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Graft Versus Host DiseasePhase 1NCT02086513

Phase I Trial of LDE225 for Steroid-refractory Chronic GVHD After Allogeneic HSCT

A Phase 1 study testing LDE225 in people with Graft Versus Host Disease, run by Massachusetts General Hospital at 3 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is a phase I trial of LDE225 for the treatment of steroid-refractory chronic Graft Versus Host Disease (GVHD). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Graft Versus Host Disease
What is being tested?
LDE225
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
17 participants
Where
3 sitesUnited States
Study dates
Apr 2014to Dec 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients eligible for inclusion in this study have to meet all of the following criteria:
  • Patients must provide written informed consent prior to any screening procedures.
  • Age 18 years or older.
  • Recipients of allogeneic hematopoietic cell transplantation (HCT) after either myeloablative or reduced intensity conditioning regimens. Any donor source of stem cells is eligible.
  • Participants must be at least 100 days after HCT.
  • Patients must have steroid refractory classic cutaneous, myofascial, or sclerodermatous cGVHD (+/- other organ involvement, clinically diagnosed), defined as having persistent signs and symptoms of chronic GVHD despite the use of prednisone at ≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks in the preceding 12 months (or equivalent dosing of alternate corticosteroids) without complete resolution of signs and symptoms or if not improving on any line of therapy beyond steroids or if treating physician feels that increasing or adding steroids is not in the patient's best interests. Note that the dose of systemic steroids can certainly be lower than 0.25 mg/kg/day at enrollment.
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  • Stable dose of corticosteroids for 4 weeks prior to enrollment
  • No addition or subtraction of other immunosuppressive medications (e.g., calcineurin inhibitors, sirolimus, mycophenolate mofetil) for 4 weeks prior to enrollment. The dose of immunosuppressive medicines may be adjusted based on the therapeutic range of that drug
  • ECOG performance status ≤ 3
  • Serum Cr ≤ 2 gm / dL
  • Adequate hepatic function (total bilirubin < 2.0 mg/dl, AST < 5x ULN), unless hepatic dysfunction is a manifestation of cGVHD. For patients in whom a diagnosis of hemolysis or Gilbert's is made, the total bilirubin is allowed to be elevated. For patients with abnormal LFTs above the thresholds, documented cGVHD on liver biopsy will be required prior to enrollment.
  • Patients must have adequate bone marrow function as defined by ANC ≥ 1000 / µl and platelets ≥ 20,000 / µl without growth factor or transfusional support
  • Plasma creatine phosphokinase (CK) < 1.5 x ULN
  • Patient is able to swallow and retain oral medication

Who cannot join

  • Patients who have had major surgery within 4 weeks of initiation of study medication.
  • Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.
  • Patients unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes.
  • Patients who have previously been treated with systemic LDE225 or with other Hh pathway inhibitors.
  • Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting LDE225 treatment. If it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution.
  • Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided whilst on LDE225 treatment.
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  • Patients who have taken part in an experimental drug study within 4 weeks or 5 half-lives, whichever is longer, of initiating treatment with LDE225.
  • Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted therapy or radiotherapy) concurrently or within 2 weeks of starting treatment with LDE225.
  • Patients who are receiving treatment with medications known to be strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have a narrow therapeutic index, and that cannot be discontinued before starting treatment with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment with LDE225. Note that patients who require antifungal prophylaxis are preferred to be on fluconazole, and, patients taking voriconazole or posaconazole who must continue are excluded from the dose escalation phase of the study. Once the MTD is established, patients taking voriconazole or posaconazole will be allowed to enroll but at a dose adjustment to be determined before the expansion phase opens.
  • Ongoing prednisone requirement > 1 mg/kg/day (or equivalent)
  • Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.
  • ECP therapy within 4 weeks prior to enrollment
  • Active disease relapse
  • Active, uncontrolled infection
  • Impaired cardiac function or clinically significant heart disease, including any one of the following:
  • Angina pectoris within 3 months
  • Acute myocardial infarction within 3 months
  • QTc > 450 msec for males and > 470 msec for females on the screening ECG
  • A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
  • Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor adherence with an antihypertensive regimen)
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
  • Patients who are not willing to apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment.
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 6 months after the final dose of study treatment. Highly effective contraception is defined as either:
  • Total abstinence: When this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
  • Sterilization: Patient has had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
  • Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female study patients, the vasectomized male partner should be the sole partner for that patient]
  • Use a combination of the following (both a+b):
  • Placement of a non-hormonal intrauterine device (IUD) or non-hormonal intrauterine system (IUS)
  • Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
  • Note: Hormonal contraception methods (e.g. oral, injected, implanted) are not allowed to count as contraception as it cannot be ruled out that the study drug decreases the effectiveness of hormonal contraception. Patients are able to continue taking oral contraceptives if desired.
  • Note: Woman are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. 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 not of child bearing potential
  • Male patient must use highly effective (double barrier) methods of contraception (e.g., spermicidal gel plus condom) for the entire duration of the study, and continue using contraception and refrain from fathering a child for 6 months following the study drug. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid
  • Sexually active males who are unwilling to use a condom during intercourse while taking the study drug and for 6 months after stopping investigational medications and agree not to father a child in this period.
  • Patients unwilling or unable to comply with the protocol.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Massachusetts General Hospital

    Boston, Massachusetts, 02215

Other trials in United States

About this study

This is a phase I trial of LDE225 for the treatment of steroid-refractory chronic Graft Versus Host Disease (GVHD).

Read the detailed description

This phase I clinical trial will enroll participants with steroid-refractory chronic GVHD, and likely take approximately 24 months to complete accrual. Treatment will consist of LDE225 given daily for continuous dosing in 28-day cycles. Participants will have undergone allogeneic SCT and have developed chronic GVHD which has not responded sufficiently to systemic corticosteroids (dose of at least 0.25 mg/kg/day of ideal body weight), have relapsed disease while tapering steroids, or not having an adequate response to steroids plus other therapies. Participants who are responding will then be eligible to receive additional courses of therapy. Participants will be followed on trial for 12 months after starting therapy and the trial will be completed when all participants have reached 12 months of follow-up or have withdrawn from the trial.

The initial dose escalation phase of 4 cohorts of participants (each cohort 3-6 participants) will have a primary endpoint of safety and toxicity of administering LDE225 in this setting.

Being tested
LDE225
Keywords
Graft versus Host Disease, Allogeneic Stem Cell Transplantation
Medical subject headings
Graft vs Host Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LDE225Drug

    Treatment with LDE225

Study groups in NCT02086513
Study groupRoleWhat they receive
LDE225ExperimentalLDE225 will be administered orally, on a continuous once daily dosing schedule at a dose of 200 mg, 400 mg, 600 mg, or 800 mg depending on the specific cohort. Starting dose 200 mg daily for a 28 day cycle. The DLT period will be for the first 2 cycles of therapy. Each cycle is 28 days in length, making the DLT period of minimum of 56 days.
Receives: Drug: LDE225

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose of LDE225 when given as treatment for steroid-refractory chronic GVHD.

    Maximum tolerated dose of LDE225 when given as treatment for steroid-refractory chronic GVHD.

    Measured: 2 years

Secondary outcomes (7)

  1. Overall Response Rate of LDE225

    Testing the efficacy of LDE225 for the treatment of steroid-refractory chronic GVHD as described by overall response rate

    Measured: 2 Years

  2. Incidence of serious infections after starting treatment with LDE225

    Incidence of serious infections after starting treatment with LDE225

    Measured: 2 Years

  3. Ability to decrease baseline steroid dose after starting therapy with LDE225 as measured by systemic steroid dosing at 3, 6, and 12 months after starting therapy with LDE225

    Ability to decrease baseline steroid dose after starting therapy with LDE225 as measured by systemic steroid dosing at 3, 6, and 12 months after starting therapy with LDE225

    Measured: 2 Years

  4. Assessing patient-reported quality of life at 3 months, 6 months, and 12 months in patients on LDE225 therapy compared to baseline measures prior to study enrollment.

    Assessing patient-reported quality of life at 3 months, 6 months, and 12 months in patients on LDE225 therapy compared to baseline measures prior to study enrollment.

    Measured: 2 Years

  5. Assessing patient-reported chronic GVHD symptom severity at 3 months, 6 months, and 12 months in patients on LDE225 therapy compared to baseline measures prior to study enrollment.

    Assessing patient-reported chronic GVHD symptom severity at 3 months, 6 months, and 12 months in patients on LDE225 therapy compared to baseline measures prior to study enrollment.

    Measured: 2 Years

  6. 6-month and 12-month cGVHD progression-free survival

    6-month and 12-month cGVHD progression-free survival

    Measured: 1 Years

  7. 6-month and 12-month overall survival

    6-month and 12-month overall survival

    Measured: 1 Year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Mar 2014 (estimated)
  2. Study startApr 2014
  3. Primary completionDec 2016
  4. Study completionDec 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
17 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02086513
Sponsor's protocol ID
13-598
Status last verified
Mar 2018
First submitted
11 Mar 2014
Last updated
19 Mar 2018
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • DeFilipp Z, Nazarian RM, El-Jawahri A, Li S, Brown J, Del Rio C, Smith M, Valles B, Ballen KK, McAfee SL, Rosenblatt J, Antin JH, Cutler CS, Chen YB. Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease. Blood Adv. 2017 Oct 5;1(22):1919-1922. doi: 10.1182/bloodadvances.2017011239. eCollection 2017 Oct 10.

    PubMed 29296838

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing LDE225 in people with Graft Versus Host Disease, run by Massachusetts General Hospital at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 19 Mar 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early. Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose of LDE225 when given as treatment for steroid-refractory chronic GVHD. (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02086513, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2018.

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