Primary:* To assess the safety and tolerability of LAM-001 administered daily by dry powder inhaler (DPI) for 14 days in patients with lymphangioleiomyomatosis (LAM) (Period 1).* To assess the longer-term safety and tolerability of LAM-001…
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic Endpoints
The following are the primary rapamycin PK endpoints:
* Cmax: Period 1, Days 1 and 14; Period 2, Day 84
* AUC0-24: Period 1, Days 1 and 14; Period 2, Day 84
* AUC0-t: Period 1, Days 1 and 14; Period 2, Day 84
Secondary outcome
Exploratory Biomarker Endpoints
The endpoints for VEGF-D and other biomarkers are absolute concentration,
changes over time, and variability.
Efficacy Endpoints
Not applicable.
Safety Endpoints
* AE monitoring and recording
* Clinical laboratory results (hematology, serum chemistry, and urinalysis)
* PFTs
* 6MWT
* Vital sign measurements (systolic and diastolic blood pressures, heart rate,
respiratory rate, and body temperature)
* Resting pulse oximetry
* 12-lead ECG results
* Physical examination findings
Background summary
There is a compelling rationale to determine if direct administration of
inhaled rapamycin (LAM-001) into the lungs can deliver a dose that suppresses
inappropriate mTOR signaling over long periods to slow or halt decline in lung
function and cystic lung destruction without the systemic toxicities that occur
with oral rapamycin administration.
The rationale for LAM-001 development is the hypothesis that direct dosing of
rapamycin to the lungs will allow similar or improved efficacy at lower
systemic availability and a corresponding lower systemic toxicity in comparison
to oral administration, as treatment of LAM requires chronic therapy.
See also protocol background and rationale.
Study objective
Primary:
* To assess the safety and tolerability of LAM-001 administered daily by dry
powder inhaler (DPI) for 14 days in patients with lymphangioleiomyomatosis
(LAM) (Period 1).
* To assess the longer-term safety and tolerability of LAM-001 administered
daily by DPI for up to 12 weeks in patients with LAM (Period 2).
Secondary:
* To assess the systemic exposure of LAM-001 administered daily by DPI for 14
days in patients with LAM (Period 1).
* To assess the systemic exposure of LAM-001 administered daily by DPI for up
to 12 weeks in patients with LAM (Period 2).
Exploratory:
* To explore the feasibility and variability of assessing vascular endothelial
growth factor-
Study design
This is a Phase 1b multicenter, open-label, repeat-dose study to be conducted
in patients with LAM.
The SRC will oversee this study.
Period 1: An initial cohort of 6 patients is planned. A sentinel patient will
be enrolled at a dose of 100 *g LAM-001 and be assessed before opening dosing
to additional patients. Only after the SRC has reviewed the safety and PK data
through Day 14 for the sentinel patient will approval be given to allow dosing
of the remaining 5 patients in the cohort. The assessments for the sentinel
patient will be the same as those for the other patients.
Including the screening period (up to 4 weeks), dosing (2 weeks), and follow up
for PK blood collection (4 weeks after the final dose), the study duration for
an individual patient in Period 1 will be up to 10 weeks.
Period 2: After an individual patient completes Period 1, provided continued
dosing is approved by the SRC and drug supply is adequate, they have the option
to continue into Period 2, and receive up to 12 weeks of additional daily
dosing. An additional cohort of up to 6 patients may be enrolled directly into
Period 2 of the study. Including the screening period, if applicable (4 weeks),
treatment (up to 12 weeks), and follow up for PK blood collection (4 weeks
after the final dose), the study duration for an individual patient in Period 2
will be up to 20 weeks
Intervention
Capsules of LAM-001 will contain 100 *g (up to a maximum of 200 *g) of
rapamycin formulated in hydroxypropyl methyl cellulose dry-powder capsules,
using lactose as the excipient.
Study burden and risks
The subject will need to complete following procedures:
Health and Medical questions (4 times in period 1, 6 times in period 2)
Completion of diary each day.
See overview in protocol.
Side effects related to the study:
The study drug will be given at a different form (inhaler). The most common
side effects known are the ones that were occurred in LAM patients taken it
orally:
* wounds in the mouth
* diarrhoea
* abdominal pain
* nausea
* common cold
* acne
* chest pain
* swelling of tissues, usually in the lower limbs, due to a build up of fluids
* upper respiratory tract infection
* headache
* dizziness
* muscle pain
* increased cholesterol in the blood
* weight decrease
More serious reported side effects:
* swelling of the pouch around the heart and abnormal heart rhythm
* high heart rate and accumulation of fluids due to kidney damage
Common side effects in transplant patients:
* infections: pneumonia (lung infection), fungal infection, viral infection,
bacterial infection, herpes simplex infection, urinary tract infection
* blood disorders: low platelets (tiny round blood cells that help your body
form clots to stop bleeding) in the blood and possibly an increased risk of
unexpected bleeding or increased bruising, low red blood cells in the blood,
low white blood cells in the blood
* metabolic disorders (illnesses): low level of potassium (K+) in the blood
serum, low level of phosphate in the blood serum, high lipids (including high
cholesterol), high triglycerides, high blood sugar, diabetes mellitus
* headache
* high heart rate
* high blood pressure
* increase of lymphatic fluid within the body
* digestive illnesses: abdominal (stomach or gut) pain, constipation,
diarrhoea, nausea
* skin disorders: rash, acne
* joint pain
* reduced or decreased kidney function
* menstrual disorder
* general disorders: swelling of tissues, usually in the lower limbs, due to
the build up of fluids, fever, generalised (located in a specific place) pain,
slower capability to heal wounds or cuts
* investigations: increased blood creatinine, increased blood lactate
dehydrogenase (a general sign of tissue and cellular damage), abnormal liver
function test
Old Whitfield Street 530
Guilford CT 06437
US
Old Whitfield Street 530
Guilford CT 06437
US
Listed location countries
Age
Inclusion criteria
1. The patient is independently capable of providing informed consent
and provides signed informed consent, witnessed by clinic staff, before
any study-related assessments or procedures are performed.
2. The patient is female and from 18 to 70 years of age, inclusive, with a
body mass index from 18.0 to 32.0 kg/m2, inclusive, at the time of
screening (Visit 1)
a. Patients cannot be pregnant or lactating/breast feeding and must be
surgically sterile, postmenopausal (no menses for the previous 12
months), or practicing a highly effective method of birth control as
described in this protocol. Acceptable methods of birth control are:
certain types of hormonal contraception (eg, birth control pill, injection,
implant, transdermal patch, or vaginal ring. Progestin-based
contraception is allowed. Only low dose estrogen-containing
contraceptives are allowed [estrogen dose between 10 and 25 *g]),
intrauterine device, tubal ligation (tied tubes), or a partner with a
vasectomy. High dose estrogen containing contraceptives are not
allowed in this study. Gonadotropin-releasing hormone agonist
contraceptives are not allowed in this study.
b. Patients must not be planning to become pregnant during the study
and agree to use highly effective contraception for at least 90 days after
the last dose of study drug.
3. The patient has a confirmed diagnosis of LAM as determined by prior
clinical evaluation, including compatible chest CT AND one of the
following:
a. Biopsy (lung, abdominal mass, lymph node, or kidney) or cytology
(from thoracic or abdominal sources that show HMB45 positive staining
of spindles/epithelioid cells); OR
b. Tuberous sclerosis, angiomyolipoma (diagnosed by prior high
resolution chest CT, magnetic resonance imaging, ultrasonography, or
biopsy); OR
c. Chylous pleural effusion, as verified by thoracentesis (without other
etiology); OR
d. Serum VEGF-D level *800 pg/mL as part of the previous diagnostic
evaluation.
4. The patient's pulmonary symptoms and lung function have been
stable, as judged by the investigator, over the 3 months before Visit 1.
5. The patient has the ability to perform study procedures, including
correct use of the RS01 DPI and the spirometry maneuvers.
6. The patient agrees to comply with all protocol requirements.
Exclusion criteria
1. The patient has a pre-bronchodilator FEV1 of *60% of predicted
during the screening or baseline visits.
2. The patient has used mTOR inhibitors (e.g., rapamycin, everolimus)
within 90 days before Visit 1.
3. The patient is considered likely to need oral rapamycin or another
mTOR inhibitor within 6 months following Visit 1, in the opinion of the
investigator.
4. The patient has had a pneumothorax within the 2 months before Visit
1.
5. The patient is a smoker. Patients will be defined as ex smokers and
eligible for participation in the study if they have not consumed tobacco
products or other forms of nicotine replacement therapy for at least 6
months before Visit 1.
6. The patient has a concurrent significant respiratory disease, including
any of the following:
a. Confirmed or suspected smoking-related chronic obstructive
pulmonary disease.
b. Other significant respiratory disorder including, but not limited to,
pulmonary hypertension, cor pulmonale, pulmonary fibrosis, or
bronchiectasis.
c. Previous lung transplantation or is active on a transplant list.
7. The patient requires regular use of inhaled corticosteroids.
8. The patient has significant or uncontrolled disease of any organ
system, including psychological illness, that is likely to interfere with the
study conduct, patient safety, or the interpretation of study evaluations,
as determined by the investigator, including but not limited to the
following:
a. Unstable angina, myocardial infarction, previous history of
pericarditis, or cerebrovascular event within the past 12 months before
screening or uncontrolled hypertension or arrhythmia.
b. Uncontrolled dyslipidemia.
c. Poorly controlled diabetes mellitus, as evidenced by hemoglobin A1c >8.5%.
d. Known history of human immunodeficiency virus or chronic viral
hepatitis infection
e. Diagnosed with active or untreated latent tuberculous infection or
active pulmonary nontuberculous mycobacterial infection. A tuberculosis
screening test is not required. Patients who completed a course of
antituberculous therapy at least 1 year before screening with no clinical
or radiological evidence of disease recurrence may be eligible for
screening.
f. History of malignancy or treatment for malignancy in the 2 years
before screening. Patients who have received curative treatment with
resection of nonmelanoma skin cancer or with in situ carcinoma of the
cervix may be eligible.
9. The patient has a known allergy to rapamycin or has previously
discontinued rapamycin due to pulmonary or other safety concerns.
10. The patient has a history of severe milk protein allergy (patients with
lactose intolerance are eligible).
11. The patient requires supplemental oxygen therapy as either longterm
oxygen therapy or as required ambulatory oxygen.
12. The patient has a significantly abnormal laboratory result at Visit 1,
including any of the following:
a. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
>2 × upper limit of normal (ULN)
b. Hemoglobin <100 kg/m3
c. Platelets <120,000/mm3
d. Absolute neutrophil count <1,500/mm3
e. Total white blood cell count <4,000/mm3
f. Serum creatinine >1.5 mg/dL
13. The patient has significantly abnormal ECG results at Visit 1. The
investigator will use clinical judgment when assessing the significance of
ECG abnormalities. The investigator is encouraged to discuss the
enrollment of these patients with the study medical monitor in cases of
uncertainty.
14. The patient has an intercurrent infection that has not adequately
resolved within 2 weeks prior to Visit 1. Patients experiencing an
infection during the screening period should be treated appropriately
and may be rescreened after the infection has resolved.
15. The patient has had recent surgery that involved entry into a body
cavity or required 3 or more sutures within 4 weeks prior to Visit 1.
16. The patient is unable or unwilling to attend the scheduled clinic visits
or agree to home healthcare follow-up.
17. The patient has participated in another investigational study
involving any investigational product (i.e., study drug, biologic, device)
within 30 days or 6 half-lives, whichever is longer, before the planned
date of the first dose of study drug.
18. The patient has used any medications not allowed in the study, as
they may impact the PK of LAM-001 or other medications.
19. The patient has used estrogen-containing medications within 30 days
of Visit 1. Exception: continuation of low- dose estrogen-containing
contraceptives (estrogen dose between 10 and 25 *g) is allowed if the
patient has been taking them for a minimum of 30 days before Visit 1.
20. The patient is an employee or first-degree relative of sponsor, PPD,
or study site personnel or is considered vulnerable by local regulations
(e.g., is imprisoned or institutionalized).
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 | EUCTR2017-005071-33-NL |
| CCMO | NL67634.041.18 |