A Study of AL102 in Patients With Progressing Desmoid Tumors

Study Overview
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Brief Summary
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The current study is designed to evaluate the efficacy and safety of AL102 in patients with progressive desmoid tumors.

Detailed Description
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This is a Phase 2/3, randomized study in subjects with progressive desmoid tumors consisting of 2 parts. Phase2/Part A is an open-label, dose regimen finding study; Phase3/Part B is a double blind, placebo-controlled study and Open Label Extension utilizing the dose regimen selected in Phase2/Part A.

Official Title
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RINGSIDE: A Phase 2/3, Randomized, Multicenter Study to Evaluate AL102 in Patients With Progressing Desmoid Tumors

Conditions
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Desmoid, Desmoid Tumor

Intervention / Treatment
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* Drug: AL102
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Part A: At least 18 years of age (inclusive) at the time of signing the ICF. Histologically confirmed desmoid tumor (aggressive fibromatosis) by local pathologist (prior to informed consent). Disease progression, assessed locally by the investigator, defined as having at least one of the following: Unidimensional growth of desmoid tumor(s) by ≥10%, using the sum of the largest diameters of target lesion(s), within 18 months of the screening MRI Having desmoid tumor-related pain that is not adequately controlled with nonopioid medication At least 1 measurable lesion amenable to volume measurements by MRI at screening (Part A only) One of the following: Treatment naïve subjects for whom, in the opinion of the investigator, the IP is deemed appropriate, OR Recurrent/refractory disease following at least one line of therapy (including surgery, radiation, or systemic therapy) Agrees to provide formalin-fixed paraffin embedded archival or fresh tumor tissue for re- confirmation of disease. Must be able to swallow whole capsules with no GI condition affecting absorption; nasogastric or G-tube administration is not allowed. Exclusion Criteria Part A: Diagnosed with a malignancy in the past 2 years with some exceptions. Current or recent (within 2 months of IP administration) GI disease or disorders that increase the risk of diarrhea, such as inflammatory bowel disease and Crohn's disease. 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) at Screening. Myocardial infarction within 6 months prior to enrollment, greater than Class 1 angina pectoris, or has New York Heart Association (NYHA) Class III or IV heart failure, , symptomatic ventricular arrhythmias, sustained ventricular tachycardia, Torsade's de Pointes (TdP), the long QT syndrome, pacemaker dependence, or electrocardiographic evidence of acute ischemia. 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. Pregnant or breastfeeding or expecting to conceive children within the projected duration of the study. Eastern Cooperative Oncology Group (ECOG) performance status ≥2 Abnormal organ and marrow function at Screening defined as: Neutrophils <1000/mm3, Platelet count <100,000/mm3, Hemoglobin <9 g/dL, Total bilirubin >1.5x upper limit of normal (ULN) (except known Gilbert's syndrome), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5x ULN, Serum creatinine > ULN and creatinine clearance (CrCl) <60 mL/min (calculation of CrCl will be based on acceptable institution standard) Uncontrolled triglyceride ≥Grade 2 elevations per common terminology criteria for adverse events (CTCAE) v5.0 (>300 mg/dL or >3.42 mmol/L). ECG Exclusions (Part A only) Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 msec. QRS duration > 110 ms PR interval > 240 ms Marked ST-T wave abnormalities which would make it difficult to measure the QT interval Any treatments for desmoid tumors within 4 weeks prior to first dose of investigational therapy; subject must have recovered from therapy related toxicity to < CTCAE Grade 2 or clinical baseline. Therapy includes: Locoregional tumor directed therapies such as major surgery, radiation, radiofrequency ablation, or cryosurgery Systemic therapy including chemotherapy, biologic (anti-neoplastic agent, antibodies), TKIs (e.g., sorafenib, pazopanib, imatinib), hormonal therapy, or investigational therapy Chronic NSAIDs for the treatment of desmoid tumors within 4 weeks of first dose of IP; Inclusion Criteria Part B ≥12 years of age (inclusive) and ≥ 40 kg at the time of signing the ICF. Histologically confirmed desmoid tumor (aggressive fibromatosis) by local pathologist (prior to informed consent) that has progressed by ≥ 20% as measured by RECIST v1.1 within 12 months of the screening visit scan. Evidence of measurable disease by CT/MRI scan. Measurable lesions are defined according to RECIST v1.1. Subject and/or legally authorized representative (i.e. parent/guardian) must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF. Minor subjects must be capable of giving written assent as appropriate per the applicable age (per local regulatory requirements). For all other inclusion criteria refer to Part A inclusion criteria. Exclusion Criteria Part B The subjects must be excluded from participating in the study if they meet any of the exclusion criteria for Part A, except where otherwise noted.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Main Study 1.2 mg daily<br>AL102 1.2 mg | Drug: AL102<br>* AL102 is an inhibitor of gamma secretase-mediated Notch signaling.<br>|
| Experimental: Part A Main Study 2 mg Intermittent<br>AL102 2 mg | Drug: AL102<br>* AL102 is an inhibitor of gamma secretase-mediated Notch signaling.<br>|
| Experimental: Part A Main Study 4 mg Intermittent<br>AL102 4 mg | Drug: AL102<br>* AL102 is an inhibitor of gamma secretase-mediated Notch signaling.<br>|
| Experimental: Part B AL102<br>AL102, recommended dose regimen from Part A, 1.2 mg daily | Drug: AL102<br>* AL102 is an inhibitor of gamma secretase-mediated Notch signaling.<br>|
| Placebo Comparator: Part B Placebo<br>Placebo to match recommended dose regimen from Part A | Other: Placebo<br>* Placebo to match AL102<br>|
| Experimental: Open Label Extension<br>AL102, recommended dose regimen from Part A, 1.2 mg daily | Drug: AL102<br>* AL102 is an inhibitor of gamma secretase-mediated Notch signaling.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival (PFS) as defined as the time from randomization until the date of assessment of progression (as assessed by BICR based on RECIST v1.1) or death by any cause | Approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Overall response rate (ORR) defined as the proportion of subjects with ORR (CR and PR) by BICR based on RECIST v1.1. | Approximately 2 years | 
| Duration of response | Duration of response defined by the time from CR or PR (by BICR based on RECIST v1.1) until the earlier of the first documentation of disease progression or death from any cause. | Approximately 2 years | 
| Patient reported outcome | Change from baseline in quality of life as measured by GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Symptom Scale and Impact Scale (GODDESS) | Approximately 2 years | 
| Patient reported outcome | Change from baseline in quality of life as measured by Patient-reported outcomes measurement information system (PROMIS) Physical Function | Approximately 2 years | 
| Patient reported outcome | Change from baseline in quality of life as measured by EuroQol 5-dimensional questionnaire(EQ-5D) | Approximately 2 years | 
| Patient reported outcome | Change from baseline in pain assessment using brief pain inventory (BPI) short form | Approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RINGSIDE