E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Progressing desmoid tumors |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059352 |
E.1.2 | Term | Desmoid tumour |
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 |
Part A: To evaluate the safety and tolerability of AL102 in subjects with progressing desmoid tumors
Part B: To evaluate effects of AL102 on disease progression in subjects with progressing desmoid tumors |
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E.2.2 | Secondary objectives of the trial |
Part A: To assess the effects of AL102 on desmoid tumor size in subjects with progressing desmoid tumors
Part B: 1. To evaluate additional effects of AL102 on tumor response; 2. To evaluate effects of AL102 on quality of life; 3. To evaluate the safety and tolerability of AL102 in subjects with progressing desmoid tumors |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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: a) 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 b) Having desmoid tumor-related pain that is not adequately controlled with non-opioid 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. A desmoid tumor in which continued progressing disease will not result in immediate significant risk to the subject. 7. Agrees to provide formalin-fixed paraffin embedded (FFPE) archival or fresh tumor tissue. 8. Must be able to swallow whole capsules with no GI condition affecting absorption (not including history of colectomy); nasogastric or G-tube administration is not allowed. 9. Male or female subjects. 10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of investigational product (IP). An extension up to 72 hours is permissible in situations where results cannot be obtained within the standard 24 hour window. 11. WOCBP and men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of the treatment with IP plus 120 days post-treatment completion. Contraception methods should be consistent with local regulations. 12. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
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. One of the following: • Treatment naïve subjects for whom, in the opinion of the investigator, treatment with IP is deemed appropriate; OR • Recurrent/refractory disease following at least one line of therapy (including surgery, radiation, or systemic therapy). 5. A desmoid tumor in which continued progressing disease will not result in immediate significant risk to the subject. 6. Agrees to provide FFPE archival or fresh tumor tissue. 7. Must be able to swallow whole capsules with no GI condition affecting absorption (not including history of colectomy); nasogastric or G-tube administration is not allowed. Gender and Reproductive Considerations 8. Male or female subjects. 9. 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. An extension up to 72 hours is permissible in situations where results cannot be obtained within the standard 24-hour window. 10. WOCBP and men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of the treatment with IP plus 120 days post-treatment completion. Contraception methods should be consistent with local regulations. 11. 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. 12. Minor subjects must be capable of giving written assent as appropriate per the applicable age (per local regulatory requirements). |
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E.4 | Principal exclusion criteria |
Part A 1. Diagnosed with a malignancy in the past 2 years. However, subjects with the following diagnoses may enroll: • Non-melanoma skin cancers • Melanoma in situ • Treated thyroid cancer • Treated cervical carcinoma in situ • Early-stage prostate cancer that has undergone definitive treatment or under active surveillance • Resected DCIS of breast • Resected stage 1 colorectal carcinoma 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 4. Myocardial infarction within 6 months prior to enrollment, greater than Class 1 angina pectoris, or has NYHA Class III or IV heart failure, symptomatic ventricular arrhythmias, sustained ventricular tachycardia, TdP, the long QT syndrome, pacemaker dependence, or electrocardiographic evidence of acute ischemia 5. History of additional risk factors for TdP 6. Unstable or severe uncontrolled medical condition or any important medical illness or abnormal laboratory finding 7. Pregnant or breastfeeding or expecting to conceive children during the study 8. ECOG performance status ≥2 9. Abnormal organ and marrow function at Screening defined as: a. Neutrophils <1500/mm3 b. Platelet count <100,000/mm3 c. Hemoglobin <9 g/dL d. Electrolytes (potassium, calcium, magnesium, and phosphorus, using corrected value if low serum albumin level is present) outside the normal limits of the local laboratory e. Total bilirubin >1.5x ULN (except known Gilbert’s syndrome >3x ULN) f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5x ULN g. Serum or plasma creatinine > ULN and creatinine clearance (CrCl) <60 mL/min h. Uncontrolled triglyceride ≥Grade 2 elevations per CTCAE v5.0 (>300 mg/dL or >3.42 mmol/L) 10. ECG Exclusions a. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥450 msec b. QRS duration > 110 ms c. PR interval > 240 ms d. Marked ST-T wave abnormalities which would make it difficult to measure the QT interval 11. Any treatments for desmoid tumors within 4 weeks prior to first dose 12. Chronic NSAIDs for the treatment of desmoid tumors within 4 weeks of first dose 13. Prior treatment with GSI or other agents targeting the Notch pathway 14. Use of strong inhibitors of CYP3A4 or strong inducers of CYP3A4 18. Contraindication to MRI
Part B 1. Diagnosed with a malignancy in the past 2 years. However, subjects with the following may enroll: • Non-melanoma skin cancers • Melanoma in situ • Treated thyroid cancer • Treated cervical carcinoma in situ • Early-stage prostate cancer that has undergone definitive treatment or under active surveillance • Resected DCIS of breast • Resected stage 1 colorectal carcinoma 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 4. Myocardial infarction within 6 months prior to enrollment, greater than Class 1 angina pectoris, or has NYHA Class III or IV heart failure, symptomatic ventricular arrhythmias, sustained ventricular tachycardia, TdP, the long QT syndrome, pacemaker dependence, or electrocardiographic evidence of acute ischemia 5. History of additional risk factors for TdP 6. Unstable or severe uncontrolled medical condition or any important medical illness or abnormal laboratory finding 7. Pregnant or breastfeeding or expecting to conceive children during the study Diagnostic Assessments 8. ECOG performance status ≥2 9. Abnormal organ and marrow function at Screening defined as: a. Neutrophils <1500/mm3 b. Platelet count <100,000/mm3 c. Hemoglobin <9 g/dL d. Electrolytes (potassium, calcium, magnesium, and phosphorus, using corrected value if low serum albumin level is present) outside the normal limits of the local laboratory e. Total bilirubin >1.5x ULN (except known Gilbert’s syndrome >3x ULN) f. AST and ALT >2.5x ULN g. Serum or plasma creatinine > ULN and CrCl <60 mL/min (calculation of CrCl will be based on acceptable institution standard) h. Uncontrolled triglyceride ≥Grade 2 elevations per CTCAE v5.0 (>300 mg/dL or >3.42 mmol/L) 10. ECG Exclusions a. Mean QTcF ≥450 msec b. Second or third degree AV block 11. Any treatments for desmoid tumors within 4 weeks prior to first dose 12. Chronic NSAIDs for the treatment of desmoid tumors within 4 weeks of first dose 13. Prior treatment with GSI or other agents targeting the Notch pathway 14. Use of strong inhibitors of CYP3A4 or strong inducers of CYP3A4
Other protocol defined criteria could apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A: Frequency, duration and severity of TEAEs ans SAEs; time to treatment discontinuation due to TEAE
Part B: Progression free survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: throughout study duration
Part B: from randomization until the date of assessment of progression or death by any cause |
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E.5.2 | Secondary end point(s) |
Part A: change from baseline to week 16 in tumor volume
Part B: 1. proportion of subjects with ORR; 2. duration of response; 3. change from baseline in quality of life; 4. change from baseline in pain assessment; 5. frequency, duration and severity of TEAEs and SAEs; 6. time to treatment discontinuation due to TEAE |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: from beseline to week 16
Part B: 1, 3-6. baseline and throughout study duration 2. time from CR or PR until the earlier first documentation of disease progression or death from any cause |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 |
Part A: open label; Part B: double blind |
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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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Australia |
Austria |
Belgium |
Canada |
Germany |
Greece |
Israel |
Italy |
Korea, Republic of |
Netherlands |
New Zealand |
Poland |
Spain |
Taiwan |
United Kingdom |
United States |
France |
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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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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 | 4 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |