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

Study Overview
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Brief Summary
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This is a prospective Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and pharmacokinetics of alpelisib in pediatric and adult participants with PIK3CA-related overgrowth spectrum (PROS).

Detailed Description
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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), 6-17 years old pediatric participants (Group 2), two exploratory sets of 2-5 years old pediatric participants (Group 3 treated with granules and Group 4 treated with film-coated tablets (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]). 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 enrolled later, after the completion of the primary analysis when the efficacy, safety and PK data will be available from the participants in Groups 1 and 2 in addition to the data from Group 4 and 5 as available, in order to select the recommended dose for participants in Group 3. 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.

Official Title
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EPIK-P2: A Phase II Double-blind Study With an Upfront, 16-week Randomized, Placebo-controlled Period, to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (PROS)

Conditions
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PIK3CA-related Overgrowth Spectrum (PROS)

Intervention / Treatment
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* Drug: Alpelisib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 are performed Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by blinded independent review committee (BIRC) assessment Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories A tissue sample (fresh or archival) is 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, 2 and 5, if it is not clinically contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not mandatory. For China only: Tissue sample collection 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. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at study entry) performance status index ≥50 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) 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 (Magnetic resonance imaging), and associated with complaints, clinical symptoms or functional limitations affecting the patient's everyday life. Measurability must be confirmed by BIRC before randomization. Exclusion Criteria: 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 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) 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. Debulking or other major surgery performed within 3 months at time of informed consent 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. Note: Participants receiving anticoagulants for PROS-related coagulopathy, primary or secondary prophylaxis of thrombosis may be included in the study Participants in Groups 1, 2 ad 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 is not related to PROS. Participants 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 Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent 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. Participants with clinically significant worsening of PROS-related laboratory anomalies, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) 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 includes but is not limited to hypercoagulability state in participants not receiving prophylactic treatment. Other inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adult cohort (group 1)- Alpelisib<br>During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive alpelisib (125 mg, oral, once daily). After Week 16, participants will continue their active treatment at the same dose level. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>|
| Placebo Comparator: Adult cohort (group 1)- Placebo<br>During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive placebo (125 mg, oral, once daily). After Week 16, participants will be switched to active treatment with alpelisib at the placebo dose level received at the end of the placebo period. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>Drug: Placebo<br>* Participants will receive matching placebo once daily up to week 16.<br>|
| Experimental: Pediatric cohort (group 2: 6 to 17 years old) -Alpelisib<br>During double-blind randomized study period (from baseline up to Week 16, pediatric participants (6 to 17 years old) will be randomized to receive alpelisib (50 mg, oral, once daily). After Week 16, participants will continue their active treatment at the same dose level. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>|
| Placebo Comparator: Pediatric cohort (group 2: 6 to 17 years old)-Placebo<br>During double-blind randomized study period (from baseline up to Week 16), pediatric participants (6 to 17 years old) will be randomized to receive Placebo (50mg, oral, once daily). After Week 16, participants will be switched to active treatment with alpelisib at the placebo dose level received at the end of the placebo period. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>Drug: Placebo<br>* Participants will receive matching placebo once daily up to week 16.<br>|
| Experimental: Pediatric cohort (group 3: 2 to 5 years old)- Alpelisib granules<br>Pediatric participants (2 to 5 years old) will receive alpelisib with the alpelisib granules formulation at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 and 5 as available. An extrapolation approach will be used for dose selection for this group. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>|
| Experimental: Pediatric cohort (group 4: 2 to 5 years old)- Alpelisib FCT<br>Pediatric participants (2 to 5 years old) will receive 50 mg of alpelisib film-coated tablets (FCT) once daily in an open-label setting. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>|
| Experimental: Pediatric cohort (group 5: 6-17 years old)-Alpelisib FCT<br>Pediatric participants (6 to 17 year old) will receive 125 mg alpelisib film-coated (FCT) once daily, in an open-label setting. | Drug: Alpelisib<br>* Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 2 to 5 years old) will receive alpelisib granules at dose determined based on the primary analysis for efficacy, safety and PK of alpelisib in Groups 1 and 2 in addition to the data from Group 4 as available. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants randomized to alpelisib with a confirmed objective response by BIRC in Group 1 and Group 2 | 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)), 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. | Up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with response at Week 16 by BIRC in Group 1 and Group 2 | 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. | Week 16 | 
| Proportion of participants with a response at Week 24 (by BIRC) in Groups 1 and 2 | 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 24, 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. | Week 24 | 
| Frequency and severity of adverse events in Groups 1 and 2 up to Week 16 | Type, frequency, seriousness, and severity of treatment-emergent adverse events per CTCAE v4.03 criteria in Groups 1 and 2 up to Week 16. | Up to Week 16 | 
| Frequency and severity of adverse events in all Groups of participants over time | Type, frequency, seriousness, and severity of treatment-emergent adverse events per CTCAE v4.03 criteria in participants with PROS over time. | Up to approximately 5 years | 
| Change from baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain intensity in Group 1 and 2 | The Brief Pain Inventory (BPI) item that assesses worst pain intensity in the past 24 hours will be recorded on a PRO diary. Participants respond to the item on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). Change from baseline in scores at Week 16 will be assessed in adult (≥ 18 years old) and pediatric (12 to 17 years old) populations. | Baseline to Week 16 | 
| Change from baseline to Week 16 in Patient Global Impression of Symptom Severity (PGIS) in Group 1 and 2 | The PGIS is a single item to assess the participant's perception in the severity of their symptoms experienced and clinical meaningfulness of treatment effects experienced using a 5-point verbal rating scale, from No Symptoms to Very Severe. Change from baseline severity at Week 16 will be assessed in adult (≥ 18 years old) and pediatric (12 to 17 years old) populations. | Baseline to Week 16 | 
| Percentage change from baseline in target and MRI-measurable non- target lesion volume in Group 1 and Group 2 | Percentage change from baseline in the sum of target lesion volume, MRI-measurable non-target lesion volume and all MRI measurable (target an non-target) lesion volume as assessed by BIRC. Target lesions are defined as anatomically reproducibly defined tissue(s) masses, which may be composed of one or several tissue types, and can be accurately measured by imaging technique MRI. Target lesion(s) (up to 3) should be identified at screening, be at least 2 cm in the longest diameter at baseline (for each selected lesion) and may be further reproducibly assessed by MRI. MRI-measurable non-target lesions are defined as all anatomic lesions other than selected as target and may be measured at radiologic assessment (at least 2 cm in the longest diameter at baseline, the volume may be further reproducibly assessed by MRI). | From Baseline up to approximately 5 years | 
| Proportion of participants with changes from baseline in other non-target lesions in Group 1 and Group 2 | Percentage change from baseline in other non-target lesions (by BIRC). Non Target lesions are defined as: Anatomic lesions, limb/trunkal areas affected by PROS, organomegaly when they may be measured only by caliper/ruler (e.g., circumference of changed limb or body part) Truly non-measurable lesions (e.g., small lesions less than 2 cm on MRI, superficial visual lesions, masses, organomegaly, PROS-related enlargement of anatomic area identified by physical exam that is not measurable by reproducible imaging technique) | From Baseline up to approximately 5 years | 
| Proportion of participants with new lesions in Group 1 and Group 2 | The proportion of patients with new lesions (as assessed by BIRC) will be assessed throughout the study. | From Baseline up to approximately 5 years | 
| Pharmacokinetics (PK) of alpelisib in Group 1 and Group 2: Maximum Concentration (Cmax) | Maximum concentration of alpelisib following drug administration will be assessed for Group 1 and Group 2. After Week 28, blood samples will be collected only for participants who had dose escalation at next scheduled visit 4 weeks after the first dose escalation. | Week 17 Day 1 (Pre-dose, 1h post dose, 3h post dose, 5h post dose, 8h post dose , 24h post dose/ Pre-dose of Day 2), Week 20 Day 1 (Pre-dose, 3h post dose) and after Week 28, on Day 1 (Pre-dose and 3h post dose) 4 weeks after the first dose escalation | 
| Pharmacokinetics (PK) of alpelisib in Group 1 and Group 2: Trough concentration (Ctrough) | The trough observed concentration of alpelisib will be assessed for Group 1 and Group 2. After Week 28, blood samples will be collected only for participants who had dose escalation at next scheduled visit 4 weeks after the first dose escalation. | Week 17 Day 1 (Pre-dose and 24 h post dose/ Pre-dose of Day 2), Week 20 Day 1 (Pre-dose) and after Week 28, on Day 1 (Pre-dose) 4 weeks after the first dose escalation | 
| Change from Baseline in patient-reported pain assessed by Brief Pain Inventory (BPI) Worst Pain intensity item or Wong-Baker Faces Scale (age appropriate) in pediatric and adult populations | Change in scores from Brief Pain Inventory (BPI) items, or Wong-Baker Faces Scale (age appropriate). The BPI item that assesses worst pain intensity in the past 24 hours will be used to assess pain intensity for adult participants (≥18 years old) and pediatric participants (≥12 years old). Participants respond to the item on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). For children under 12, the Wong-Baker Faces Scale will be used in place of the BPI worst pain intensity item. This scale is a single-item that includes drawings of 6 faces that are associated with both a numeric rating and a descriptor (ranging from 0/no hurt - 10/hurts worst) | From Baseline up to approximately 5 years | 
| Changes from Baseline in patient-reported health-related quality of life assessed by PROMIS-profile (Patient Reported Outcome Measurement Information System) in pediatric and adult populations | Change in scores from the PROMIS-profile (Patient Reported Outcome Measurement Information System). The PROMIS Profiles are a group of PROMIS short forms measuring different domains of health-related quality of life (physical function, fatigue, ability to participate in social/peer relationships, pain interference, pain severity, anxiety, depression and sleep disturbance). All items include 5 response options, except for the pain intensity item, which has 11 response options. | From Baseline up to approximately 5 years | 
| Changes from Baseline in patient-reported overall impression of symptoms assessed by Patient Global Impression of Symptom Severity (PGIS) in pediatric and adult populations | Change in PGIS item. The PGIS is a single item to assess the participant's perception in the severity of their symptoms using a 5-point verbal rating scale, from No symptoms to Very Severe. | From Baseline up to approximately 5 years | 
| Duration of response (DOR) in participants who received alpelisib in Group 1 and Group 2 | Duration of response (DOR) is defined as the time from first documented response until progression of PROS lesions by BIRC or death. | From first documented response until progression of PROS lesions or death, assessed up to approximately 5 years | 
| Time to treatment failure in participants who received alpelisib in Group 1 and Group 2 | Time from randomization/alpelisib treatment start date until the discontinuation of study treatment due to lack of efficacy (including unsatisfactory therapeutic effect, disease progression) or safety reasons (including adverse events, death). Participants who complete the study or discontinue study treatment for other reasons (e.g. discontinuation due to Participant/Guardian decision, technical problems) will be censored at the date of last study treatment received. | From Baseline up to approximately 5 years | 
| Overall clinical response rate as assessed by investigator in participants who received alpelisib in Group 1 and Group 2 | Proportion of participants with overall clinical response reported as improvement, stable or worsening of clinical condition, as assessed by the investigator | Week 16, 24, 40, 48, 72, 96 and thereafter every 48 weeks | 
| Proportion of participants with response during the extension period in Group 1 and Group 2 | Response (yes/no) at scheduled protocol visit. Response is 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)), 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. | Week 40, 48, 72, 96, 144, 192, 240 and 264. | 
| Changes in symptoms and complications/comorbidities up to Week 16 on treatment with alpelisib as compared to placebo in Group 1 and Group 2 | Change in PROS-related symptoms and complications/comorbidities associated with PROS up to Week 16 among participants with symptoms and complications/comorbidities present at baseline | Baseline up to Week 16 | 
| Changes in symptoms and complications/comorbidities associated with PROS over time in Group 1 and Group 2 | Change in PROS-related symptoms and complications/comorbidities among participants with symptoms and complications/comorbidities present at baseline | Baseline up to approximately 5 years | 
| Proportion of participants with healthcare visit/hospitalized due to PROS in Group 1 and Group 2 | Proportion of participants with healthcare visit/hospitalized due to PROS will be assessed for Group 1 and Group 2. | From Baseline up to approximately 5 years | 
| Proportion of participants requiring rescue surgery due to PROS in Group 1 and Group 2 | Proportion of participants requiring rescue surgery due to PROS will be assessed for Group 1 and Group 2. | From Baseline up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alpelisib, BYL719, Adult, Pediatric, Phase II, PIK3CA-related overgrowth spectrum (PROS)