A Study of AL102 in Patients With Progressing Desmoid Tumors (RINGSIDE)

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Desmoid Tumor; Desmoid
• Intervention / Treatment: Drug: AL102; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 192
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Johnathan Yovell, MD; Phone Number: +972-8-3731535; Email: clinicaltrials@ayalapharma.com
• Study Contact Backup: Name: Yelena Lalazar, RN, MPH; Phone Number: +972-8-3731535; Email: clinicaltrials@ayalapharma.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Chris O'Brien Lifehouse
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Kurralta Park, South Australia, Australia, 5037
      • Adelaide Cancer Centre
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis
  • Leuven, Belgium
    • Universitaire Ziekenhuizen Leuven
• Germany
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin-Buch
  • Mannheim, Germany, 68167
    • Mannheim university medical center
• Israel
  • Ashkelon, Israel
    • Oncology Institute Barzilai Medical Center
  • Haifa, Israel, 3109601
    • Rambam MC
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital - Ein Kerem
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Italy
  • Bologna, Italy, 40136
    • IRCCS Istituto Ortopedico Rizzoli
  • Milano, Italy, 20133
    • IRCCS Fondazione Istituto Nazionale dei Tumori
  • Rome, Italy, 00128
    • Campus Bio-Medico University Hospital
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 43-gil
    • Asan Medical Center
• Netherlands
  • Amsterdam, Netherlands, 1066CX
    • The Netherlands Cancer Institute
  • Leiden, Netherlands
    • Leiden University Medical Center
  • Rotterdam, Netherlands, 3015 AA
    • Erasmus Medisch Centrum
• Poland
  • Warsaw, Poland, 00-001
    • Maria Sklodowska-Curie National Research Institute of Oncology
• Spain
  • Barcelona, Spain, 08035
    • Vall d´Hebrón University Hospital
  • Barcelona, Spain, 08908
    • Catalan Institute of Oncology (ICO)
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jiménez Díaz
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Western General Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Research Center
    • Santa Monica, California, United States, 90404
      • University of California at Los Angeles Hematology/Oncology
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Illinois
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System
  • Massachusetts
    • Boston, Massachusetts, United States, 02214
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Jefferson City, Missouri, United States, 65109
      • Jefferson City Medical Group
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center, Hillman Cancer Center
  • Texas
    • Dallas, Texas, United States, 75235
      • UTSW Simmons Cancer Center
    • Houston, Texas, United States, 77005
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria Part A:

1. At least 18 years of age (inclusive) at the time of signing the ICF.
2. Histologically confirmed desmoid tumor (aggressive fibromatosis) by local pathologist (prior to informed consent).

3. 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
4. At least 1 measurable lesion amenable to volume measurements by MRI at screening (Part A only)

5. 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)
6. Agrees to provide formalin-fixed paraffin embedded archival or fresh tumor tissue for re- confirmation of disease.
7. 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:

1. Diagnosed with a malignancy in the past 2 years with some exceptions.
2. 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.
3. 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.
4. 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.
5. 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.
6. Pregnant or breastfeeding or expecting to conceive children within the projected duration of the study.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≥2

8. Abnormal organ and marrow function at Screening defined as:

   1. Neutrophils <1000/mm3,
   2. Platelet count <100,000/mm3,
   3. Hemoglobin <9 g/dL,
   4. Total bilirubin >1.5x upper limit of normal (ULN) (except known Gilbert's syndrome),
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5x ULN,
   6. Serum creatinine > ULN and creatinine clearance (CrCl) <60 mL/min (calculation of CrCl will be based on acceptable institution standard)
   7. Uncontrolled triglyceride ≥Grade 2 elevations per common terminology criteria for adverse events (CTCAE) v5.0 (>300 mg/dL or >3.42 mmol/L).

9. ECG Exclusions (Part A only)

   1. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 msec.
   2. QRS duration > 110 ms
   3. PR interval > 240 ms
   4. Marked ST-T wave abnormalities which would make it difficult to measure the QT interval

10. 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:

    1. Locoregional tumor directed therapies such as major surgery, radiation, radiofrequency ablation, or cryosurgery
    2. Systemic therapy including chemotherapy, biologic (anti-neoplastic agent, antibodies), TKIs (e.g., sorafenib, pazopanib, imatinib), hormonal therapy, or investigational therapy
11. Chronic NSAIDs for the treatment of desmoid tumors within 4 weeks of first dose of IP;

Inclusion Criteria Part B

1. ≥12 years of age (inclusive) and ≥ 40 kg at the time of signing the ICF.
2. 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.
3. Evidence of measurable disease by CT/MRI scan. Measurable lesions are defined according to RECIST v1.1.
4. 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.
5. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ayala Pharmaceuticals, Inc,
• Investigators: Principal Investigator: Mrinal Gounder, MD, MSKCC

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2021
• Primary Completion (Estimated): January 15, 2025
• Study Completion (Estimated): February 25, 2025

Study Registration Dates

• First Submitted: April 23, 2021
• First Submitted That Met QC Criteria: May 3, 2021
• First Posted (Actual): May 4, 2021

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: RINGSIDE
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Fibrous Tissue; Fibroma; Fibromatosis, Aggressive
• Other Study ID Numbers: AL-DES-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No