A Study of AL102 in Patients With Progressing Desmoid Tumors

Desmoid Tumor Clinical Trial

— RINGSIDE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04871282
• Other study ID #: AL-DES-01
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: March 30, 2021
• Est. completion date: February 25, 2025

Study information

• Verified date: March 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 AL102 in patients with progressive desmoid tumors.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 192
• Est. completion date: February 25, 2025
• Est. primary completion date: January 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Desmoid
• Desmoid Tumor

Intervention

Drug:
• AL102
AL102 is an inhibitor of gamma secretase-mediated Notch signaling.

Other:
• Placebo
Placebo to match AL102

Locations

Country	Name	City	State
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Adelaide Cancer Centre	Kurralta Park	South Australia
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Belgium	Universitair Ziekenhuis	Gent
Belgium	Universitaire Ziekenhuizen Leuven	Leuven
Germany	Helios Klinikum Berlin-Buch	Berlin
Germany	Mannheim university medical center	Mannheim
Israel	Oncology Institute Barzilai Medical Center	Ashkelon
Israel	Rambam MC	Haifa
Israel	Hadassah University Hospital - Ein Kerem	Jerusalem
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	IRCCS Istituto Ortopedico Rizzoli	Bologna
Italy	IRCCS Fondazione Istituto Nazionale dei Tumori	Milano
Italy	Campus Bio-Medico University Hospital	Rome
Korea, Republic of	ASAN Medical Center	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Netherlands	The Netherlands Cancer Institute	Amsterdam
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Erasmus Medisch Centrum	Rotterdam
Poland	Maria Sklodowska-Curie National Research Institute of Oncology	Warsaw
Spain	Catalan Institute of Oncology (ICO)	Barcelona
Spain	Vall d´Hebrón University Hospital	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Western General Hospital	Edinburgh	Scotland
United Kingdom	The Royal Marsden Hospital	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United States	University of Michigan	Ann Arbor	Michigan
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	UTSW Simmons Cancer Center	Dallas	Texas
United States	City of Hope	Duarte	California
United States	NorthShore University Health System	Evanston	Illinois
United States	MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic	Jacksonville	Florida
United States	Jefferson City Medical Group	Jefferson City	Missouri
United States	Columbia University Irving Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic	Phoenix	Arizona
United States	University of Pittsburgh Medical Center, Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University	Saint Louis	Missouri
United States	Sarcoma Oncology Research Center	Santa Monica	California
United States	University of California at Los Angeles Hematology/Oncology	Santa Monica	California
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Stanford University Medical Center	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Ayala Pharmaceuticals, Inc,

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Germany,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Patient reported outcome	Change from baseline in quality of life as measured by EuroQol 5-dimensional questionnaire(EQ-5D)	Approximately 2 years
Secondary	Patient reported outcome	Change from baseline in pain assessment using brief pain inventory (BPI) short form	Approximately 2 years