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

NCT02086513 | Terminated Phase 1 DMC

• 1 other identifier: 13-598
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 3

Brief Summary

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

Conditions

Graft Versus Host Disease

Keywords

Graft versus Host Disease; Allogeneic Stem Cell Transplantation

Outcome Measures

Primary Outcomes (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.

  2 years

Secondary Outcomes (7)

• Overall Response Rate of LDE225

  2 Years

• Incidence of serious infections after starting treatment with LDE225

  2 Years

• 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

  2 Years

• 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.

  2 Years

• 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.

  2 Years

Study Arms (1)

LDE225

EXPERIMENTAL

LDE225 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.

Drug: LDE225

Interventions

LDE225 DRUG

Treatment with LDE225

LDE225

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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:

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Novartis: collaborator

Study Sites (3)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• 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.

  PMID: 29296838 DERIVED

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

sonidegib

Condition Hierarchy (Ancestors)

Immune System Diseases

Study Officials

• Yi-Bin Chen, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigators

Study Record Dates

• First Submitted: March 11, 2014
• First Posted: March 13, 2014
• Study Start: April 1, 2014
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: March 19, 2018

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)