Clinical trial NCT04461600: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Keywords: TNBC, Notch activated
Lead sponsor: Ayala Pharmaceuticals, Inc,
Sponsor class: INDUSTRY
First posted: 2020-07-08
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 12 month
Secondary outcomes:
measure: Clinical Benefit Response Rate (CBR)
timeFrame: 12 month
measure: Duration of Response (DOR) by Investigator Review Based on RECIST v1.1
timeFrame: 12 month
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Saint Petersburg
country: United States
facility: Comprehensive Hematology Oncology
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Urbana
country: United States
facility: Carle Clinic
state: Illinois
city: Louisville
country: United States
facility: University of Louisville- James Brown Cancer Center
state: Kentucky
city: Columbia
country: United States
facility: Maryland Oncology Hematology
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bolivar
country: United States
facility: Central Cancer Care
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center (MSKCC)
state: New York
city: Cleveland
country: United States
facility: University Health Cleveland Medical Center
state: Ohio
city: Charleston
country: United States
facility: Charleston Oncology
state: South Carolina
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Leuven
country: Belgium
facility: UZ Leuven
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Hospital
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Reẖovot
country: Israel
facility: Kaplan Medical Center
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Barcelona
country: Spain
facility: Institut Català d'Oncologia
city: Málaga
country: Spain
facility: Hospital Clinico Universitario Virgen de la Victoria
city: Manchester
country: United Kingdom
facility: The Christie Hospital
state: England
city: Edinburgh
country: United Kingdom
facility: University Hospital of Edinburgh
state: Scotland
Study officials:
affiliation: Executive Vice President & Chief Medical Officer
name: Andres Gutierrez, MD, PhD
role: STUDY_DIRECTOR
References: