| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Progressing desmoid tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| 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
OLE: To evaluate the safety and tolerability of AL102 in subjects with
progressive desmoid tumors
|
|
| 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
OLE:
1. To evaluate the efficacy of AL102 in subjects with progressive
desmoid tumors
2. To evaluate effects of AL102 on quality of life
|
|
| 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 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) in countries which allow participation of adolescentsand 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 per RECIST v1.1 (≥20% or new lesion) by investigator 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 by investigator.
4. One of the following:
• Recurrent/refractory disease following at least one line of therapy(including surgery, radiation, or systemic therapy); OR
• Treatment naïve subjects for whom, in the opinion of the investigator,surgery or radiation therapy is not deemed appropriate;
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. Premenstrual female subjects with a history of ovulatory dysfunction may be enrolled
10. WOCBP must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of hCG) within 24hours prior to the start of IP.
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. 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.
13. Minor subjects must be capable of giving written assent as
appropriate per the applicable age (per local regulatory requirements).
OLE
1. One of the following:
a. 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
b. Participating in Part B and were noted to have radiographic
progressive disease by BICR, OR
c. Are on study after completion of Part B
2. Must be able to swallow whole capsules with no GI condition affecting
absorption; nasogastric or G-tube administration is not allowed.
3. 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.
4. Minor subjects must be capable of giving written assent as
appropriate per the applicable age (per local regulatory requirements).
|
|
| E.4 | Principal exclusion criteria |
Part A
1. Diagnosed with a malignancy in the past 2 years, unless for protocol defined allowed malignancies
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
15. Contraindication to MRI
Part B
1. Diagnosed with a malignancy in the past 2 years, unless for protocol
defined allowed malignancies
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 antibacterial,
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. 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);i.Any other laboratory abnormality ≥Grade 3
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
OLE
1. Unstable or severe uncontrolled medical condition or any important
medical illness, abnormal ECG or laboratory finding.
2. Ongoing TEAE from Part A or Part B that requires discontinuation.
3. Breastfeeding or expecting to conceive children within the projected
duration of the study.
4. Use of any therapy that is prohibited in Part A or Part B of the study.
5. Concurrent enrollment in another clinical study unless it is an
observational (non-interventional) clinical study.
6. Hypersensitivity to AL102 and any of its excipients.
Other protocol defined criteria could apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A: Frequency and severity of TEAEs and SAEs; time to treatment discontinuation due to TEAE
Part B: Progression free survival
OLE: Frequency and severity of TEAEs and SAEs
|
|
| 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
OLE: throughout OLE duration |
|
| 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. PFS as defined as the time from randomization until the date of radiographic progression by BICR or clinical progression
4.change from baseline to WK28 in quality of life;
5.Change from baseline to Week 28 in the worst pain intensity (WPI)
6. frequency and severity of TEAEs and SAEs;
7. time to treatment discontinuation due to TEAE
OLE:
1. PFS as defined as the time of radiographic progression
2. Proportion of subjects with ORR (CR and PR) by BICR based on RECIST v1.1
3. DOR as 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
4. PFS as defined as the time to radiographic progression as assessed by BICR based on RECIST v1.1, OR clinical progression
5.Change from baseline (defined as from the start of AL102 treatment)
in
− Quality of life as determined by GODDESS DTSS Total Symptom Score
− GODDESS DTIS Physical Functioning Domain Score
− WPI using BPI short form
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: from beseline to week 16
Part B:
1, 6-7. baseline and throughout study duration
2. time from CR or PR until the earlier first documentation of disease progression or death from any cause
3. from randomization until the date of radiographic progression by BICR or clinical progression
4-5. from baseline to week 28
OLE: baseline and throughout OLE duration |
|
| 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 |
|
| 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; OLE- cross over, open label |
|
| 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 | 2 |
| 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 |
| India |
| Israel |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 |
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