This study has been transitioned to CTIS with ID 2023-508530-34-00 check the CTIS register for the current data. Primary objective:* To demonstrate the efficacy of alpelisib as measured by the proportion of participants randomized to alpelisib with…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
- Skin vascular abnormalities
- Skin and subcutaneous tissue therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Endpoint for primary objective:
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)) 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.
Confirmation of response requires a subsequent imaging assessment performed at
least 4 weeks after the onset of the response.See Section 2.1 for Primary
Estimands and Section 8.3 for response definition.
Secondary outcome
Endpoint for key secondary objective:
Response at week 16 (by BIRC): See Section 2.2 for secondary Estimands and
Section 8.3 for response definition.
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
For endpoints for other and exploratory objectives see also protocol section 2
(Objectives, endpoints and estimands
Background summary
The results described in preclinical studies including a mouse model have shown
that alpelisib inhibits the PI3K/AKT/mTOR signaling pathway and rescues the
PROS phenotype in the mouse model efficaciously. The first reported case series
demonstrated that alpelisib is clinically effective and well tolerated by both
pediatric and adult participants with PROS. The drug improved the disease
symptoms in all 19 participants treated in a single center over a variable
period of time (beyond 18 months for some participants) (Venot et al 2018).
Alpelisib demonstrated therapeutic activity in participants with PROS
regardless of the type of PIK3CA mutation and was effective in treatment naive
participants and those who previously received mTOR inhibitor Sirolimus. The
first experience with alpelisib in overgrowth related to mutation in PIK3CA
gene provides the direct evidence of clinical improvement in participants
supporting PIK3CA inhibition as a promising therapeutic strategy in
participants with PROS.
In Aug-2021, results from EPIK-P1 (CBYL719F12002) study, a retrospective
noninterventional study of 57 patients with PIK3CA Related Overgrowth Spectrum
(PROS) were available and later presented at the European Society for Medical
Oncology (ESMO) congress 2021 (Canaud et al 2021). This study*s results provide
evidence of meaningful clinical benefit of alpelisib for the treatment of
patients aged 2 years and older with PROS.
The EPIK-P1 data supports the first direct evidence of clinical improvement in
PROS participants reported by Venot et al (2018) and confirms that PIK3CA
inhibition is a promising therapeutic strategy in participants with PROS.
See also protocol section 1.1 (background)
Study objective
This study has been transitioned to CTIS with ID 2023-508530-34-00 check the CTIS register for the current data.
Primary objective:
* To demonstrate the efficacy of alpelisib as measured by the proportion of
participants randomized to alpelisib with a response at Week 24 in at least one
of the following groups:
* Group 1 (>= 18 yr-old)
* Group 2 (6 - 17 yr-old)
Key secondary objective:
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
For other secondary objectives and exploratory objectives see also protocol
section 2 (Objectives, endpoints and estimands)
Study design
The study 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.
A total of approximately 156 participants (of age >= 6 years) will be randomized
in the study. Two additional groups of approximately 12 participants in Group 3
(2 to 5 years old) and 6 participants in Group 4 (2 to 5 years old) will be
enrolled for exploratory purposes.
Core, Extension 1 and Extension 2 periods will be applied to the participants
>=6 years old (Group 1 - adults, Group 2 - participants 6 to 17 years old).
Group 3 will include the participants who are 2 to 5 years old and it will be
an exploratory group.
Group 1 and Group 2 will be enrolled in parallel. Group 3 will be enrolled
later, after 24-week efficacy, safety and PK data are available from the first
two age groups, in order to select the recommended dose for this group.
Group 4 will be open to enrollment immediately after the implementation of
Global Protocol Amendment 01, whereas Group 3 will be open to enrollment after
the primary analysis of patients in Groups 1 and Group 2 will be available and
only after implementation of a future substantial Global Protocol Amendment
Group 5 of approximately 15 participants, 6 to 17 years of age, will be open to
enrollment immediately after the implementation of Global Protocol Amendment 02.
See also protocol section 3 (Study design)
Intervention
Groups 1 and 2: Intervention with alpelisib or placebo in the first 16 weeks.
From week 17 onwards alpelisib.
The participants in Group 4 will receive alpelisib FCT 50 mg once daily in an
open-label setting
Group 3 will be enrolled later, when the 24-week efficacy, safety and PK data
are available from the other participants, in order to select the appropriate
dose for this group. The participants in Group 3 will receive alpelisib in an
open-label setting, Group 3 will be an exploratory group.
Group 5 of approximately 15 participants, 6 to 17 years of age, treated with a
starting dose of 125 mg alpelisib film-coated tablets.
For more details, please refer to Section 3 Study Design.
Details are presented in Table 6-1, Table 6-2, Table 6-3, Table 6-4 , Table
6-5.
Study burden and risks
Risk: potential side effects of study treatment
Burden:
A tumor sample will be taken for PIK3CA mutation testing in case no tissue is
available.
The patient will come to the study doctor*s clinic 8 times in the first 24
weeks; 6 times in the second 24 weeks (till week 48) and then every 24 weeks
till end of study (week 264). After the patient discontinues study treatment,
he/she will be followed for safety.
See question E4 for all study assessments.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
1. 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
2. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in
local laboratories
3. A tissue sample (fresh or archival) must be available 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.
4. Karnofsky (in patients > 16 years old at study entry)/Lansky (<=16 yrs of age
at study entry) performance status index >=50
5. 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 within.
6. 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, and associated with complaints, clinical symptoms or
functional limitations affecting the patient's everyday life. Measurability
must be confirmed by BIRC before randomization.
For the full inclusion criteria, please refer to Section 5.1. of protocol
Exclusion criteria
1. 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.
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. Participants (receiving anticoagulants for
PROS-related coagulopathy, primary or secondary prophylaxis of thrombosis may
be included in the study).
6. Participants with documented pneumonitis or interstitial lung disease 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
sprectrum at time of informed consent, when epilepsy is not controlled and/or
the patient may not be switched to non-enzyme inducing antiepilectic drug(s) at
time of informed consent.
10. Participants with clinically significant worsening of the PROS-related
signs and symptoms (e.g. increase of D-dimers, worsening of underlying
pain, newly occurring swelling or redness) indicating an uncontrolled
condition during screening phase, particularly if systemic treatment with
any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior
to the start of the study treatment. This includes but is not limited to
hypercoagulability state in participants not receiving prophylactic
treatment.
For the full inclusion criteria, please refer to Section 5.2 of protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508530-34-00 |
| EudraCT | EUCTR2020-000561-16-NL |
| ClinicalTrials.gov | NCT04589650 |
| CCMO | NL74406.091.20 |