EPIK-P2: A Phase II Double-blind Study With an Upfront, 16-week Randomized, Placebo-controlled Period, to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (PROS)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 206
- 试验地点
- 46
- 主要终点
- Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2
研究概览
简要总结
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)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 0 Days 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≥
- •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.
排除标准
- •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.
- •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
研究组 & 干预措施
Pediatric cohort (group 3: 0 to 5 years old)- Alpelisib granules
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).
干预措施: Alpelisib (Drug)
Pediatric cohort (group 2: 6 to 17 years old) -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.
干预措施: Alpelisib (Drug)
Adult cohort (group 1)- 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.
干预措施: Alpelisib (Drug)
Adult cohort (group 1)- 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.
干预措施: Alpelisib (Drug)
Adult cohort (group 1)- 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.
干预措施: Placebo (Drug)
Pediatric cohort (group 2: 6 to 17 years old)-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.
干预措施: Placebo (Drug)
Pediatric cohort (group 2: 6 to 17 years old)-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.
干预措施: Alpelisib (Drug)
Pediatric cohort (group 4: 2 to 5 years old)- 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.
干预措施: Alpelisib (Drug)
Pediatric cohort (group 5: 6-17 years old)-Alpelisib FCT
Pediatric participants (6 to 17 year old) will receive 125 mg alpelisib film-coated (FCT) once daily, in an open-label setting.
干预措施: Alpelisib (Drug)
结局指标
主要结局
Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2
时间窗: 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.
次要结局
- 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)
- Time to Treatment Failure in Participants Who Received Alpelisib in Group 1 and Group 2(From Baseline up to approximately 5 years)
- Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2(Week 16)
- Frequency and Severity of Adverse Events in All Groups of Participants Over Time(Up to approximately 5 years)
- 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)
- 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)
- Proportion of Participants With a Response at Week 24 (by BIRC) in Groups 1 and 2(Week 24)
- 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 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)
- Number of Participants With Global Impression of Symptom Severity (PGIS) Score up to Week 16(Week 4, Week 8, Week 16)
- 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)
- Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16(Up to Week 16)
- 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)
- Proportion of Participants With New Lesions in Group 1 and Group 2(From Baseline up to approximately 5 years)
- 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)
- 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)
- 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)
- Changes in Symptoms and Complications/Comorbidities Associated With PROS Over Time in Group 1 and Group 2(Baseline up to approximately 5 years)
- 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 Response During the Extension Period in Group 1 and Group 2(Week 40, 48, 72, 96, 144, 192, 240 and 264.)
- Changes in Symptoms and Complications/Comorbidities up to Week 16 on Treatment With Alpelisib as Compared to Placebo in Group 1 and Group 2(Baseline up to Week 16)
- Proportion of Participants Requiring Rescue Surgery Due to PROS in Group 1 and Group 2(From Baseline up to approximately 5 years)