PIK3CA-related Overgrowth Spectrum (PROS) Clinical Trial
— EPIK-P2Official title:
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)
This is a prospective Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and pharmacokinetics of alpelisib in pediatric and adult participants with PIK3CA-related overgrowth spectrum (PROS).
Status | Recruiting |
Enrollment | 189 |
Est. completion date | March 11, 2031 |
Est. primary completion date | March 20, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 2 Years and older |
Eligibility | Inclusion Criteria: 1. Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative or guardian prior to any study related screening procedures are performed 2. Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by blinded independent review committee (BIRC) assessment 3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories 4. A tissue sample (fresh or archival) is be sent to a Novartis-designated central laboratory. If archival tissue is not available, collection of a fresh tissue biopsy is required for participants in Groups 1, 2 and 5, if it is not clinically contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not mandatory. For China only: Tissue sample collection and biomarker assessments are not applicable. For Germany only: If archival tissue is available, it must be sent to a Novartis designated central laboratory. If no archival tissue is available, obtaining a fresh tissue biopsy is recommended, if it is not clinically contraindicated, but is not mandatory. 5. Karnofsky (in patients > 16 years old at study entry)/Lansky (=16 yrs of age at study entry) performance status index =50 6. Adequate bone marrow and organ function including Fasting plasma glucose (FPG) = 140 mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) = 6.5% (both criteria have to be met) (as assessed by central laboratory for eligibility) 7. Presence of at least one PROS-related measurable lesion defined as a lesion with longest diameter =2 cm, when the volume can be accurately and reproducibly measured by MRI (Magnetic resonance imaging), and associated with complaints, clinical symptoms or functional limitations affecting the patient's everyday life. Measurability must be confirmed by BIRC before randomization. Exclusion Criteria: 1. Participant with only isolated macrodactyly, skin nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent 2. Previous treatment with alpelisib and/or any other PI3K inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib) 3. Radiation exposure for PROS treatment purpose within the previous 12 months on those PROS areas which are expected to qualify for target lesions (except lesion(s) progressing after completion of radiotherapy) at time of informed consent. 4. Debulking or other major surgery performed within 3 months at time of informed consent 5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent. Note: Participants receiving anticoagulants for PROS-related coagulopathy, primary or secondary prophylaxis of thrombosis may be included in the study 6. Participants in Groups 1, 2 ad 5 with documented pneumonitis or interstitial lung disease at time of informed consent and with impaired lung function (e.g., FEV1 or DLCO = 70% of predicted) that is not related to PROS. Participants in Groups 3 and 4 with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent 7. History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent 8. Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent 9. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time of informed consent, when epilepsy is not controlled and/or the patient may not be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent. 10. Participants with clinically significant worsening of PROS-related laboratory anomalies, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase, particularly if systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. This includes but is not limited to hypercoagulability state in participants not receiving prophylactic treatment. Other inclusion/exclusion criteria may apply |
Country | Name | City | State |
---|---|---|---|
Canada | Novartis Investigative Site | Montreal | Quebec |
Canada | Novartis Investigative Site | Montreal | Quebec |
Canada | Novartis Investigative Site | Toronto | Ontario |
China | Novartis Investigative Site | Beijing | |
China | Novartis Investigative Site | Shanghai | |
France | Novartis Investigative Site | Bordeaux Cedex | |
France | Novartis Investigative Site | Dijon | |
France | Novartis Investigative Site | Paris 15 | |
France | Novartis Investigative Site | Tours 9 | |
Germany | Novartis Investigative Site | Duesseldorf | |
Germany | Novartis Investigative Site | Freiburg | |
Germany | Novartis Investigative Site | Hamburg | |
Germany | Novartis Investigative Site | Heidelberg | |
Germany | Novartis Investigative Site | Leipzig | |
Hong Kong | Novartis Investigative Site | Pokfulam | |
Italy | Novartis Investigative Site | Roma | RM |
Italy | Novartis Investigative Site | Torino | TO |
Netherlands | Novartis Investigative Site | Nijmegen | |
Norway | Novartis Investigative Site | Oslo | |
Spain | Novartis Investigative Site | Esplugues De Llobregat | Barcelona |
Spain | Novartis Investigative Site | Madrid | |
Switzerland | Novartis Investigative Site | Bern | |
Switzerland | Novartis Investigative Site | Zuerich | |
United Kingdom | Novartis Investigative Site | London | |
United Kingdom | Novartis Investigative Site | Manchester | |
United Kingdom | Novartis Investigative Site | West Midlands | Birmingham |
United States | Childrens Healthcare of Atlanta . | Atlanta | Georgia |
United States | Childrens Hospital Colorado . | Aurora | Colorado |
United States | UNC Chapel Hill | Chapel Hill | North Carolina |
United States | Cincinnati Children s Hospital Medical Center | Cincinnati | Ohio |
United States | Uni of TX SW Med Ctr . | Dallas | Texas |
United States | Baylor College Of Medicine | Houston | Texas |
United States | Uni Of California Los Angeles | Los Angeles | California |
United States | University of Wisconsin Hospital | Madison | Wisconsin |
United States | NYU Langone Health . | New York | New York |
United States | CHOP Abramson Pediatric Resch Ctr | Philadelphia | Pennsylvania |
United States | Washington Univ School of Medicine . | Saint Louis | Missouri |
United States | UCSF Birthmarks and Vascular Center | San Francisco | California |
United States | Childrens Hosp and Regional Med Ctr | Seattle | Washington |
Lead Sponsor | Collaborator |
---|---|
Novartis Pharmaceuticals |
United States, Canada, China, France, Germany, Hong Kong, Italy, Netherlands, Norway, Spain, Switzerland, United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Proportion of participants randomized to alpelisib with a confirmed objective response by BIRC in Group 1 and Group 2 | Response defined by achieving at least 20% reduction from baseline in the sum of target lesion volumes (1 to 3 lesions, assessed by MRI by a blinded independent review committee (BIRC)), provided that none of the individual target lesions has = 20% increase from baseline and in absence of progression of non-target lesions and without new lesions. Confirmation of response requires a subsequent imaging assessment performed at least 4 weeks after the onset of the response. | Up to 48 weeks | |
Secondary | Proportion of participants with response at Week 16 by BIRC in Group 1 and Group 2 | Response defined by achieving at least 20% reduction from baseline in the sum of target lesion volumes (1 to 3 lesions, assessed by MRI by a blinded independent review committee (BIRC)) at Week 16, provided that none of the individual target lesions has = 20% increase from baseline and in absence of progression of non-target lesions and without new lesions. | Week 16 | |
Secondary | Proportion of participants with a response at Week 24 (by BIRC) in Groups 1 and 2 | Response defined by achieving at least 20% reduction from baseline in the sum of target lesion volumes (1 to 3 lesions, assessed by MRI by a blinded independent review committee (BIRC)) at Week 24, provided that none of the individual target lesions has = 20% increase from baseline and in absence of progression of non-target lesions and without new lesions. | Week 24 | |
Secondary | Frequency and severity of adverse events in Groups 1 and 2 up to Week 16 | Type, frequency, seriousness, and severity of treatment-emergent adverse events per CTCAE v4.03 criteria in Groups 1 and 2 up to Week 16. | Up to Week 16 | |
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. | 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 | The Brief Pain Inventory (BPI) item that assesses worst pain intensity in the past 24 hours will be recorded on a PRO diary. Participants respond to the item on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). Change from baseline in scores at Week 16 will be assessed in adult (= 18 years old) and pediatric (12 to 17 years old) populations. | Baseline to Week 16 | |
Secondary | Change from baseline to Week 16 in Patient Global Impression of Symptom Severity (PGIS) in Group 1 and 2 | The PGIS is a single item to assess the participant's perception in the severity of their symptoms experienced and clinical meaningfulness of treatment effects experienced using a 5-point verbal rating scale, from "No Symptoms" to "Very Severe". Change from baseline severity at Week 16 will be assessed in adult (= 18 years old) and pediatric (12 to 17 years old) populations. | Baseline to Week 16 | |
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). |
From Baseline up to approximately 5 years | |
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) |
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. | 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. | 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. | 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 | Change from Baseline in patient-reported pain assessed by Brief Pain Inventory (BPI) Worst Pain intensity item or Wong-Baker Faces Scale (age appropriate) in pediatric and adult populations | Change in scores from Brief Pain Inventory (BPI) items, or Wong-Baker Faces Scale (age appropriate). The BPI item that assesses worst pain intensity in the past 24 hours will be used to assess pain intensity for adult participants (=18 years old) and pediatric participants (=12 years old). Participants respond to the item on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). For children under 12, the Wong-Baker Faces Scale will be used in place of the BPI worst pain intensity item. This scale is a single-item that includes drawings of 6 faces that are associated with both a numeric rating and a descriptor (ranging from 0/no hurt - 10/hurts worst) | From Baseline up to approximately 5 years | |
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. | 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". | From Baseline up to approximately 5 years | |
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. | From first documented response until progression of PROS lesions or death, assessed up to approximately 5 years | |
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. |
From Baseline up to approximately 5 years | |
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 | Week 16, 24, 40, 48, 72, 96 and thereafter every 48 weeks | |
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. | Week 40, 48, 72, 96, 144, 192, 240 and 264. | |
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 | Baseline up to Week 16 | |
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 | 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. | From Baseline up to approximately 5 years | |
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. | From Baseline up to approximately 5 years |
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