Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum

This is a prospective Phase II multi-center study with an initial 16-week, randomized, double-blind, placebo-controlled period, followed by two extension periods to assess the efficacy, safety and pharmacokinetics (PK) of alpelisib in pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS)

This study consists of a screening period of up to 42 days, core period of 24 weeks, extension period of 24 weeks and long-term extension period of up to approximately 5 years. The study will enroll adult participants (Group 1; treated with film-coated tablets (FCT)), 6 to 17 years old pediatric participants (Group 2; treated with FCT), two exploratory groups of pediatric participants less than 6 years old (Group 3, 0-5 years old treated with granules and Group 4, 2-5 years old treated with FCT) and an exploratory group of 6 to 17 years old pediatric participants (Group 5, treated with FCT \[at a higher starting dose than Group 2\]).

For groups 1 and 2, eligible participants aged ≥6 years old will be randomized in a 2:1 ratio to alpelisib or matching placebo. Both age groups (group 1 and group 2) will be enrolled in the study in parallel. In the core period, participants will receive treatment in blinded fashion, with an upfront 16-week placebo-controlled period. After Week 16 those participants who were randomized to receive placebo will be switched to active treatment with alpelisib. Those participants who were randomized to receive alpelisib will continue their active treatment. Participants in Group 4 will be enrolled before Group 3. Group 5 will be open to enrollment after enrollment of Group 2 has been completed. All participants will receive alpelisib in an open-label setting. Group 3 will be an exploratory group of participants who are 0 to 5 years old and will receive the alpelisib granules formulation with an age-dependent starting dose and maximum dose levels ranging from 20 mg every other day to 50 mg once daily.

Group 3 will be open to enrollment only after implementation of Global Protocol Amendment 05.

Dose escalation is allowed once a participant has reached the age of 6 years, has completed the initial 24 weeks of study treatment (Week 25).

The planned duration of alpelisib treatment in the study will be up to 5 years after randomization/treatment start for all age groups. Participant may be discontinued from treatment with alpelisib earlier due to unacceptable toxicity, confirmed disease progression, death, and/or any other reason at the discretion of the investigator or the participant.

Eligibility Criteria:
Key Inclusion Criteria:

* Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative, or guardian prior to any study-related screening procedures were performed.
* Male or female patients age above 0 day at the time of informed consent: Group 1: ≥ 18 years old, Group 2: 6-17 years old, Group 3: ≥ 0-5 years old, Group 4: ≥ 2-5 years old, Group 5: 6-17 years old.
* Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by BIRC assessment who had syndromic disease or isolated features at the time of informed consent. Patients, who previously had been receiving systemic treatment for PROS, could enter the study.
* Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test validated according to the local regulations at the time of informed consent.
* A tissue sample (fresh or archival) was to be sent to a Novartis-designated central laboratory.
* Karnofsky (in patients \> 16 years old at study entry)/Lansky (≤ 16 years of age at study entry) performance status index ≥ 50.
* Adequate bone marrow and organ function as assessed by central laboratory for eligibility.
* Presence of at least one PROS-related measurable lesion defined as a lesion with longest diameter ≥ 2 cm, when the volume could be accurately and reproducibly measured by MRI, and associated with complaints, clinical symptoms or functional limitations affecting the patient's everyday life. Measurability was confirmed by BIRC before randomization.
* Able to swallow study drug (as assessed within 7 days before study treatment start):
* Groups 1, 2, 4, and 5: FCT, or as drinkable suspension when applicable.
* Group 3: granules. Drug administration via feeding tube is allowed.

Key Exclusion Criteria:

* Patient with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any three of them), in absence of other PROS-related lesions at the time of informed consent.
* Previous treatment with alpelisib and/or any other PI3K inhibitor(s).
* Radiation exposure for PROS treatment purpose within the previous 12 months on those PROS areas, which were expected to qualify for target lesions (except lesion(s) progressing after completion of radiotherapy) at time of informed consent.
* Debulking or other major surgery performed within 3 months at time of informed consent.
* Clinically meaningful bleeding related to PROS: Grade 2 within 14 days or grade 3 and more within 28 days before study treatment start as per CTCAE v4.03.
* Clinically meaningful PROS-related thrombotic event (grade 2 and more as per CTCAE v4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent.
* History of prior and or ongoing malignancy or ongoing investigations or treatment for malignancy at time of informed consent.
* Clinically significant heart disease at time of informed consent.
* Patients in Groups 1, 2, and 5 with documented pneumonitis or interstitial lung disease at time of informed consent and with impaired lung function (e.g., FEV1 or DLCO ≤ 70% of predicted) that was not related to PROS. Patients in Groups 3 and 4 with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent.
* History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent.
* Patients with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent.
* Known impairment of gastrointestinal (GI) function due to concomitant GI disease that may significantly alter the absorption of the study drug at time of informed consent.
* History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the excipients of alpelisib at time of informed consent.
* Known history of Steven Johnson's syndrome, erythema multiforme or toxic epidermal necrolysis at time of informed consent.
* Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time of informed consent, when epilepsy was not controlled and/or the patient may not be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent.
* Patient with other concurrent severe and/or uncontrolled medical conditions that could, in the Treating Physician's judgment, contraindicate administration of alpelisib at time of informed consent. Patient with an active documented COVID-19 infection at time of informed consent could be included only when completely recovered and had no symptoms for at least 28 days before first dose of study medication.
* Pregnant or breastfeeding female patients at time of informed consent.
* Female patients of child-bearing potential who did not consent to use a highly effective method of contraception and male patients who did not consent to use a condom and/or a highly effective method of contraception for the duration of the study and for one week following discontinuation of alpelisib.
* Patient was receiving any of the following medications and could not discontinue 7 days prior to the start of the treatment: strong inducers of CYP3A4 or inhibitors of breast cancer resistance protein (BCRP).
* Not able to understand and to comply with study instructions and requirements at time of informed consent.
* Participation in a prior investigational study within 4 weeks prior to study treatment start or within 5 half-lives of the investigational product, whichever was longer.
* Patients with clinically significant worsening of PROS-related laboratory anomalies, physical signs and symptoms indicating an uncontrolled condition during the screening phase, particularly if systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. This included but was not limited to hypercoagulability state in patients not receiving prophylactic treatment.

Other inclusion/exclusion criteria may apply