Pomalidomide for Chronic Graft-versus-Host Disease

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.

- 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.