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

Phase 2

Active, not recruiting

Conditions: PIK3CA-related Overgrowth Spectrum (PROS)

Interventions: Drug: Alpelisib
Drug: Placebo

Registration Number: NCT04589650

Lead Sponsor: Novartis Pharmaceuticals

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

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

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

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

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

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 205

Inclusion Criteria

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

Key

Exclusion Criteria

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

Other inclusion/exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pediatric cohort (group 2: 6 to 17 years old) -Alpelisib	Alpelisib	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.
Pediatric cohort (group 3: 0 to 5 years old)- Alpelisib granules	Alpelisib	Pediatric participants (0 to 5 years old) will receive alpelisib granules formulation with an age-dependent starting dose (\<1 month: 20 mg every other day; 1 to \<6 months: 20 mg daily; 6 to \<2 years: 40 mg daily; 2 to \<6 years: 50 mg daily).
Adult cohort (group 1)- Alpelisib	Alpelisib	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.
Adult cohort (group 1)- Placebo	Alpelisib	During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive placebo. 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.
Adult cohort (group 1)- Placebo	Placebo	During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive placebo. 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.
Pediatric cohort (group 2: 6 to 17 years old)-Placebo	Alpelisib	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. 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.
Pediatric cohort (group 2: 6 to 17 years old)-Placebo	Placebo	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. 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.
Pediatric cohort (group 4: 2 to 5 years old)- Alpelisib FCT	Alpelisib	Pediatric participants (2 to 5 years old) will receive 50 mg of alpelisib film-coated tablets (FCT) once daily in an open-label setting.
Pediatric cohort (group 5: 6-17 years old)-Alpelisib FCT	Alpelisib	Pediatric participants (6 to 17 year old) will receive 125 mg alpelisib film-coated (FCT) once daily, in an open-label setting.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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)
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.
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.
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".
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.
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.
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.
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 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.
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)
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
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 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
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.

Trial Locations

Locations (12): UCSF Birthmarks and Vascular Center
🇺🇸
San Francisco, California, United States
Cincinnati Children s Hospital Medical Center
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Cincinnati, Ohio, United States
CHOP Abramson Pediatric Resch Ctr
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Philadelphia, Pennsylvania, United States
Childrens Hospital Colorado
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Aurora, Colorado, United States
UNC Chapel Hill
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Chapel Hill, North Carolina, United States
Washington Univ School Of Medicine
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Saint Louis, Missouri, United States
NYU Langone Health
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New York, New York, United States
University of Texas Southwestern Medical Center
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Dallas, Texas, United States
Childrens Hospital and Regional Medical Center
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Seattle, Washington, United States
Baylor College Of Medicine
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Houston, Texas, United States
University of Wisconsin Hospital
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Madison, Wisconsin, United States
Novartis Investigative Site
🇬🇧
Manchester, United Kingdom