Alpelisib for PIK3CA-related overgrowth spectrum (PROS)

Inclusion criteria

• {"criterion_text":"- Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative or guardian must be obtained prior to any study related screening procedures are performed.\n- Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by BIRC assessment.\n- Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories.\n- A tissue sample (fresh or archival) is to 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.\n- Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at study entry) performance status index ≥50.\n- 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).\n- 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

• {"criterion_text":"- Participant with only isolated macrodactyly, epidermal 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.\n- 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.\n- 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)\n- 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.\n- Debulking or other major surgery performed within 3 months at time of informed consent.\n- 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.\n- Participants 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 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.\n- History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent.\n- Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent\n- 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."}

Primary endpoints

• {"endpoint_text":"- Response (yes/no) 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.","definition_or_measurement_approach":"Measured by MRI assessments of 1–3 target lesion volumes, centrally reviewed by a Blinded Independent Review Committee (BIRC). Response = ≥20% reduction from baseline in the sum of target lesion volumes, with no individual target lesion showing ≥20% increase and no progression of non-target lesions and no new lesions."}

Secondary endpoints

• {"endpoint_text":"- The key secondary objective is to demonstrate the efficacy of alpelisib based on the comparison of the proportion of participants achieving response at Week 16 with alpelisib versus placebo in Groups 1 or Group 2.","definition_or_measurement_approach":"Comparison of proportion of participants achieving the primary response endpoint (as defined above) at Week 16 between alpelisib and placebo arms (randomized, placebo-controlled up-front 16-week period)."}

Other endpoints

• {"endpoint_text":"- To demonstrate the efficacy of alpelisib vs placebo based on the comparison of the proportion of participants with response at Week 16 in Group 1 or Group 2","definition_or_measurement_approach":"Comparison of response proportions at Week 16 (BIRC-assessed) between alpelisib and placebo in Groups 1 (adults) and 2 (children/adolescents)."}
• {"endpoint_text":"- To assess the efficacy of alpelisib as measured by the proportion of participants with a response at Week 24 (by BIRC) in Groups 1 and 2","definition_or_measurement_approach":"Proportion of participants with BIRC-confirmed response at Week 24 in Groups 1 and 2."}
• {"endpoint_text":"- To assess safety and tolerability of alpelisib as compared to placebo in Groups 1 and 2 up to Week 16","definition_or_measurement_approach":"Safety and tolerability assessed by adverse events, laboratory parameters and clinical assessments up to Week 16 comparing arms."}
• {"endpoint_text":"- To assess the overall safety and tolerability of alpelisib in participants with PROS over time","definition_or_measurement_approach":"Longitudinal safety assessments (AEs, labs, vital signs) over study duration including extension periods."}
• {"endpoint_text":"- To assess changes in patient-reported pain intensity and overall severity of symptoms at Week 16 on treatment with alpelisib as compared to placebo in pediatric and adult populations","definition_or_measurement_approach":"Patient-reported outcomes (pain intensity and symptom severity) measured by PRO instruments at baseline and Week 16; comparison between arms."}
• {"endpoint_text":"- To assess changes in target and non-target lesions over time and appearance of new lesions on treatment from baseline over time","definition_or_measurement_approach":"Imaging assessments (MRI) of target/non-target lesions over scheduled visits to evaluate size/volume changes and new lesion appearance."}
• {"endpoint_text":"- To assess the PK of alpelisib in adult and pediatric patients with PROS","definition_or_measurement_approach":"Pharmacokinetic sampling and analysis in designated participants (PK parameters measured and summarized by age group)."}
• {"endpoint_text":"- To assess changes in patient-reported pain, health-related quality of life and overall impression of symptoms in pediatric and adult populations over time","definition_or_measurement_approach":"Serial PRO and HRQoL instruments administered at scheduled visits and analyzed longitudinally."}
• {"endpoint_text":"- To assess the duration of response in participants who receive alpelisib","definition_or_measurement_approach":"Time from first documented response to objective progression or censoring; analyzed in participants receiving alpelisib."}
• {"endpoint_text":"- To assess the time to treatment failure in participants who are on treatment with alpelisib","definition_or_measurement_approach":"Time from randomization/start of treatment to discontinuation due to progression, toxicity, death, or other defined failure criteria."}
• {"endpoint_text":"- To assess the rate of overall clinical response as assessed by Investigator at the scheduled protocol visits for disease evaluation (e.g., Week 16, 24, 40, 48, 72, 96 and thereafter every 48 weeks and at Week 264 until the end of extension 2)","definition_or_measurement_approach":"Investigator-assessed clinical response rates at scheduled visits per protocol-defined assessment schedule (listed weeks); includes long-term follow-up to Week 264 for extension 2."}
• {"endpoint_text":"- To assess the proportion of participants with a response at the scheduled protocol visits for disease evaluation during the extension periods.","definition_or_measurement_approach":"Proportion of participants meeting response criteria at scheduled extension visit timepoints."}
• {"endpoint_text":"- To assess changes in symptoms and complications/comorbidities up to Week 16 on treatment with alpelisib as compared to placebo.","definition_or_measurement_approach":"Clinical assessments and patient-reported symptom measures compared between arms up to Week 16."}
• {"endpoint_text":"- To assess changes in symptoms and complications/comorbidities associated with PROS over time","definition_or_measurement_approach":"Longitudinal monitoring of PROS-related symptoms and complications across study duration."}
• {"endpoint_text":"- To assess the frequency of healthcare visits/hospitalizations due to PROS, rescue surgeries for PROS (incl. avoidance/delay in planned disease-related surgery) over time","definition_or_measurement_approach":"Collection and analysis of healthcare utilization events (visits, hospitalizations, rescue surgeries) over time."}

Spain

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

19-03-2026

Processing Time Days

601

Number Of Sites

2

Number Of Participants

40

Italy

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

20-03-2026

Processing Time Days

602

Number Of Sites

2

Number Of Participants

9

France

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

23-03-2026

Processing Time Days

605

Number Of Sites

4

Number Of Participants

66

Norway

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

599

Number Of Sites

1

Number Of Participants

7

Germany

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

18-03-2026

Processing Time Days

600

Number Of Sites

5

Number Of Participants

25

Netherlands

Earliest CTIS Part Ii Submission Date

26-07-2024

Latest Decision Or Authorization Date

15-04-2026

Processing Time Days

628

Number Of Sites

1

Number Of Participants

17

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Syneos Health Inc.

Responsibilities

code:1

Name

Icon Clinical Research Limited

Responsibilities

code:1

Name

IQVIA Limited

Responsibilities

codes:1,3

Name

Parexel International (IRL) Limited

Responsibilities

code:12

Third parties

• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"code:1","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"code:1","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"code:4","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Study services: image tracking, reporting, processing, quality control, review, evaluation and archival; codes:11,13,5,6","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"RWS Life Sciences Inc.","duties_or_roles":"PRO formatting, translations, and licensing","organisation_type":"Pharmaceutical company"}
• {"country":"India","full_name":"Veeda Clinical Research Limited","duties_or_roles":"Laboratory analysis of PK samples; code:10","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"codes:1,3","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Ardea Outcomes Inc.","duties_or_roles":"Goal Attainment Scaling","organisation_type":"Pharmaceutical company"}
• {"country":"Norway","full_name":"Evidia Norge AS (Previously Aleris Røntgen Oslo)","duties_or_roles":"MR assessments","organisation_type":"Health care"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"code:12","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Phardis S.r.l.","duties_or_roles":"Local equipment storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Jumo Health USA Inc.","duties_or_roles":"Educational materials","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"France","full_name":"Kayentis","duties_or_roles":"Distributes ePRO tablets and collects ePRO data/eDiaries; codes:15,5,6,7","organisation_type":"Non-Pharmaceutical company"}