HV cohort 1Primary Objectives* To characterize the local tolerability of topical bimiralisib after 21 days* To characterize the systemic PK of topical bimiralisib after 21 daysSecondary Objective* To characterize the safety of topical bimiralisib…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's T-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Application site assessment of erythema and edema
Change from baseline on composite Assessment of Index Lesions Disease Severity
Score (CAILS).
Secondary outcome
Healthy Volunteers: (S)AEs, Laboratory assessments, Systemic PK
MF patients:
* Application site assessment of erythema and edema, (S)AEs, Lab assessments,
Systemic PK
* Objective Response Rate (ORR) based on the CAILS: patients who achieved
partial (PR) or a complete response (CR) after six (6) weeks of treatment.
* Time To Response (TTR) based on ORR up to six (6) weeks
Background summary
Cutaneous T-cell Lymphoma (CTCL) is characterized by the abnormal accumulation
of activated T-cells in the epidermis and dermis. The overall incidence of CTCL
has increased from 2.8 per million population (1972) to 10.2 per million
population as of 2009. This increase in incidence is thought to be a result of
improved detection methods and more efficient medical coverage of the general
population. CTCL in men and African-Americans have the highest incidence rates
(Korgavkar 2013). The most common type of CTCL is Mycosis Fungoides (MF), which
can progress through patch, plaque, and tumor phases. MF lesions often respond
to skin directed therapies, like topical corticosteroids, topical
mechlorethamin, and/or topical carmustine (Liner 2018). However, not all MF
patients respond to these therapies and / or suffer from substantial side
effects, highlighting the need for new safe and effective skin-directed therapy
options.
Study objective
HV cohort 1
Primary Objectives
* To characterize the local tolerability of topical bimiralisib after 21 days
* To characterize the systemic PK of topical bimiralisib after 21 days
Secondary Objective
* To characterize the safety of topical bimiralisib after 21 days
Exploratory Objectives
* Bimiralisib skin concentrations (via skin biopsy)
* Changes in bimiralisib and/or vehicle treated skin as measured by various
imaging modalities.
MF patients cohort 2
Primary Objective
* To evaluate the effect of bimiralisib versus placebo after 6 weeks of
treatment on selected target lesions
Secondary Objectives
* To characterize local tolerability, safety, and systemic exposure of topical
bimiralisib on target MF lesions.
* To characterize other parameters of efficacy of topical bimiralisib on target
lesions.
Exploratory Objectives
* To explore the effect of topical bimiralisib on relevant tissue and plasma
biomarkers with different methods
* To explore bimiralisib skin concentrations at the end of treatment.
* To explore the effect of bimiralisib after 12 weeks of treatment
Study design
The study is comprised of two (2) cohorts, separated by a data monitoring
committee (DMC) review of the available data from Cohort 1. Cohort 1 will
enroll six ( 6) healthy volunteers, for a treatment duration of 21 consecutive
days. Cohort 2 will enroll 18 patients with MF stages 1A/1B, randomized 1:1 to
two treatment arms (bimiralisib or placebo). Each patient will be treated for
six (6) weeks (main treatment phase).
Healthy Volunteers: Cohort 1
Six (6) healthy volunteers will be concomitantly treated with bimiralisib and
vehicle, applied to two (2) independent skin areas for 21 consecutive days:
* once daily (QD) vehicle on 100cm2,
* once daily (QD) bimiralisib 2.0% on 400cm2,
followed by a 2 week safety follow up. Initial healthy volunteer dosing will
occur in-house for the first 4 days (3 nights) to establish a well-controlled
start. For the remainder of the treatment period, subjects will visit the unit
daily for application of study treatment (by study staff) and to monitor safety
and local tolerability.
MF Patients: Cohort 2
Following a washout of any topical treatment of at least two weeks and any
systemic treatment of at least 4 weeks, every patient will be treated with
bimiralisib or vehicle for six weeks (i.e., the Main Treatment Period) on one
or more (up to three) target lesion(s) with a total (combined) area of
minimally 150cm2 and maximally 200cm2. This will be the basis for the primary
analysis.
Extended Treatment Period * Cohort 2
For patients achieving at least a 15% reduction from baseline on CAILS at the
end of the main six (6) week treatment period, an optional treatment extension
is planned to evaluate whether an extension from six (6) to 12 weeks of
treatment might further improve response to topical bimiralisib. Treatment
extension will only be considered in the absence of safety / tolerability
issues in the respective patient and only if the patient is willing to
continue. The blind will be maintained throughout the treatment extension.
Treatment extension will be followed by a four (4) week safety follow-up. It is
important to note that response to treatment extension from 6 to 12 week
constitutes an exploratory objective of the study, as opposed to the primary
endpoint which solely considers the difference between placebo and active after
the main six (6) week treatment period.
Any of the following will prevent treatment extension for a patient:
* no improvement of target lesions (individual percentage change from baseline
of <15% on CAILS)
* progression of any lesion (non-target or target) requiring treatment (as
measured by a clinically significant increase in modified Severity Weighted
Assessment Tool (mSWAT) score
* complete response (CR = 100% change from baseline on CAILS) of the target
lesions
* unacceptable toxicity
* the patient is unwilling to continue treatment in the study
Instead, the patient will directly enter the safety follow up of 4 weeks.
Potential Dose Levels for Cohort 2:
* Bimiralisib (or matching vehicle) 2.0% once daily (QD)
* Bimiralisib (or matching vehicle) 2.0% twice weekly (BIWK)
* Bimiralisib (or matching vehicle) 2.0% once weekly (QWK)
Intervention
Topical bimiralisib/vehicle non-aqueous gel to be administered to target
lesion(s) of up to 400cm2 (in healthy volunteers) or up to 200cm2 (in MF
patients) in the following dose levels:
* Vehicle
* bimiralisib 2.0% QWK
* bimiralisib 2.0% BIWK
* bimiralisib 2.0% QD
Patients are allowed to treat non-target lesions with a commercially available
bland emollient at libitum, which is not considered IMP. The bland emollient
will be provided by the site as required.
Study burden and risks
The dose justification for the first-on-human topical bimiralisib dose takes
into account the safety profile of oral bimiralisib from more than 230 patients
and therefore focusses (1) on the detection and prevention of strong skin
reactions, and (2) keeping systemic exposure to bimiralisib as low as possible
to reduce the risk for systemic adverse events to a minimum.
No benefit is foreseen for the healthy volunteers. For MF patients, treatment
with bimiralisib may result in clinical benefit of the treated (target-)
lesions. No clinical benefit is expected for the non-target lesions.
After oral administration of bimiralisib in patients with various oncologic
diseases, the following adverse reactions have been observed, which are
considered related to systemic exposure to bimiralisib: anemia, body weight
decreased, depression, fatigue, gastro-intestinal signs and symptoms, increases
in ALT and AST, pneumonitis, hyperglycemia, neutropenia, pruritus, and rash. As
described in the dose justification, the selected doses for all participants in
the current study are not expected to result in systemic exposures to
bimiralisib concentrations that would be high enough to elicit the above
described adverse events. At this time, it is unknown what the mechanism of
action is for oral bimiralisib to cause the aforementioned skin reactions.
After topical administration in minipigs, erythema and edema have been observed
after longer (>23 days) of treatment with higher dose concentrations (3.0% and
higher) of topical bimiralisib gel. Therefore, it cannot be excluded that local
tolerability issues might occur in humans with treatment with similar dose
concentrations that extend beyond four weeks, hence the primary endpoint of the
Healthy Volunteer Cohort is the evaluation of the target area for events of
erythema or other local skin reactions. If these kind of events occur, the
protocol specifically requires the patient to interrupt dose administration
until the event has resolved completely or at least has reduced in severity to
Grade 1. Level of knowledge about mechanism of action
The drug bimiralisib inhibits the PI3K/mTOR pathway. This pathway plays a major
role in various physiological processes including * but not limited to -
glucose metabolism and immune response. This pathway is an ubiquitous pathway.
Hochbergerstrasse 60C
Basel CH-4057
CH
Hochbergerstrasse 60C
Basel CH-4057
CH
Listed location countries
Age
Inclusion criteria
Healthy volunteers may be included in the study if they meet all the below
inclusion criteria:
1. Males * 18 years of age
2. Fitzpatrick skin type I, II, III or IV
3. No clinical significant skin disease in the treatment area(s) and no
hypertrophic scarring
4. Willing and able to washout and withhold any topical treatment in the
treatment area (2 weeks)
5. Subjects must understand the investigational nature of this study and sign
an independent ethics committee-approved written informed consent form prior to
any study related procedure.
6. Willing to comply with all study requirements.
7. Subjects of reproductive potential must agree to use double contraception
from screening until 90 days after discontinuing study treatment and withhold
from any sperm donation.Patients may be included in the study if they meet all
the below inclusion criteria:
1. Males or females * 18 years of age
2. Confirmed diagnosis of CTCL (MF): MF stage 1A or 1B (maximum T2N0M0B1) as
per Modified ISCL/EORTC revisions (Olsen-2011):
a. Confirmed histopathological diagnosis from skin biopsy representative of
current disease by pathologist with expertise in cutaneous lymphoma. The date
of biopsy should be within the last 5 years. If diagnosis is not confirmed by
light microscopic examination, ISCL diagnostic criteria must be used.
3. At least 1, 2 and up to 3 target lesions with a (combined) total size of at
least 150 cm2
4. Willing and able to washout any previous topical treatment (at least 2
weeks) and any systemic treatment (at least 4 weeks) prior to first application
of topical bimiralisib.
5. Otherwise healthy, i.e. absence of clinically significant or unstable
disease, with acceptable organ function with lab values within normal range or
as specified below:
a. eGFR (mCockcroft-Gault) > 30 mL/min.
b. AST and ALT <<= 2.5x ULN
c. Total bilirubin <<= 1.5x ULN (except patients with Gilbert*s syndrome, who
may have total bilirubin <<= 3x ULN)
d. Platelet count ><= 100*000 /mm3
e. WBC count ><= 1500 /mm3
f. ANC count ><= 1500 /mm3
g. Fasting blood glucose <<= 125 mg/dL
6. Patient must understand the investigational nature of this study and sign an
independent ethics committee/ approved written informed consent form prior to
any study related procedure.
7. Willing to comply with all study requirements.
8. Patients of reproductive potential must agree to use double contraception
from screening until 90 days after discontinuing study treatment.
9. Females who had a menstrual cycle within 2 years of Screening must have a
negative serum pregnancy test at Screening and a negative urine pregnancy test
on their first dosing
Exclusion criteria
Healthy volunteers will be excluded from the study if they meet any of the
below exclusion criteria:
1. Known hypersensitivity to any of the excipients of bimiralisib gel.
2. Evidence of any clinically significant active or unstable chronic disease or
condition that could interfere with, or for which the treatment of might
interfere with, the conduct of the study, or that would pose an unacceptable
risk to the subject in the opinion of the investigator (following a detailed
medical history, physical examination, vital signs (systolic and diastolic
blood pressure, pulse rate, body temperature) and 12-lead electrocardiogram
(ECG) at screening or pre-dose). Minor deviations from the normal range may be
accepted, if judged by the Investigator to have no clinical relevance.
3. Clinically significant abnormalities, as judged by the investigator, in
laboratory test results (including hepatic and renal panels, complete blood
count, chemistry panel and urinalysis) at screening or pre-dose. In the case of
uncertain or questionable results, tests performed during screening may be
repeated before randomization to confirm eligibility or judged to be clinically
irrelevant for healthy subjects;
4. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab),
or human immunodeficiency virus antibody (HIV Ab) at screening, or other known
infection requiring antibiotic therapy within the last three months prior to
the study.
5. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times in the past year;
6. Donation of blood or blood loss of >500 mL within 3 months prior to
screening or donation of plasma within 14 days
7. Any condition that in the opinion of the investigator would complicate or
compromise the study or the well-being of the subjectPatients will be excluded
from the study if they meet any of the below exclusion criteria:
1. Known hypersensitivity to any of the excipients of bimiralisib gel.
2. Patients who are on (or will require) any systemic treatment to treat their
disease (MF) during the study.
3. Concurrent severe and/or uncontrolled medical conditions that would, in the
investigator*s judgment, contraindicate patient participation in the clinical
study or require concomitant skin-directed or systemic therapy (e.g., active or
uncontrolled severe infection, chronic active hepatitis, immuno-compromised,
acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial
lung disease, etc.).
4. Has other active malignancies that require systemic treatment.
5. Has a known history of HIV infection or hepatitis (testing not mandatory).
6. Pregnant or nursing (lactating) women.
7. Has a known history of alcohol or drug abuse within the past 1 year.
8. Psychiatric illness, disability or social situation that would compromise
the subject*s safety or ability to provide consent, or limit compliance with
study requirements.
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 |
|---|---|
| EudraCT | EUCTR2019-001383-30-NL |
| CCMO | NL69869.056.19 |