Desmoid, Desmoid Tumor
Conditions
Keywords
RINGSIDE
Brief summary
The current study is designed to evaluate the efficacy and safety of AL102 in patients with progressive desmoid tumors.
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.
Interventions
DRUGAL102
AL102 is an inhibitor of gamma secretase-mediated Notch signaling.
OTHERPlacebo
Placebo to match AL102
Sponsors
Immunome, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part A: 1. At least 18 years of age (inclusive) at the time of signing the informed consent form (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 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. 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). OLE Key Inclusion Criteria: 1\. One of the following: 1. Participated in Part A (including MRI at Week 16) and were still on study at time that Part B/OLE dose selection was made, OR 2. Participating in Part B and were noted to have radiographic progressive disease by BICR, OR 3. Are on study treatment (placebo or varegacestat) after completion of Part B
Exclusion criteria
Parts A and B: 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 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 OLE Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Safety and Tolerability - Adverse Events | Approximately 1.5 years | Evaluation of the safety and tolerability of AL102 in subjects with progressing desmoid tumors as defined by as defined by the frequency and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) |
| Part B: Progression free survival (PFS) | Approximately 2 years | PFS as defined as the time from randomization until the date of assessment of progression as assessed by BICR based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death by any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change in Tumor Volume | Approximately 16 weeks | Change from baseline to Week 16 in tumor volume as measured by centrally read magnetic resonance imaging (MRI) by Blinded Independent Central Review (BICR) |
| Part B: Overall response rate (ORR) | Approximately 2 years | Defined as the proportion of subjects with confirmed ORR (complete response \[CR\] and partial response \[PR\]) by BICR based on RECIST v1.1. |
| Part B: Change in Tumor Volume | Approximately 24 weeks | Change from baseline at Week 24 in estimated tumor volume measured by T2 weighted (T2W) MRI or CT by BICR |
| Part B: Duration of response (DOR) | Approximately 2 years | Defined by the time from confirmed 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 |
| Part B: PFS with inclusion of Clinical Progression as an event | Approximately 2 years | Defined as the time from randomization until the date of radiographic progression as assessed by BICR or clinical progression as assessed by the investigator or death by any cause |
| Part B: Patient Reported Outcome (PRO) | Approximately 12 weeks | Change from baseline to Week 12 in the worst pain intensity (WPI) using GOunder/Desmoid Tumor Research Foundation (DTRF) DEsmoid Symptom Scale and Impact Scale (GODDESS) Desmoid Tumor Symptom Scale (DTSS) |
| Part B: Safety and Tolerability - Adverse Events | Approximately 2 years | Evaluation of the safety and tolerability of AL102 in subjects with progressing desmoid tumors as defined by the frequency and severity of TEAEs and SAEs |
| Part B: Safety and Tolerability - Time to Treatment Discontinuation | Approximately 2 years | Evaluation of the safety and tolerability of AL102 in subjects with progressing desmoid tumors as defined by the time to treatment discontinuation due to TEAE |
| Open Label Extension (OLE): Safety and Tolerability | Approximately 12 months | Evaluation of the safety and tolerability of AL102 in subjects with progressing desmoid tumors as defined by the frequency and severity of TEAEs and SAEs |
| OLE: PFS | Approximately 12 months | PFS as defined as the time to radiographic progression as assessed by BICR based on RECIST v1.1 or death by any cause |
| OLE: Confirmed ORR | Approximately 12 months | Proportion of participants with confirmed ORR (CR and PR) by BICR based on RECIST v1.1 |
| OLE: DOR | Approximately 12 months | DOR as defined by the time from confirmed 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 |
| OLE: PRO - GODDESS DTSS Total Symptom Score | Approximately 12 months | Change from baseline in quality of life (QoL) as determined by GODDESS DTSS Total Symptom Score |
| OLE: PRO - GODDESS DTSS Physical Functioning Domain Score | Approximately 12 months | Change from baseline in QoL as determined by GODDESS DTSS Physical Functioning Domain Score |
| OLE: PRO - WPI using GODDESS DTSS Item 1 | Approximately 12 months | Change from baseline in QoL as determined by WPI using GODDESS DTSS Item 1 |
Countries
Australia, Belgium, Germany, Israel, Italy, Netherlands, Poland, South Korea, Spain, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORMrinal Gounder, MD
MSKCC
Outcome results
None listed