Pomalidomide for the Treatment of Bleeding in HHT

HHT is associated with substantial morbidity, leading to a reduced quality of life, decreased rate of employment and a high incidence of depression. There currently exists no medical therapy recognized as consistently efficacious in HHT. Reports of the efficacy of thalidomide in HHT, as well as interim results of a pilot trial of pomalidomide in HHT provide evidence of efficacy with minimal toxicity. The favorable efficacy:toxicity ratio of pomalidomide suggest that it may benefit patients with HHT.

This study is designed as a Phase II placebo-controlled double-blind study of pomalidomide in HHT patients with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks.

Primary Objective: To determine efficacy of pomalidomide compared to placebo for the reduction in severity of epistaxis after 24 weeks of treatment.

Secondary Objectives: To determine the safety and tolerability of pomalidomide for the treatment of HHT; to determine if pomalidomide treatment improves quality of life in HHT; to determine whether a continued response to pomalidomide is evident 4 weeks after treatment discontinuation; to develop a biorepository for future studies to define biomarkers predictive of pomalidomide response and allow investigations into the biology of HHT and mechanisms of pomalidomide.

Inclusion criteria

• A clinical diagnosis of HHT as defined by the Curacao criteria
• Age ≥ 18 years
• Platelet count ≥ 100,000/µl
• White Blood Count (WBC) ≥ 2,500/µl
• International Normalized Ratio (INR) ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or partial thromboplastin time (PTT) per local laboratory designation) by local laboratory criteria (except for patients on a stable dose of warfarin or direct oral anticoagulants)
• Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the screening visit
• A requirement for anemia, as determined by local laboratory hemoglobin assessment and normal ranges, and/or parenteral infusion of at least 250 mg of iron or transfusion of 1 unit of blood over the 24 weeks preceding the screening visit
• All study participants must agree to be registered into the FDA mandated POMALYST Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program
• Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the POMALYST REMS program. FCBP must have a negative pregnancy test with a sensitivity of at least 50 milli-international units per milliliter (mIU/mL) within 10 - 14 days prior to and again within 24 hours prior to prescribing pomalidomide and must either commit to continued abstinence from heterosexual intercourse or use two (2) 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, during therapy and for at least 4 weeks following discontinuation of therapy. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy.
• Ability to understand and sign informed consent

Exclusion criteria

• Women currently breast feeding
• Renal insufficiency, serum creatinine > 2.0 mg/dl
• Hepatic insufficiency, bilirubin > 2.0 (or >4.0 in the setting of a prior clinical or genetic diagnosis of Gilbert's syndrome) or transaminases > 3.0x normal
• Prior treatment with thalidomide or other Immunomodulatory imide drugs within previous 6 months
• Prior treatment with bevacizumab (systemic or nasal) within previous 6 weeks*
• Prior treatment with pazopanib within previous 6 weeks*
• The use of octreotide or oral estrogens within the previous month*
• History of prior unprovoked thromboembolism confirmed by venous ultrasound or other imaging modalities
• Peripheral neuropathy, confirmed by neurologic consultation
• Known underlying hypoproliferative anemia (i.e. myelodysplasia, aplastic anemia)
• Currently enrolled in other interventional trials
• Known hypersensitivity to thalidomide or lenalidomide.
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
• Known SMAD Family Member 4 (SMAD-4) mutation, unless there has been a colonoscopy with normal (negative) results, or in which the patient has had no more than 5 small (in the opinion of the gastroenterologist) colonic polyps completely removed within the preceding 18 months
• Anything that in the investigator's opinion is likely to interfere with completion of the study

• * Use of these treatments is not permitted during study participation.