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

• ClinicalTrials.gov Identifier: NCT04461600
• Recruitment Status: Active, not recruiting
• First Posted: July 8, 2020
• Last Update Posted: April 1, 2022
• Sponsor: Ayala Pharmaceuticals, Inc,
• Information provided by (Responsible Party): Ayala Pharmaceuticals, Inc,

Tracking Information

• First Submitted Date: June 29, 2020
• First Posted Date: July 8, 2020
• Last Update Posted Date: April 1, 2022
• Actual Study Start Date: August 14, 2020
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 2, 2020)

Overall response rate (ORR) [ Time Frame: 12 month ]

ORR is defined as partial response (PR) + complete response (CR) as assessed by investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 2, 2020)

• Clinical benefit response rate (CBR) [ Time Frame: 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
• Duration of response (DOR) by investigator review based on RECIST v1.1 [ Time Frame: 12 month ]
• Progression free survival (PFS) [ Time Frame: 12 month ]
• Proportion of subjects who have Progression free survival (PFS) at 6 months [ Time Frame: 6 month ]
• Overall survival (OS) [ Time Frame: 12 month ]
• Quality of life (QoL)-QLQ-C30 [ Time Frame: 12 month ]
  The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / Quality of life scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / Quality of life represents a high Quality of life, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
• Quality of life (QoL)- QLQ-BR45 [ Time Frame: 12 month ]
  Quality of life (QoL) as determined by European Organization for Research and Treatment of Cancer, by breast cancer quality of life questionnaire QLQ-BR45. QLQ-BR45 is a supplementary questionnaire module to be employed in conjunction with the QLQ-C30. The QLQ-BR45 incorporates nine multi-item scales to assess body image, sexual functioning, breast satisfaction, systemic therapy side,effects, arm symptoms, breast symptoms, endocrine therapy symptoms, skin mucosis symptoms, endocrine sexual symptoms. In addition, single items assess sexual enjoyment, future perspective and being upset by hair loss. All of the scales and single item measures range in score from 0 to 100. A high score for the functional scales and functional single items represents a high/healthy level of functioning, whereas a high score for the symptom scales and symptom item represents a high level of symptomatology or problems.
• Frequency, duration and severity of treatment-emergent adverse events and serious adverse events in subjects with recurrent or metastatic Triple Negative Breast Cancer receiving AL101 monotherapy. [ Time Frame: 12 month ]
  Frequency, duration and severity of treatment-emergent adverse events and serious adverse events. The incidence of clinically significant abnormalities in laboratory parameters, electrocardiograms, vital signs and physical examination will be used to describe treatment-emergent adverse events and serious adverse events.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer
• Official Title: A Phase 2, Multi-center, Open-label, Single Arm Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Triple Negative Breast Cancer

Intervention

Drug: AL101

AL101 is an inhibitor of gamma secretase-mediated Notch signaling.

Study Arms

Experimental: AL101

AL101 is an inhibitor of gamma secretase-mediated Notch signaling.

Intervention: Drug: AL101

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 2, 2020): 67
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Israel, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04461600
• Other Study ID Numbers: AL-TNBC-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ayala Pharmaceuticals, Inc,
• Original Responsible Party: Same as current
• Current Study Sponsor: Ayala Pharmaceuticals, Inc,
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Ayala Pharmaceuticals, Inc,
• Verification Date: October 2021