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

Triple Negative Breast Cancer Clinical Trial

— TENACITY  

Official title:

A Phase 2, Multi-center, Open-label, Single Arm Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04461600
• Other study ID #: AL-TNBC-01
• Status: Terminated
• Phase: Phase 2
• Start date: August 14, 2020
• Est. completion date: October 11, 2022

Study information

• Verified date: January 2024
• Source: Ayala Pharmaceuticals, Inc,
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 18
• Est. completion date: October 11, 2022
• Est. primary completion date: March 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

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

Locations

Country	Name	City	State
Belgium	Institut Jules Bordet	Brussels
Belgium	UZ Leuven	Leuven
Israel	Rambam Medical Center	Haifa
Israel	Hadassah Medical Center	Jerusalem
Israel	Shaare Zedek Hospital	Jerusalem
Israel	Rabin Medical Center	Petah Tikva
Israel	Kaplan Medical Center	Re?ovot
Spain	Institut Català d'Oncologia	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	Hospital Clinico Universitario Virgen de la Victoria	Málaga
United Kingdom	University Hospital of Edinburgh	Edinburgh	Scotland
United Kingdom	The Christie Hospital	Manchester	England
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado	Aurora	Colorado
United States	Central Cancer Care	Bolivar	Missouri
United States	Charleston Oncology	Charleston	South Carolina
United States	The University of Chicago	Chicago	Illinois
United States	University Health Cleveland Medical Center	Cleveland	Ohio
United States	Maryland Oncology Hematology	Columbia	Maryland
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Louisville- James Brown Cancer Center	Louisville	Kentucky
United States	Memorial Sloan Kettering Cancer Center (MSKCC)	New York	New York
United States	Mayo Clinic	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	Comprehensive Hematology Oncology	Saint Petersburg	Florida
United States	University of California at San Francisco	San Francisco	California
United States	H. Lee Moffitt Cancer Center	Tampa	Florida
United States	Carle Clinic	Urbana	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Ayala Pharmaceuticals, Inc,

Countries where clinical trial is conducted

United States,  Belgium,  Israel,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	12 month
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.	12 month
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.	12 month