| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PIK3CA-related overgrowth spectrum (PROS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| PROS is a group of so-called overgrowth syndromes caused by changes in functioning of PI3K pathway |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081236 |
| E.1.2 | Term | PIK3CA related overgrowth spectrum |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 |
| To demonstrate the efficacy of alpelisib as measured by the proportion of participants randomized to alpelisib with a confirmed objective response by BIRC in at least one of the following groups: Group 1 (≥ 18 yr-old); Group 2 (6 - 17 yr-old) |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objective:
- To demonstrate the efficacy of alpelisib vs placebo based on the
comparison of the proportion of participants with response at Week 16
in Group 1 or 2
Other secondary objectives: To assess
- Efficacy of alpelisib as measured by the proportion of participants with
a response at Week 24 (by BIRC) in Groups 1 and 2
- Safety and tolerability of alpelisib as compared to placebo in Groups 1
and 2 up to week 16
- The overall safety and tolerability of alpelisib over time
- Changes in patient-reported pain intensity and overall severity of
symptoms at Week 16 on treatment with alpelisib as compared to placebo in pediatric and adult populations
- Changes in target and non-target lesions and appearance of new lesions on treatment from baseline over time
- The PK of alpelisib in adult and pediatric patients
Other objectives are listed in the protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent and assent (when applicable) from the
patient, parent, legal authorized representative or guardian prior to any study related screening procedures are performed
2. Patients with diagnosis of PROS with symptomatic and /or
progressive overgrowth and at least one measurable PROS-related lesion
confirmed by BIRC assessment
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene
performed in local laboratories
4. A tissue sample (fresh or archival) is to be sent to a Novartis designated
central laboratory. If archival tissue is not available, collection of a fresh tissue biopsy is required for participants in Groups 1 and 2 and 5, if it's not clinically contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not mandatory.
For China only: Tissue sample collections and biomarker assessments are not applicable.
For Germany only: If archival tissue is available, it must be sent to a
Novartis-designated central laboratory. If no archival tissue is available, obtaining a fresh tissue biopsy is recommended, if it is not clinically contraindicated, but is not mandatory.
5. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs
of age at study entry) performance status index ≥50
6. Adequate bone marrow and organ function including Fasting plasma
glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated hemoglobin
(HbA1c) ≤ 6.5% (both criteria have to be met) (as assessed by central
laboratory for eligibility)
7. Presence of at least one PROS-related measurable lesion defined as a
lesion with longest diameter ≥2 cm, when the volume can be accurately
and reproducibly measured by MRI, and associated with complaints,
clinical symptoms or functional limitations affecting the patient's
everyday life. Measurability must be confirmed by BIRC before
randomization.
Other protocol-defined inclusion criteria may apply. |
|
| E.4 | Principal exclusion criteria |
1. Participant with only isolated macrodactyly, skin nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent
2. Previous treatment with alpelisib and/or any other PI3K inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib)
3. Radiation exposure for PROS treatment purpose within the previous 12 months on those PROS areas which are expected to qualify for target lesions (except lesion(s) progressing after completion of radiotherapy) at time of informed consent.
4. Debulking or other major surgery performed within 3 months at time of informed consent
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for vascular complications
performed within 6 weeks before informed consent. Participants (receiving anticoagulants for PROS related coagulopathy, primary or secondary prophylaxis of thrombosis may be included in the study)
6. For participants in Groups 1 and 2 and 5 (i.e., those ≥ 6 years of age):
Participants with documented pneumonitis or interstitial lung disease at the time of informed consent and with impaired lung function (e.g., FEV1 (Forced expiratory volume) or DLCO (Diffusing Capacity of the Lung for Carbon Monoxide) ≤ 70% of predicted) that is not related to PROS.
For participants in Groups 3 and 4 (i.e., those who are 2 to 5 years of age): Participants with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent. 7. History of acute pancreatitis within 1 year before informed consent or
past medical history of chronic pancreatitis at time of informed consent
8. Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent
9. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time of informed consent, when epilepsy is not controlled and/or the patient may not be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent.
10. Participants with clinically significant worsening of the PROS-related signs and symptoms (e.g. increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during screening phase, particularly if systemic treatment with
any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of the study treatment. This includes but is not limited to hypercoagulability state in participants not receiving prophylactic treatment.
Other protocol-defined exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Response defined by achieving at least 20% reduction from baseline in the sum of target lesion volumes (1 to 3 lesions, assessed by MRI by ablinded independent review committee (BIRC)), provided that none of the individual target lesions has ≥ 20% increase from baseline and in absence of progression of non-target lesions and without new lesions.
Confirmation of response requires a subsequent imaging assessment performed at least 4 weeks after the onset of the response. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Confirmed objective response at any time during the treatment period of this study |
|
| E.5.2 | Secondary end point(s) |
| Response defined by achieving at least 20% reduction from baseline in the sum of target lesion volumes (1 to 3 lesions, assessed by MRI by a blinded independent review committee (BIRC)) at Week 16, provided that none of the individual target lesions has ≥ 20% increase from baseline and in absence of progression of non-target lesions and without new lesions. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Switzerland |
| Hong Kong |
| Korea, Democratic People's Republic of |
| Canada |
| China |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| 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
|
| End of the trial is defined as when the last participant, regardless of study period, finishes their study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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