Triple Negative Breast Cancer
Conditions
Keywords
TNBC, Notch activated
Brief summary
The current study is designed to evaluate the efficacy and safety of AL101 monotherapy in subjects with Notch-activated recurrent or metastatic TNBC; Notch activation will be determined by a Next Generation Sequencing (NGS) test.
Interventions
DRUGAL101
AL101 is an inhibitor of gamma secretase-mediated Notch signaling.
Sponsors
Ayala Pharmaceuticals, Inc,
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male of female subjects who are at least 18 years of age (inclusive) at the time of signing the Informed Consent Form (ICF). 2. Have at least one measurable lesion per RECIST v1.1. 3. Have formalin-fixed paraffin-embedded (FFPE) tissue available from a metastatic lesion; a tumor block or 25 unstained slides from an archived (within 2 years) or fresh tumor samples (core or punch needle biopsy) are acceptable. 4. Documented tumor progression following no more than 3 lines of systemic chemotherapy, PARP inhibitor therapy or immunotherapy for metastatic disease, as appropriate. Of note, neoadjuvant and adjuvant therapy will not count as prior lines of therapy. 5. Histologically confirmed diagnosis of inoperable locally advanced or metastatic TNBC defined as ER and progesterone receptor staining \<10%, and HER2 negative defined as IHC 0 to 1+ 6. Documented Notch activation from tumor biopsy results from within the last 2 years from a commercially available NGS assay, LDT or other validated IUO clinical trial assay. 7. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test.
Exclusion criteria
1. A known additional malignancy that is progressing or requires active treatment that is considered medically active and may interfere in the ability to detect responses in this subject. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that have undergone potentially curative therapy or in situ cervical cancer. 2. BC that, in the opinion of the investigator, is considered amenable to potentially curative treatment. 3. Symptomatic central nervous system (CNS) metastases. 4. Current or recent (within 2 months of IP administration) gastrointestinal (GI) disease or disorders that increase the risk of diarrhea, such as inflammatory bowel disease and Crohn's disease. 5. Developed immune-mediated colitis with immunotherapy unless resolved to G1 or lower and without requirement of steroid treatment for at least 14 days prior to first dose of IP. 6. Peripheral neuropathy Grade 2 for at least 14 days prior to first dose of IP. 7. Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or anti-fungal therapy ≤7 days prior to administration of IP such as known active infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). 8. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac or pulmonary function or uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the subject associated with his or her participation in the study. 9. Eastern Cooperative Oncology Group (ECOG) performance status ≥2. 10. Abnormal organ and marrow function defined as: 1. neutrophils \<1000/mm3, 2. platelet count \<75,000/mm3, 3. hemoglobin \<8 g/dL, 4. total bilirubin \>1.5 upper limit of normal (ULN) (except known Gilbert's syndrome whereby the total bilirubin must be \< 5 mg/dL), 5. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \>2.5 ULN OR \>5 ULN for subjects with liver metastases, 6. creatinine clearance (CrCl) \<50 mL/min (calculation of CrCl will be based on acceptable institution standard), 7. uncontrolled triglyceride ≥Grade 2 elevations per CTCAE v5.0 (\>300 mg/dL or \>3.42 mmol/L). 11. Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. 12. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥480 msec. 13. Completed palliative radiation therapy \< 7 days prior to initiating IP. 14. Prior treatment with gamma secretase inhibitors. 15. Last chemotherapy, biologic, or investigational therapy agent at least 4 weeks or 5 half-lives (whichever is shorter) prior to initiating IP; at least 6 weeks if the last regimen included BCNU or mitomycin C. Prior treatment with investigational monoclonal antibody will be reviewed case-by-case by the Sponsor. 16. Receiving chronic systemic steroid therapy (in dosing exceeding 10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of IP. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. 17. Use of strong inhibitors of CYP3A4 within 1 week or 5 half-lives (whichever is longer) or strong inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer). 18. Life expectancy is less than 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 12 month | ORR is defined as partial response (PR) + complete response (CR) as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Response Rate (CBR) | 12 month | Clinical benefit response rate (CBR) is defined as complete response (CR) + partial response (PR) + stable disease (SD) by investigator review based on RECIST v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage (at least 30%) to qualify for PR nor sufficient increase (more than 20%) to qualify for PD, taking as reference the smallest sum diameters. |
| Duration of Response (DOR) by Investigator Review Based on RECIST v1.1 | 12 month | Duration of response (DOR) is defined as the time from randomization to disease progression or death in patients who achieve complete or partial response. |
Countries
Belgium, Israel, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AL101 4mg AL101 is an inhibitor of gamma secretase-mediated Notch signaling. 4mg of AL101 was administered using an IV infusion pump over 60 minutes, once a week. | 12 |
| AL101 6mg AL101 is an inhibitor of gamma secretase-mediated Notch signaling. 6mg of AL101 was administered using an IV infusion pump over 60 minutes, once a week. | 6 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | AL101 4mg | AL101 6mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 11 Participants | 6 Participants |
| Age, Continuous | 48 years | 48 years | 45 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 9 Participants | 5 Participants |
| Region of Enrollment Belgium | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Israel | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Spain | 5 participants | 5 participants | 0 participants |
| Region of Enrollment United States | 10 participants | 5 participants | 5 participants |
| Sex: Female, Male Female | 18 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 6 / 12 |
| other Total, other adverse events | 6 / 6 | 12 / 12 |
| serious Total, serious adverse events | 5 / 6 | 2 / 12 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR is defined as partial response (PR) + complete response (CR) as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 12 month
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AL101 6mg | Overall Response Rate (ORR) | 0 Participants |
| AL101 4mg | Overall Response Rate (ORR) | 0 Participants |
Secondary
Clinical Benefit Response Rate (CBR)
Clinical benefit response rate (CBR) is defined as complete response (CR) + partial response (PR) + stable disease (SD) by investigator review based on RECIST v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage (at least 30%) to qualify for PR nor sufficient increase (more than 20%) to qualify for PD, taking as reference the smallest sum diameters.
Time frame: 12 month
Population: Efficacy Evaluable Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AL101 6mg | Clinical Benefit Response Rate (CBR) | 1 Participants |
| AL101 4mg | Clinical Benefit Response Rate (CBR) | 3 Participants |
Secondary
Duration of Response (DOR) by Investigator Review Based on RECIST v1.1
Duration of response (DOR) is defined as the time from randomization to disease progression or death in patients who achieve complete or partial response.
Time frame: 12 month
Population: Duration of response data was not collected as there were no patients with either CR or PR