Recruitment

Recruitment Status
Terminated
Estimated Enrollment
34

Exclusion Criteria

QTc > 450 msec for males and > 470 msec for females on the screening ECG
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.
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:
...
QTc > 450 msec for males and > 470 msec for females on the screening ECG
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.
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:
Patients unwilling or unable to comply with the protocol.
Active disease relapse
A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
Ongoing prednisone requirement > 1 mg/kg/day (or equivalent)
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).
Placement of a non-hormonal intrauterine device (IUD) or non-hormonal intrauterine system (IUS)
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.
ECP therapy within 4 weeks prior to enrollment
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)
Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.
Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
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.
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
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 unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes.
Angina pectoris within 3 months
Active, uncontrolled infection
Acute myocardial infarction within 3 months
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
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.
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.
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.
Patients who have had major surgery within 4 weeks of initiation of study medication.
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.
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]
Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.
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.

Summary

Conditions
  • Graft -Versus-host-disease
  • Graft Versus Host Disease
Type
Interventional
Phase
Phase 1
Design
  • Allocation: N/A
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

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 develo...

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.

Exclusion Criteria

QTc > 450 msec for males and > 470 msec for females on the screening ECG
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.
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:
...
QTc > 450 msec for males and > 470 msec for females on the screening ECG
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.
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:
Patients unwilling or unable to comply with the protocol.
Active disease relapse
A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome
Ongoing prednisone requirement > 1 mg/kg/day (or equivalent)
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).
Placement of a non-hormonal intrauterine device (IUD) or non-hormonal intrauterine system (IUS)
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.
ECP therapy within 4 weeks prior to enrollment
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)
Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.
Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
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.
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
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 unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes.
Angina pectoris within 3 months
Active, uncontrolled infection
Acute myocardial infarction within 3 months
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
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.
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.
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.
Patients who have had major surgery within 4 weeks of initiation of study medication.
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.
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]
Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.
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.

Tracking Information

NCT #
NCT02086513
Collaborators
Novartis
Investigators
  • Principal Investigator: Yi-Bin Chen, MD Massachusetts General Hospital
  • Yi-Bin Chen, MD Massachusetts General Hospital
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