Trial Title:
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
NCT ID:
NCT05983159
Condition:
Slow-Flow Vascular Malformation
Fast-Flow Vascular Malformation
Vascular Malformations
Venous Malformation
Lymphatic Malformation, Low Flow
Lymphatic Malformation
Lymphangioma
Arteriovenous Malformations
Venous Malformation, Low Flow
Cystic Hygroma
Vascular Anomaly
Vascular Anomalies
PI3K Gene Mutation
MAP2K1 Gene Mutation
PIK3CA-related Overgrowth Spectrum
Arteriovenous Malformation (AVM)
KRAS G12C
KRAS G12D
Conditions: Official terms:
Hemangioma
Lymphangioma
Arteriovenous Malformations
Vascular Malformations
Lymphatic Abnormalities
Congenital Abnormalities
Conditions: Keywords:
Targeted therapy
vascular malformations
skin diseases, vascular
Phosphatidylinositol 3-Kinases
MEK inhibitor 1
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
i) Participants with slow-flow vascular malformations with an eligible gene mutation will
receive 48 weeks of treatment with open-label alpelisib.
ii) Participants with fast-flow vascular malformations with an eligible gene mutation
will receive 48 weeks of treatment with open-label mirdametinib
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Alpelisib
Description:
Oral alpha-specific PI3-kinase inhibitor
Arm group label:
Module 1: Slow-flow vascular malformations
Other name:
BYL719
Intervention type:
Drug
Intervention name:
Mirdametinib
Description:
An investigational oral MEK inhibitor
Arm group label:
Module 2: Fast-flow vascular malformations
Summary:
Recent studies have demonstrated that growth of vascular malformations can be driven by
genetic variants in one of 2 signalling pathways. Targeted drugs specific to these
pathways have been developed and shown to be effective in treating cancer. This study
will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants
with slow-flow vascular malformations and a gene mutation in one of these signalling
pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with
fast-flow vascular malformations and a gene mutations in the other signalling pathway
(module 2).
Detailed description:
TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies
for patients with vascular malformations. Patients with vascular malformations which are
refractory to standard therapies, or in whom standard therapy is not appropriate, are
potentially eligible for the clinical trial. Vascular malformations will be classified as
slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to
identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K)
signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein
Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed
using research protocols or commercial testing assays that are external to this clinical
trial.
The study consists of individual modules, each evaluating the clinical efficacy of 48
weeks of targeted therapy. The treatment modules are:
1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with
slow-flow vascular malformations with an identified causative variant in the PI3K
signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase
inhibitor for a total duration of 48 weeks as monotherapy (treatment period),
followed by 24 weeks of follow-up (follow-up period).
2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with
fast-flow vascular malformations with an identified causative variant in the MAPK
signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor
for a total duration of 48 weeks as monotherapy (treatment period), followed by 24
weeks of follow-up (follow-up period).
TARGET-VM will be conducted only in Victoria, Australia.
Criteria for eligibility:
Criteria:
MODULE 1
Inclusion Criteria:
1. Adult or paediatric patient, 2 years of age or over
2. Patient has a clinical diagnosis of a slow-flow vascular malformation
3. Patient has received standard therapy for the vascular malformation or in which, in
the opinion of the investigator, standard therapy is not appropriate
- Note: standard therapy may include treatment with sirolimus. A minimum of 14
days since the last dose of sirolimus is required prior to starting treatment
with alpelisib
4. A documented genetic alteration in the PI3K signalling pathway identified by genetic
sequencing prior to enrolment in this study
5. Adequate performance status (Eastern Cooperative Oncology Group Performance Status
Scale (ECOG) 0-2 in patients ≥ 16 years of age; Lansky > 50 in patients < 16 years
of age)
6. Patient has a life expectancy ≥ 12 weeks
7. Patient is able to swallow and retain oral medication
8. Adequate haematologic and end-organ function:
- Haematology: Haemoglobin ≥ 9.0 g/dL; Absolute neutrophil count ≥ 1.5 x 109/L;
Platelets ≥ 90 x 109/L, except where bleeding leading to low haemoglobin level
is an indication for treatment, in which case haemoglobin < 9.0 g/dL is
acceptable.
- Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase
(AT) ≤ 3 x ULN; Total bilirubin < 2x ULN except for participants with Gilbert's
syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or
direct bilirubin ≤ 1.5 x ULN
- Renal function: Serum creatinine < 1.5 x ULN
- Biochemistry: Calcium (corrected for serum albumin) and magnesium within normal
limits or ≤ Grade 1 according to NCI-CTCAE v5.0 if judged clinically not
significant by the investigator; Potassium within normal limits, or corrected
with supplements
- Fasting blood glucose ≤ 7.0 mmol/L and Glycosylated Haemoglobin (HbA1c) ≤ 6.4%
(both criteria must be met)
9. Patient agrees to abstinence or highly effective contraceptive measures for males
and women of childbearing potential (WOCBP)
- Males who are sexually active must use a condom during intercourse while taking
alpelisib and for at least 4 weeks after stopping alpelisib and should not
father a child in this period. A condom is required to be used also by
vasectomised men in order to prevent delivery of the drug via seminal fluid. In
addition, male participants must not donate sperm during the study and for at
least 4 weeks after stopping alpelisib
- Females who are of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, must use a highly effective
method of contraception during study treatment and for at least 1 week after
the last dose of any study treatment. Highly effective contraceptive methods
include:
- Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject) Periodic abstinence (eg., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception;
- Female sterilisation (have had surgical bilateral oophorectomy with or
without hysterectomy), total hysterectomy or bilateral tubal ligation at
least 6 weeks before taking study treatment. In case of oophorectomy
alone, only when the reproductive status of the women has been confirmed
by follow up hormone level assessment;
- Male partner sterilisation (at least 6 months prior to screening) of the
sole partner of a female participant on the study;
- Use of oral (estrogen and progesterone), injected or implanted combined
hormonal method of contraception or placement of an intrauterine device
(IUD) or intrauterine system (IUS), or forms of hormonal contraception
that have comparable efficacy (failure rate < 1%), for example hormonal
vaginal ring or transdermal hormone contraception. In the case of use of
oral contraception, women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
- Women are considered postmenopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhoea with an appropriate
clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study
treatment. In the case of oophorectomy alone, only when the reproductive status
of the woman has been confirmed by follow up hormone level assessment is she
considered to be not of child bearing potential.
10. Patient has signed informed consent and is willing and able to comply with the
protocol for the duration of the study, including undergoing treatment and scheduled
visits and examinations
Exclusion Criteria:
1. History of hypersensitivity to any drugs or metabolites of PI3K inhibitors or any of
the excipients of alpelisib
2. Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment
3. Patient has had a major surgical procedure within 4 weeks prior to enrolment
4. Prior use of an alpha-specific PI3K inhibitor
5. History of pneumonitis or interstitial lung disease
6. Patient is pregnant or lactating at the time of study registration. A pregnancy test
is mandated for women of child-bearing potential in the screening period
7. Established diagnosis of type I diabetes mellitus, type II diabetes mellitus
requiring anti-hyperglycaemic medication or any participant with HbA1c > 6.4%
8. Patient who is currently receiving medication with a known risk of prolonging the QT
interval or inducing Torsades de Pointes
9. Patient is currently receiving any of the following medications and cannot be
discontinued 7 days prior to the start of treatment:
- Strong inducers of CYP3A4
- Strong inhibitors of CYP3A4
- Inhibitors of BCRP
10. History of acute pancreatitis within 1 year of screening or past history of chronic
pancreatitis
11. Patient with Child Pugh score B or C
12. Unresolved osteonecrosis of the jaw
13. Impairment of GI function or GI disease that may significantly alter the absorption
of the study drug based on investigator discretion
14. Known history of Human Immunodeficiency Virus (HIV) infection (testing for HIV is
not mandatory in screening)
15. Known history of severe cutaneous reactions like Stevens-Johnson Syndrome (SJS),
Toxic Epidermal Necrolysis (TEN), Erythema Multiforme (EM), or Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS)
16. Known history of clinically significant, uncontrolled heart disease and/or recent
cardiac events including:
- History of angina pectoris, coronary artery bypass graft (CABG), symptomatic
pericarditis, or myocardial infarction within 6 months prior to the start of
study treatment;
- History of documented congestive heart failure (New York Heart Association
functional classification III-IV);
- History of impaired Left Ventricular Ejection Fraction (LVEF) < 50% (an
assessment of LVEF is not mandatory in screening)
- History of clinically significant cardiac arrhythmias, (e.g., ventricular
tachycardia), complete left bundle branch block, high grade Atrioventricular
(AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block
without pacemaker in place);
- Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg, with or without
anti-hypertensive medication. Initiation or adjustment of antihypertensive
medication(s) is allowed prior to screening;
- Long QT syndrome, family history of idiopathic sudden death or congenital long
QT syndrome, or corrected QT interval > 470 msec at screening (using Fridericia
correction);
- Bradycardia (heart rate < 50 beats per minute at rest), by electrocardiogram
(ECG) or pulse
17. Patient has other concurrent severe and/or uncontrolled medical conditions that
would, in the Treating Physician's judgement, contraindicate administration of
alpelisib (eg. active or uncontrolled severe infection, chronic active hepatitis,
immune-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure)
18. Patient is unable to understand and comply with treatment instructions and
requirements
MODULE 2
Inclusion Criteria:
1. Adult or paediatric patient, 2 years of age or over where Body Surface Area (BSA) is
greater than or equal to 0.4m2.
2. Patient has a clinical diagnosis of a fast-flow vascular malformation
3. Patient has received standard therapy for the vascular malformation or in which, in
the opinion of the investigator, standard therapy is not appropriate
- Note: standard therapy may include treatment with sirolimus. A minimum of 14
days since the last dose of sirolimus is required prior to starting treatment
with mirdametinib
4. A documented genetic alteration in the RAS-MEK-ERK signalling pathway identified by
genetic sequencing prior to enrolment in this study
5. Adequate performance status (Eastern Cooperative Oncology Group Performance Status
Scale (ECOG) 0-2 in patients ≥ 16 years of age; Lansky > 50 in patients < 16 years
of age)
6. Patient has a life expectancy ≥ 12 weeks
7. Participant has the ability to swallow capsules whole if the capsule dosage form is
being utilized. This criterion does not apply if participant is utilizing the
dispersible tablet form of study treatment
8. Adequate haematologic and end-organ function:
- Haematology: Haemoglobin ≥ 9.0 g/dL; Absolute neutrophil count ≥ 1.5 x 109/L;
Platelets ≥ 90 x 109/L, except where bleeding leading to low haemoglobin level
is an indication for treatment, in which case haemoglobin < 9.0 g/dL is
acceptable.
- Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase
(AT) ≤ 2 x upper limit of normal (ULN); Total bilirubin < 1.5x ULN (isolated
bilirubin > 1.5x ULN is acceptable if bilirubin is fractioned and direct
bilirubin < 35%), except where impaired hepatic function is a consequence of
the fast-flow malformation and hence is an indication for treatment, in which
case impaired hepatic function is acceptable.
- Renal function: Serum creatinine < 1.5 x ULN
- Biochemistry: Calcium (corrected for serum albumin) and magnesium within normal
limits or ≤ Grade 1 according to NCI-CTCAE v5.0 if judged clinically not
significant by the investigator; Potassium within normal limits or corrected
with supplements; Phosphate ≤ 1x ULN.
9. Patient agrees to abstinence or highly effective contraceptive measures if of
childbearing potential (WOCBP)
- Males who are sexually active must use a condom during intercourse while taking
mirdametinib and for at least 90 days after stopping mirdametinib and should
not father a child in this period. A condom is required to be used also by
vasectomised men in order to prevent delivery of the drug via seminal fluid. In
addition, male participants must not donate sperm during the study and for at
least 90 days after stopping mirdametinib
- Females who are of child-bearing potential, defined as all individuals
physiologically capable of becoming pregnant, must use a highly effective
method of contraception during study treatment and for at least 180 days after
the last dose of any study treatment. Highly effective contraceptive methods
include:
- Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject) Periodic abstinence (eg., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception;
- Female sterilisation (have had surgical bilateral oophorectomy with or
without hysterectomy), total hysterectomy or bilateral tubal ligation at
least 6 weeks before taking study treatment. In case of oophorectomy
alone, only when the reproductive status of the women has been confirmed
by follow up hormone level assessment;
- Male partner sterilisation (at least 6 months prior to screening) of the
sole partner of a female participant on the study;
- Use of oral (estrogen and progesterone), injected or implanted combined
hormonal method of contraception or placement of an intrauterine device
(IUD) or intrauterine system (IUS), or forms of hormonal contraception
that have comparable efficacy (failure rate < 1%), for example hormonal
vaginal ring or transdermal hormone contraception. In the case of use of
oral contraception, women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
- Women are considered postmenopausal and not of childbearing potential if they
have had 12 months of natural (spontaneous) amenorrhoea with an appropriate
clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study
treatment. In the case of oophorectomy alone, only when the reproductive status
of the woman has been confirmed by follow up hormone level assessment is she
considered to be not of childbearing potential.
10. Patient has signed informed consent and is willing and able to comply with the
protocol for the duration of the study, including undergoing treatment and scheduled
visits and examinations
Exclusion Criteria:
1. History of hypersensitivity to any drugs or metabolites of MEK inhibitors or any of
the excipients of mirdametinib
2. Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment
3. Patient has had a major surgical procedure within 4 weeks prior to enrolment
4. Prior use of a MEK inhibitor
5. Patient has abnormal QT interval corrected by Fridericia's formula (> 450 msec for
male participants, > 470 msec for female participants, or > 480 msec for
participants with bundle branch block) (triplicate ECG readings taken approximately
2 to 3 minutes apart and averaged) at Screening;
6. Patient is pregnant or lactating at the time of study registration. A pregnancy test
is mandated for persons of child-bearing potential in the screening period
7. Impairment of GI function or GI disease that may significantly alter the absorption
of the study drug based on investigator discretion
8. Any clinically significant active or known history of liver disease, or known
hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or
asymptomatic gallstones)
9. Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal cell
or squamous epithelial carcinomas of the skin that have been resected with no
evidence of metastatic disease for 3 years;
10. Breast cancer within the past 5 years;
11. Known history of Human Immunodeficiency Virus (HIV) infection (testing for HIV is
not mandatory in screening)
12. Known history of severe cutaneous reactions like Stevens-Johnson Syndrome (SJS),
Toxic Epidermal Necrolysis (TEN), Erythema Multiforme (EM), or Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS)
13. Patient has a history of, or evidence of, retinal pathology on ophthalmologic
examination that is considered a risk factor for central serous retinopathy, retinal
vein occlusion (RVO), or neovascular macular degeneration. Patients will be excluded
from study participation if they have any of the following risk factors for RVO at
Screening:
- Intraocular pressure > 21 mmHg;
- Serum cholesterol > 7.8 mmol/L;
- Serum triglycerides > 3.4 mmol/L;
- Hyperglycaemia (fasting blood glucose > 7.0 mol/L );
- Age specific hypertension
- Patients ≥ 13 years of age with a blood pressure ≥ 140/90 mmHg
- Patients ≤ 12 years of age with a blood pressure ≥ 95th percentile for age
+ 12 mmHg
14. Known history of glaucoma
15. Known history of clinically significant, uncontrolled heart disease and/or recent
(within 6 months [24 weeks] of signing informed consent/assent) cardiac events
including:
- History of angina pectoris, coronary artery bypass graft (CABG), symptomatic
pericarditis, or myocardial infarction within 6 months prior to the start of
study treatment;
- History of documented congestive heart failure (New York Heart Association
functional classification III-IV);
- History of clinically significant cardiac arrhythmias, (e.g., ventricular
tachycardia), complete left bundle branch block, high grade Atrioventricular
(AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block
without pacemaker in place);
- Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 140 mmHg
and/or Diastolic Blood Pressure (DBP) ≥ 90 mmHg, with or without
anti-hypertensive medication. Initiation or adjustment of antihypertensive
medication(s) is allowed prior to screening;
- Long QT syndrome, family history of idiopathic sudden death or congenital long
QT syndrome, or corrected QT interval > 470 msec at screening (using Fridericia
correction);
- Bradycardia (heart rate < 50 beats per minute at rest), by electrocardiogram
(ECG) or pulse
16. Patient has recorded a left ventricular ejection fraction (LVEF) < 55% at Screening
17. Patient has experienced a cerebrovascular accident, transient ischaemic attach, or
symptomatic pulmonary embolism within 6 months (24 weeks) of signing informed
consent/assent.
18. Patient has other concurrent severe and/or uncontrolled medical conditions that
would, in the Treating Physician's judgement, contraindicate administration of
mirdametinib (eg. active or uncontrolled severe infection, chronic active hepatitis,
immune-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure)
19. Patient is unable to understand and comply with treatment instructions and
requirements
Gender:
All
Minimum age:
2 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Peter MacCallum Cancer Centre
Address:
City:
Parkville
Zip:
3052
Country:
Australia
Contact:
Last name:
Stephen Luen, MBChB, FRACP
Phone:
+61385595000
Email:
stephen.luen@petermac.org
Investigator:
Last name:
Stephen Luen, MBChB, FRACP
Email:
Principal Investigator
Facility:
Name:
The Royal Children's Hospital
Address:
City:
Parkville
Zip:
3052
Country:
Australia
Contact:
Last name:
Anthony Penington, MBBS, FRACS, MD(res), Grad Dip
Phone:
+61403342847
Email:
Tony.Penington@rch.org.au
Contact backup:
Last name:
Michelle de Silva, BSc(Hons), PhD, MGenCouns
Phone:
+61400008054
Email:
Michelle.desilva@vcgs.org.au
Start date:
October 2024
Completion date:
December 2026
Lead sponsor:
Agency:
Murdoch Childrens Research Institute
Agency class:
Other
Collaborator:
Agency:
Peter MacCallum Cancer Centre, Australia
Agency class:
Other
Collaborator:
Agency:
Royal Children's Hospital
Agency class:
Other
Source:
Murdoch Childrens Research Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05983159
