PIK3CA-related Overgrowth Spectrum (PROS)
Conditions
Keywords
PIK3CA-related overgrowth spectrum (PROS), Alpelisib, BYL719, Adult, Pediatric, Phase II
Brief summary
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)
Detailed description
This is a 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 PK of alpelisib in pediatric and adult participants with PROS. Study period 1 - Core Period: Double-blind treatment, with an upfront 16-week placebo-controlled period (From Randomization to the end of Week 24) - Groups 1 and 2 At study start, participants in Group 1 and Group 2 will be enrolled and randomized in a 2:1 ratio (104 participants in the active arms and 52 participants in the placebo arms) to alpelisib or matching placebo. The upfront placebo-controlled period will continue for the first 16 weeks. At the conclusion of week 16, those participants who were randomized to receive placebo will be switched to active treatment with alpelisib in a blinded fashion at the dose level received at the end of the placebo period. Those participants who were randomized to receive alpelisib, will continue their treatment at the same dose level. During the initial 16 weeks of the Core period, study treatment will be given in a blinded fashion, starting from week 17 of the Core period in open label fashion. The randomized treatment assignment to the treatment arms will remain blinded to participants, Investigators and the study team until the time of the primary analysis, when the last participant reaches week 48 from randomization or discontinues earlier. Study period 1 - Exploratory; Group 4, open label treatment with the alpelisib FCT formulation After the implementation of Global Protocol Amendment 01, approximately 6 participants 2 to 5 years of age will be enrolled in exploratory Group 4. These participants will receive alpelisib FCT in an open label setting. Study period 2 - Extension 1: treatment with alpelisib (week 25 up to the end of week 48) - Groups 1 and 2 Participants (Group 1 and Group 2) will continue their treatment during this study period. For Groups 1 and 2, dose escalation is NOT allowed during first 4 weeks of Extension 1 period (weeks 25-28). Once a participant (Groups 1 and 2) has completed initial 24 weeks of study treatment and reached Week 29, dose escalation will be allowed (Refer to Section 6.5.1): * Group 1: Alpelisib (125mg, or 200mg, or 250 mg QD) * Group 2: Alpelisib (50mg, or 125mg, or 200mg, or 250 mg QD) Study period 2 - Exploratory: Group 4, open label treatment with the alpelisib FCT formulation For Group 4 dose escalation is allowed once participant has reached the age of 6 years old, has completed the initial 24 weeks of study treatment, and has reached week 25: • Group 4: Alpelisib (50 mg, or 125 mg, or 200 mg, or 250 mg QD) Study period 3 - Extension 2: long-term treatment with alpelisib (Week 49 up to 5 years) - Groups 1 and 2 Groups 1 and 2 participants who continue the study until Week 48 and have clinical benefit from the study treatment, will enter a long-term extension period. Dose escalation and treatment beyond progression are allowed in both Group 1 and Group 2. Study period 3 - Exploratory: Group 4, open label treatment with the alpelisib FCT formulation Group 4 participants who continue the study until Week 48 and have clinical benefit from the study treatment, will enter a long-term extension period. Dose escalation is allowed once a participant has reached the age of 6 years old, has completed the initial 24 weeks of study treatment, and has reached Week 25. Exploratory study part: Group 3, open label treatment with the alpelisib granules formulation 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, and has reached Week 25. Group 5 open-label treatment with the alpelisib FCT formulation: Participants of Group 5 will be enrolled after implementation of Global Protocol Amendment 02 and immediately after enrollment of Group 2 has been completed and will receive a starting dose of 125 mg alpelisib FCT formulation once daily in an open-label setting. Dose escalation is allowed for those who did not derive sufficient clinical benefit at the Investigator's discretion and once participant has reached at least Week 25. Study period 4 - Extension 3: treatment with alpelisib (from Week 264 until last patient enrolled completes 5 years of treatment) All participants from all groups will be followed until the last patient enrolled completes 5 years of treatment or discontinues early, to collect additional safety of alpelisib and in order to ensure patient access to treatment in the absence of global commercial supply in pediatric and adult participants with PROS. Visits will be performed every 24 weeks and additional safety assessments every 48 weeks. It is planned to enroll approximately 192 participants in total, 78 adults and 114 children and adolescents. A total of approximately 156 male or female participants (of age ≥ 6 years) with PROS will be randomized in a 2:1 ratio in Groups 1 and 2 (approximately 78 participants per age group). Additional exploratory groups (Group 3, Group 4 and Group 5) will include approximately a total of 36 participants (approximately 15 in Group 3, 6 in Group 4 and 15 in Group 5).
Interventions
DRUGAlpelisib
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: 0 to 5 years old) will receive 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. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.
DRUGPlacebo
Participants will receive matching placebo once daily up to week 16.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants, investigator staff, and persons performing the assessments will remain blinded to the identity of the treatment from the time of randomization until primary analysis i.e. the last participants (Groups 1 and 2) completes Week 48 from randomization or discontinues earlier.
Eligibility
Sex/Gender
ALL
Age
0 Days to 100 Years
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2 | Up to 48 weeks | A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC), provided that none of the individual target lesions have a \>=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 response. Participants who permanently discontinued alpelisib prior to confirmation of response, and participants who received surgery as rescue therapy prior to confirmation of response are considered as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Response During the Extension Period in Group 1 and Group 2 | Week 40, 48, 72, 96, 144, 192, 240 and 264. | 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. |
| Changes in Symptoms and Complications/Comorbidities up to Week 16 on Treatment With Alpelisib as Compared to Placebo in Group 1 and Group 2 | Baseline up to Week 16 | 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 |
| Changes in Symptoms and Complications/Comorbidities Associated With PROS Over Time in Group 1 and Group 2 | Baseline up to approximately 5 years | Change in PROS-related symptoms and complications/comorbidities among participants with symptoms and complications/comorbidities present at baseline |
| Proportion of Participants With Healthcare Visit/Hospitalized Due to PROS in Group 1 and Group 2 | From Baseline up to approximately 5 years | Proportion of participants with healthcare visit/hospitalized due to PROS will be assessed for Group 1 and Group 2. |
| Proportion of Participants Requiring Rescue Surgery Due to PROS in Group 1 and Group 2 | From Baseline up to approximately 5 years | Proportion of participants requiring rescue surgery due to PROS will be assessed for Group 1 and Group 2. |
| Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2 | Week 16 | A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC) at Week 16, provided that none of the individual target lesions have a \>=20% increase from baseline and in absence of progression of non-target lesions and without new lesions. Participants who permanently discontinued alpelisib prior to Week 16, participants who received surgery as rescue therapy prior to Week 16, and participants who had a missing/non-evaluable radiological assessment at Week 16 are considered as non-responders. |
| Proportion of Participants With a Response at Week 24 (by BIRC) in Groups 1 and 2 | Week 24 | A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC) at Week 24, provided that none of the individual target lesions have a \>=20% increase from baseline and in absence of progression of non-target lesions and without new lesions. |
| Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Up to Week 16 | An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. This includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 30 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment. |
| Frequency and Severity of Adverse Events in All Groups of Participants Over Time | Up to approximately 5 years | Type, frequency, seriousness, and severity of treatment-emergent adverse events per CTCAE v4.03 criteria in participants with PROS over time. |
| Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Baseline, Week 4, Week 8, Week 12, Week 16 | For adult and pediatric patients 12 years of age and older, the BPI item that assesses worst pain intensity in the past 24 hours was used. Patients respond to the item on an 11-point response scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). Worst pain intensity was averaged weekly over a 7-day period if a patient had completed the questionnaire for at least 4 days in the 7-day period. The weekly mean was calculated based on the available assessments. Clinically important change at Week 16 was defined as a 2-point reduction for patients who had a pain intensity score ≥ 4 at baseline. For patients with a baseline score \< 4, a 1-point reduction from baseline was also considered as a clinically important change. |
| Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4, Week 8, Week 16 | A Patient Global Impression of Symptom Severity item was used to understand the overall severity of symptoms experienced and clinical meaningfulness of treatment effects experienced during this study. This item included 5 response options: no symptoms, mild, moderate, severe, and very severe. |
| Percentage Change From Baseline in Target and MRI-measurable Non- Target Lesion Volume in Group 1 and Group 2 | From Baseline up to approximately 5 years | 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). |
| Proportion of Participants With Changes From Baseline in Other Non-target Lesions in Group 1 and Group 2 | From Baseline up to approximately 5 years | 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) |
| Proportion of Participants With New Lesions in Group 1 and Group 2 | From Baseline up to approximately 5 years | The proportion of patients with new lesions (as assessed by BIRC) will be assessed throughout the study. |
| Pharmacokinetics (PK) of Alpelisib in Group 1 and Group 2: Maximum Concentration (Cmax) | 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 | 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. |
| Pharmacokinetics (PK) of Alpelisib in Group 1 and Group 2: Trough Concentration (Ctrough) | 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 | 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. |
| 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 | From Baseline up to approximately 5 years | 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) |
| 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 | From Baseline up to approximately 5 years | 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. |
| Changes From Baseline in Patient-reported Overall Impression of Symptoms Assessed by Patient Global Impression of Symptom Severity (PGIS) in Pediatric and Adult Populations | From Baseline up to approximately 5 years | 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". |
| Duration of Response (DOR) in Participants Who Received Alpelisib in Group 1 and Group 2 | From first documented response until progression of PROS lesions or death, assessed up to approximately 5 years | Duration of response (DOR) is defined as the time from first documented response until progression of PROS lesions by BIRC or death. |
| Overall Clinical Response Rate as Assessed by Investigator in Participants Who Received Alpelisib in Group 1 and Group 2 | Week 16, 24, 40, 48, 72, 96 and thereafter every 48 weeks | Proportion of participants with overall clinical response reported as improvement, stable or worsening of clinical condition, as assessed by the investigator |
| Time to Treatment Failure in Participants Who Received Alpelisib in Group 1 and Group 2 | From Baseline up to approximately 5 years | 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. |
Countries
Canada, China, France, Germany, Hong Kong, Italy, Netherlands, Norway, Spain, Switzerland, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
The study is conducted globally across 12 countries. Recruitment in Group 3 will be open after protocol amendment 5 approval in 2025.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm Group 1 (Greater or equal to 18 years): 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. | 54 |
| Group 1 (Greater or Equal to 18 Years) - Placebo Arm Group 1: 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. | 27 |
| Group 2 (6-17 Years) - Alpelisib Arm Group 2: 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. | 56 |
| Group 2 (6-17 Years) - Placebo Arm Group 2: 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. | 28 |
| Exploratory Group 4 (2-5 Years) All Pediatrics - Alpelisib FCT Pediatric participants (2 to 5 years old) will receive 50 mg of alpelisib film-coated tablets (FCT) once daily in an open-label setting. | 7 |
| Exploratory Group 5 (6-17 Years) All Pediatrics - Alpelisib FCT Pediatric participants (6 to 17 year old) will receive 125 mg alpelisib film-coated (FCT) once daily, in an open-label setting. | 16 |
| Total | 188 |
Baseline characteristics
| Characteristic | Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Group 1 (Greater or Equal to 18 Years) - Placebo Arm | Group 2 (6-17 Years) - Alpelisib Arm | Group 2 (6-17 Years) - Placebo Arm | Exploratory Group 4 (2-5 Years) All Pediatrics - Alpelisib FCT | Exploratory Group 5 (6-17 Years) All Pediatrics - Alpelisib FCT | Total |
|---|---|---|---|---|---|---|---|
| Age, Customized 18 - < 65 years | 54 Participants | 27 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 81 Participants |
| Age, Customized Adolescent, 12 - < 18 years | 0 Participants | 0 Participants | 28 Participants | 9 Participants | 0 Participants | 4 Participants | 41 Participants |
| Age, Customized Children, 2 - < 6 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 7 Participants |
| Age, Customized Children, 6 - < 12 years | 0 Participants | 0 Participants | 28 Participants | 19 Participants | 0 Participants | 12 Participants | 59 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 3 Participants | 10 Participants | 3 Participants | 0 Participants | 2 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 48 Participants | 22 Participants | 42 Participants | 25 Participants | 7 Participants | 13 Participants | 157 Participants |
| Sex: Female, Male Female | 34 Participants | 14 Participants | 27 Participants | 12 Participants | 3 Participants | 8 Participants | 98 Participants |
| Sex: Female, Male Male | 20 Participants | 13 Participants | 29 Participants | 16 Participants | 4 Participants | 8 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 27 | 0 / 54 | 0 / 26 | 0 / 80 | 0 / 56 | 1 / 28 | 0 / 56 | 0 / 26 | 0 / 82 | 0 / 7 | 0 / 16 |
| other Total, other adverse events | 47 / 54 | 24 / 27 | 52 / 54 | 26 / 26 | 78 / 80 | 45 / 56 | 21 / 28 | 53 / 56 | 23 / 26 | 76 / 82 | 7 / 7 | 14 / 16 |
| serious Total, serious adverse events | 5 / 54 | 2 / 27 | 16 / 54 | 3 / 26 | 19 / 80 | 3 / 56 | 2 / 28 | 8 / 56 | 2 / 26 | 10 / 82 | 3 / 7 | 2 / 16 |
Outcome results
Primary
Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2
A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC), provided that none of the individual target lesions have a \>=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 response. Participants who permanently discontinued alpelisib prior to confirmation of response, and participants who received surgery as rescue therapy prior to confirmation of response are considered as non-responders.
Time frame: Up to 48 weeks
Population: Full Analysis Set (FAS) - BYL719. All patients to whom alpelisib had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2 | 16.7 % of confirmed responder by BIRC |
| Group 2 (6-17 Years) - Alpelisib Arm | Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2 | 23.2 % of confirmed responder by BIRC |
Secondary
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)
Time frame: From Baseline up to approximately 5 years
Secondary
Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2
For adult and pediatric patients 12 years of age and older, the BPI item that assesses worst pain intensity in the past 24 hours was used. Patients respond to the item on an 11-point response scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). Worst pain intensity was averaged weekly over a 7-day period if a patient had completed the questionnaire for at least 4 days in the 7-day period. The weekly mean was calculated based on the available assessments. Clinically important change at Week 16 was defined as a 2-point reduction for patients who had a pain intensity score ≥ 4 at baseline. For patients with a baseline score \< 4, a 1-point reduction from baseline was also considered as a clinically important change.
Time frame: Baseline, Week 4, Week 8, Week 12, Week 16
Population: Full Analysis Set (FAS). Only participants with a value at both Baseline and post-baseline visit included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 4 | -0.9 Score on a scale | Standard Deviation 1.87 |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 8 | -1.2 Score on a scale | Standard Deviation 2.13 |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 12 | -0.9 Score on a scale | Standard Deviation 2.55 |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 16 | -1.3 Score on a scale | Standard Deviation 2.46 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 8 | -0.7 Score on a scale | Standard Deviation 1.43 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 12 | -0.8 Score on a scale | Standard Deviation 1.41 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 16 | -0.1 Score on a scale | Standard Deviation 1.49 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 4 | -0.2 Score on a scale | Standard Deviation 1.54 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 12 | -0.4 Score on a scale | Standard Deviation 1.01 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 8 | -0.3 Score on a scale | Standard Deviation 0.91 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 16 | -0.4 Score on a scale | Standard Deviation 1.34 |
| Group 2 (6-17 Years) - Alpelisib Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 4 | 0.2 Score on a scale | Standard Deviation 0.73 |
| Group 2 (6-17 Years) - Placebo Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 16 | 0.3 Score on a scale | Standard Deviation 1.14 |
| Group 2 (6-17 Years) - Placebo Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 8 | 0.1 Score on a scale | Standard Deviation 0.69 |
| Group 2 (6-17 Years) - Placebo Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 4 | 0.3 Score on a scale | Standard Deviation 0.82 |
| Group 2 (6-17 Years) - Placebo Arm | Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2 | Change from BL at Week 12 | 0.4 Score on a scale | Standard Deviation 0.62 |
Secondary
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.
Time frame: From Baseline up to approximately 5 years
Secondary
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.
Time frame: From Baseline up to approximately 5 years
Secondary
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
Time frame: Baseline up to approximately 5 years
Secondary
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
Time frame: Baseline up to Week 16
Secondary
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.
Time frame: From first documented response until progression of PROS lesions or death, assessed up to approximately 5 years
Secondary
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.
Time frame: Up to approximately 5 years
Secondary
Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant or clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. This includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 30 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment.
Time frame: Up to Week 16
Population: Safety Set. All patients who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to discontinuation | 1 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs with grade >=3 | 5 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs requiring additional therapy | 37 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Serious Adverse Events (SAEs) | 5 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose interruption | 6 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs | 31 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related SAEs | 3 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose reduction | 0 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose adjustment/interruption | 6 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs with grade >=3 | 11 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Adverse Events (AEs) | 50 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs leading to discontinuation | 1 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs | 12 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Adverse Events (AEs) | 26 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs with grade >=3 | 5 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs with grade >=3 | 1 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Serious Adverse Events (SAEs) | 2 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related SAEs | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to discontinuation | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs leading to discontinuation | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose adjustment/interruption | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose reduction | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose interruption | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs requiring additional therapy | 19 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs | 19 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs leading to discontinuation | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose reduction | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose interruption | 4 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs with grade >=3 | 7 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs with grade >=3 | 3 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Adverse Events (AEs) | 50 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Serious Adverse Events (SAEs) | 3 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose adjustment/interruption | 4 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs requiring additional therapy | 43 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related SAEs | 1 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to discontinuation | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related SAEs | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to discontinuation | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose interruption | 4 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs leading to discontinuation | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs | 9 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose adjustment/interruption | 4 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs requiring additional therapy | 15 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs leading to dose reduction | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Treatment-related AEs with grade >=3 | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Adverse Events (AEs) | 24 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | Serious Adverse Events (SAEs) | 2 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16 | AEs with grade >=3 | 2 Participants |
Secondary
Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2
A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC) at Week 16, provided that none of the individual target lesions have a \>=20% increase from baseline and in absence of progression of non-target lesions and without new lesions. Participants who permanently discontinued alpelisib prior to Week 16, participants who received surgery as rescue therapy prior to Week 16, and participants who had a missing/non-evaluable radiological assessment at Week 16 are considered as non-responders.
Time frame: Week 16
Population: Full Analysis Set (FAS). All patients to whom study treatment was assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2 | 11.1 % of responder by BIRC |
| Group 2 (6-17 Years) - Alpelisib Arm | Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2 | 0 % of responder by BIRC |
| Group 2 (6-17 Years) - Alpelisib Arm | Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2 | 8.9 % of responder by BIRC |
| Group 2 (6-17 Years) - Placebo Arm | Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2 | 0 % of responder by BIRC |
Secondary
Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16
A Patient Global Impression of Symptom Severity item was used to understand the overall severity of symptoms experienced and clinical meaningfulness of treatment effects experienced during this study. This item included 5 response options: no symptoms, mild, moderate, severe, and very severe.
Time frame: Week 4, Week 8, Week 16
Population: Full Analysis Set (FAS). Only participants with an available value for the outcome measure.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | No symptoms | 12 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Mild | 20 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Mild | 20 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Moderate | 14 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Severe | 6 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Very severe | 1 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | No symptoms | 12 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Moderate | 11 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Severe | 7 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Very severe | 0 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | No symptoms | 15 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Mild | 14 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Moderate | 15 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Severe | 6 Participants |
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Very severe | 1 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Moderate | 7 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Moderate | 10 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Mild | 5 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | No symptoms | 8 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Severe | 1 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Severe | 2 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Very severe | 2 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Severe | 5 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | No symptoms | 7 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Mild | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Mild | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Moderate | 10 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | No symptoms | 9 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Mild | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Moderate | 2 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | No symptoms | 17 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Mild | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Moderate | 4 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Severe | 1 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Severe | 0 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | No symptoms | 18 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | No symptoms | 15 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Mild | 6 Participants |
| Group 2 (6-17 Years) - Alpelisib Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Moderate | 4 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | No symptoms | 2 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Severe | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Moderate | 1 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Mild | 2 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Severe | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | No symptoms | 3 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | No symptoms | 3 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Severe | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 16 | Mild | 4 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Very severe | 0 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Mild | 3 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 8 | Moderate | 3 Participants |
| Group 2 (6-17 Years) - Placebo Arm | Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16 | Week 4 | Moderate | 2 Participants |
Secondary
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
Time frame: Week 16, 24, 40, 48, 72, 96 and thereafter every 48 weeks
Secondary
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).
Time frame: From Baseline up to approximately 5 years
Secondary
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.
Time frame: 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
Secondary
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.
Time frame: 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
Secondary
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.
Time frame: From Baseline up to approximately 5 years
Secondary
Proportion of Participants With a Response at Week 24 (by BIRC) in Groups 1 and 2
A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC) at Week 24, provided that none of the individual target lesions have a \>=20% increase from baseline and in absence of progression of non-target lesions and without new lesions.
Time frame: Week 24
Population: Full Analysis Set (FAS) - BYL719. All patients to whom alpelisib had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Greater or Equal to 18 Years) - Alpelisib Arm | Proportion of Participants With a Response at Week 24 (by BIRC) in Groups 1 and 2 | 16.7 % of confirmed responder by BIRC |
| Group 2 (6-17 Years) - Alpelisib Arm | Proportion of Participants With a Response at Week 24 (by BIRC) in Groups 1 and 2 | 19.6 % of confirmed responder by BIRC |
Secondary
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)
Time frame: From Baseline up to approximately 5 years
Secondary
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.
Time frame: From Baseline up to approximately 5 years
Secondary
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.
Time frame: From Baseline up to approximately 5 years
Secondary
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.
Time frame: Week 40, 48, 72, 96, 144, 192, 240 and 264.
Secondary
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.
Time frame: From Baseline up to approximately 5 years