Clinical trial NCT01688466: Pomalidomide for Chronic Graft-versus-Host Disease
Official title: A Randomized Phase 2 Single-Center Study of Pomalidomide for Chronic GvHD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft vs Host Disease
Graft-Versus-Host Disease
Keywords: Immune Modulatory
Systemic Absorption
Oral Agent
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-09-20
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

- Pomalidomide is a drug that alters the body's immune response. It may help people who have chronic graft-versus-host disease (GvHD). GvHD may appear after a stem cell transplant, when immune cells in the transplant try to attack tissues in the person who received the transplant. GvHD is not easy to treat, and often does not respond to standard treatments. Researchers want to see if pomalidomide is a safe and effective treatment for GvHD.

Objectives:

- To test the safety and effectiveness of pomalidomide for GvHD that has not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have GvHD that has not responded to standard treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will also be collected. A lung function test and imaging studies will also be given.
* Participants will take pomalidomide capsules once a day for 4-week periods called cycles.
* Treatment will be monitored with frequent blood tests and imaging studies. Saliva samples and skin and mouth tissue biopsies will also be collected during treatment.
* Treatment will continue for six cycles (6 months), unless the GvHD gets worse or side effects are too severe. If the GvHD has improved at the end of the six cycles, participants may be able to continue to take pomalidomide for up to six more cycles.

Detailed description: BACKGROUND:

* Chronic graft-versus-host disease (cGvHD) is the leading cause of non-relapse morbidity and mortality in persons after allogeneic hematopoietic cell transplants.
* About 50% of persons with cGvHD have disease refractory to systemic corticosteroids and there is no standard second-line therapy.
* Thalidomide, a drug with immune-modulating effects, was active in advanced cGvHD but was difficult to use at appropriate doses.
* Pomalidomide is related to thalidomide but with higher potency and more favorable toxicity profile. It is active in multiple myeloma and myeloproliferative neoplasm associated myelofibrosis. Preliminary data in humans with cGvHD are encouraging but data are limited.

OBJECTIVES:

- Primary: Determine whether pomalidomide is effective in persons with moderate or severe cGvHD not controlled by corticosteroids.

ELIGIBILITY:

Inclusion Criteria

* Moderate or severe cGvHD per National Institutes of Health (NIH) criteria
* Age 18 to 75 years old
* Karnofsky performance score greater than or equal to 60%
* Has cGvHD that did not respond to high-dose corticosteroids (average 0.5 mg/kg/d prednisone for greater than or equal to 8 weeks) or second-line therapy
* Receiving stable or tapering doses of systemic therapy in the preceding 4 weeks
* Agree to adhere to methods of contraception and other fertility control measures as prescribed by the protocol

Exclusion Criteria

* Acute GvHD (classic and late per NIH criteria)
* Absolute neutrophils \<1.0x10(9)/L, platelets \<75x10(9)/L, estimated creatinine clearance \<50 mL/min/1.73m(2)
* NIH lung score 3
* Pregnant or lactating
* Uncontrolled infection

DESIGN:

Randomized phase 2 trial with the single stage selection design. Patients will receive either a constant low dose of pomalidomide (0.5 mg/day) for six months or a strategy of increasing dose of pomalidomide from 0.5 mg/d up through each individual patient's maximum tolerated dose, with escalations by 0.5 mg/d every 2 weeks to a maximum of 2.0 mg/d. As an early stopping rule for futility, if after 7 patients have enrolled on either arm, 0 have responded, then no further patients will be accrued to that arm as soon as this can be determined. To protect patient safety, an early stopping rule will be implemented. With two arms, each of which has a maximal accrual of 16 patients, up to 32 evaluable patients will be randomized. Response assessments will occur every 3 months with primary efficacy endpoint evaluated at 6 months. Patients with responding disease will continue therapy for another 6 months.

Eligibility criteria: * INCLUSION CRITERIA
* Moderate or severe chronic graft-versus-host disease (cGvHD) diagnosed and staged per National Institutes of Health (NIH) criteria
* Greater than or equal to18-75 years of age, because no dosing or adverse event data are currently available on the use of pomalidomide in persons greater than or equal to18 years of age
* Has cGvHD that did not respond to high-dose corticosteroids (average 0.5 mg/kg/d prednisone for \>8 weeks) or second-line systemic therapy
* If taking systemic therapy for cGvHD at the time of enrollment, must be on a stable or tapering schedule in the preceding 4 weeks (extracorporeal photopheresis has to be stopped at least by 4 weeks before enrollment)
* Karnofsky performance score greater than or equal to 60%
* Life expectancy \>3 months
* Stable primary malignancy for previous 3 months
* Agree to adhere to methods of contraception and other fertility control measures as prescribed by the protocol
* Because agents of this class are known to be teratogenic, women of childbearing potential and men must agree to use effective forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* Females of childbearing potential (FCBP) (Cross) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10

  14 days prior to and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, AND Education and Counseling Guidance Document.
* Male Subjects
* Must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation of study drug even if he has undergone a successful vasectomy
* Will be warned that sharing study drug is prohibited and will be counseled about pregnancy precautions and potential risks of fetal exposure
* Must agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation of study drug.
* Must agree that if a pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male study subject during study participation, study drug must be immediately discontinued.
* Patients must agree to not share study drug with anyone during participation in the study.
* Ability of subject to understand and the willingness to sign a written informed consent document.
* All study participants must be registered into the mandatory POMALYST REMS (TM) program, and be willing and able to comply with the requirements of the POMALYST REMS (TM) program.

EXCLUSION CRITERIA:

* Acute GvHD, classic (less than or equal to day 100) or late-onset (\>day 100)
* Systemic immune suppression or systemic therapy for cGvHD started within preceding 4 weeks including extracorporeal photopheresis
* Hypersensitivity to thalidomide, lenalidomide or pomalidomide
* Any serious medical condition which places the subject at an unacceptable risk if he or she were to participate in the study or confounds the ability to interpret data from the study, including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Neutrophil \<1.0x10(9)/L, platelets \<75x10(9)/L, estimated creatinine clearance \<50 mL/min/1.73m(2) (Cockroft-Gault formula) total bilirubin \>3 mg/dL, transaminase\>3xUNL
* Uncontrolled infection
* Active human immunodeficiency virus 1 (HIV-1), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection

Uncontrolled arrhythmias or symptomatic heart disease or left ventricular ejection fraction (LVEF) \<45%

* Other cancer except that for which the transplant was done \<2 years before study entry, except non-melanoma skin cancer or carcinoma in situ of the uterine cervix or breast
* Taking other investigational drugs
* NIH lung score 3
* Pregnant women are excluded from this study because pomalidomide has potential for teratogenic effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pomalidomide, breastfeeding must be discontinued while the mother is taking study drug and for at least 28 days after discontinuation of study drug. These potential risks may also apply to other agents used in this study.

Primary outcomes:
measure: Overall Response at 6 Months
timeFrame: 6 months
Secondary outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0
timeFrame: 50 months and 20 days
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Najla El Jurdi, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bolanos-Meade J, Vogelsang GB. Chronic graft-versus-host disease. Curr Pharm Des. 2008;14(20):1974-86. doi: 10.2174/138161208785061373.
citation: Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003 Apr;9(4):215-33. doi: 10.1053/bbmt.2003.50026.
citation: Martin PJ, Weisdorf D, Przepiorka D, Hirschfeld S, Farrell A, Rizzo JD, Foley R, Socie G, Carter S, Couriel D, Schultz KR, Flowers ME, Filipovich AH, Saliba R, Vogelsang GB, Pavletic SZ, Lee SJ; Design of Clinical Trials Working Group. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. Design of Clinical Trials Working Group report. Biol Blood Marrow Transplant. 2006 May;12(5):491-505. doi: 10.1016/j.bbmt.2006.03.004.