A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer

• AL101 (Drug): AL101 is an inhibitor of gamma secretase-mediated Notch signaling.

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Overall Response Rate (ORR) (Primary), Count of participants, Participants: AL101 6mg 0; AL101 4mg 0
• Clinical Benefit Response Rate (CBR) (Secondary), Count of participants, Participants: AL101 6mg 1; AL101 4mg 3
• Duration of Response (DOR) by Investigator Review Based on RECIST v1.1 (Secondary)

Adverse events

Time frame: 1 year and 3 months

Serious adverse events by term

Other adverse events by term

57 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2020-08-24)

• Andres Gutierrez, MD, PhD, Study director, Executive Vice President & Chief Medical Officer