. For
this reason and because dual IAP antagonist agents as well as other therapeutic
agents used in this trial are known to be teratogenic, women of child-bearing
potential must agree to practice 1 highly effective contraceptive measure of birth
control (with a failure rate of < 1% per year; preferably with low user dependency)
during the study and for 6 months after the last dose of study treatment and must
agree not to become pregnant for 6 months after completing treatment. Men with
female partners of childbearing potential must agree to use a condom and advise
their partners to practice 1 highly effective contraceptive measure of birth control
(user dependent or with low user dependency) during the study and for at least 3
months after completing treatment, and must agree not to father a child while
receiving study treatment and for at least 3 months after completing treatment
- Ability to understand and the willingness to sign a written informed consent
document. Legally authorized representatives may sign and give informed consent on
behalf of study participants
Exclusion Criteria:
- 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
- Patients with history of, or current uncontrolled autoimmune disease. Patients who
have adrenal or pituitary insufficiency who are stable on replacement therapy (i.e.,
thyroxine or physiologic corticosteroid replacement therapy that meets concomitant
medication restrictions) are allowed
- Patients with uncontrolled intercurrent illness or any other significant
condition(s) that would make participation in this protocol unreasonably hazardous
- Pregnant women are excluded from this study because ASTX660 (tolinapant) and
eribulin mesylate are anti-cancer agents with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with ASTX660
(tolinapant) and eribulin mesylate, breastfeeding should be discontinued until 2
weeks after the mother's last dose of study drugs
- The patient has a personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including,
but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest
- Patients with congenital long QT syndrome, bradyarrhythmias, or taking drugs known
to prolong the QT interval
- Patients unable to stop using any medication which is a moderate or strong CYP3A4
inhibitor or inducer within 2 weeks of the start of the study
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
November 8, 2024
Completion date:
May 17, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06590558
