E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Notch Activated Recurrent or Metastatic Triple Negative Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of AL101 monotherapy in subjects with Notch-activated recurrent or metastatic TNBC |
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E.2.2 | Secondary objectives of the trial |
- Efficacy - Secondary - To evaluate the safety and tolerability of AL101 monotherapy in subjects with recurrent or metastatic TNBC |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 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+. Note, if IHC is equivocal then do fluorescence in situ hybridization (FISH) or in situ hybridization (ISH); negative will be acceptable. Note: if FISH or ISH is equivocal then further assessment is allowed with Sponsor written approval. 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. Female or Male subjects. 8. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of IP and must agree to have a pregnancy test at least every cycle (4 weeks). An extension up to 72 hours is permissible in situations where results cannot be obtained within the standard 24-hour window. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 9. WOCBP must agree to use a highly effective birth control during the study (prior to the first dose with AL101 and for 120 days after the last dose), if conception is possible during this interval. Female subjects are considered to not be of childbearing potential if they have a history of hysterectomy or are post-menopausal defined as no menses for 12 months without an alternative medical cause. 10. Male subjects with partners who are WOCBP should use a combination of the methods specified in Section 10.4 for the women along with a male condom during the study and for 120 days after the last dose of IP, unless permanently sterile by bilateral orchidectomy. 11. Capable of giving signed informed consent form (ICF) which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. |
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E.4 | Principal 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. Any exceptions should be discussed with the Sponsor’s Medical Monitor. 2. BC that, in the opinion of the investigator, is considered amenable to potentially curative treatment. 3. Symptomatic central nervous system (CNS) metastases. Subjects with asymptomatic CNS metastases as well as those with previously treated CNS metastases are eligible for enrollment in the study if at least 28 days has elapsed since definitive treatment (either surgery, whole brain radiotherapy, stereotactic radiation), steroid therapy is either not required or dose has been weaned off over last 14 days, and the subject is deemed clinically stable by the investigator. 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. Non-chronic conditions (e.g., infectious diarrhea) that are completely resolved for at least 2 weeks prior to starting IP are not exclusionary. 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. Pregnant or breastfeeding or expecting to conceive children within the projected duration of the study. 10. Eastern Cooperative Oncology Group (ECOG) performance status ≥2. 11. Abnormal organ and marrow function defined as: a. neutrophils <1000/mm3, b. platelet count <75,000/mm3, c. hemoglobin <8 g/dL, d. total bilirubin >1.5 x upper limit of normal (ULN) (except known Gilbert’s syndrome whereby the total bilirubin must be < 5 mg/dL), e. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5 x ULN OR >5 x ULN for subjects with liver metastases, f. serum creatinine > ULN and creatinine clearance (CrCl) <50 mL/min (calculation of CrCl will be based on acceptable institution standard), g. uncontrolled triglyceride ≥Grade 2 elevations per CTCAE v5.0 (>300 mg/dL or >3.42 mmol/L). 12. 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. 13. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥480 msec. 14. Completed palliative radiation therapy < 7 days prior to initiating IP. 15. Prior treatment with gamma secretase inhibitors. Prior treatment with anti-Notch antibodies may be allowed upon discussion with the Sponsor’s medical monitor. 16. Last chemotherapy, biologic, or investigational therapy agent at least 4 weeks or 5 halflives (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. 17. 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. 18. 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). 19. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. 20. Life expectancy of less than 3 months. 21. Hypersensitivity to AL101 and any of its excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects who demonstrate an overall response rate (ORR), defined as partial response (PR) + complete response (CR) as assessed by investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the course of the study |
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E.5.2 | Secondary end point(s) |
- Clinical benefit response rate (CBR) defined as CR +PR + stable disease (SD) by investigator review based on RECIST v1.1 - Duration of response (DOR) by investigator review based on RECIST v1.1 - Progression free survival (PFS) - Proportion of subjects who have PFS at 6 months - Overall survival (OS) - Quality of life (QoL) as determined by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 questions (EORTC QLQ-C30) and Breast Cancer 45 questions (EORTC QLQ-BR45) - Frequency, duration and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) - Incidence of clinically significant abnormalities in laboratory parameters, electrocardiograms (ECGs), vital signs and physical examination. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the course of the study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Simon two-stage optimal design |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Israel |
Netherlands |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A subject is considered to have completed the study if he/she has completed EOS visit, 30 days after the last administration of the IMP. The end of the study is defined as the date of the last visit of the last subject in the study (LVLS). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |