Pomalidomide

A Phase II, Proof-of-concept, Multicenter, Randomized, Double-blind, Placebo-controlled Study To Evaluate The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics And Efficacy Of Pomalidomide (cc-4047) In Subjects With Systemic Sclerosis With Interstitial Lung Disease

INCLUSION CRITERIA

Note: All applicable inclusion and exclusion criteria must be evaluated at both the Screening and Baseline visits

Subjects must satisfy the following criteria to be enrolled in the study:

General and Demographics

1. Male or female subjects between 18 and 80 years of age (inclusive) at the time of signing the ICD
2. Body weight ≥ 80 pounds (36.3 kilograms) at Screening and Baseline
3. Understand and voluntarily sign ICDs prior to the initiation of any study-related assessments / procedures
4. Able to adhere to the study visit schedule and other protocol requirements

Disease-specific

5. Diagnosis of dc-SSc as defined by ACR criteria (Appendix A)
6. Onset of the first non-Raynaud’s manifestation of SSc within 5 years of Screening
7. FVC ≥ 45% and 80% predicted at Screening and Baseline. Source documentation confirming a ≥ 5% decrease in FVC based on 3 or more assessments within 18 months of Baseline (Visit 2) is required. Two assessments may be done during the Screening Phase provided the assessments are completed at least 2 weeks apart.
8. Repeat FVC at Baseline (Visit 2) within 5% of the FVC measured at Screening (most recent assessment if multiple assessments are performed during Screening)
9. DLco ≥ 40% and 80% of predicted value at Screening
10. Abnormalities on HRCT consistent with sclerodermatous involvement of the lung (eg, ground glass, honeycombing)

Laboratory Evaluations

11. Must meet the following laboratory criteria:
Hemoglobin 10.0 g/dL
White blood cell (WBC) count ≥ 3000 /L (≥ 3.0 x 109/L) and 14,000/L ( 14 x 109/L)
Absolute neutrophil count (ANC) ≥ 2 x 109/L
Platelet count ≥ 150,000 /L (≥ 150 X 109/L)
Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
Total bilirubin 2.0 mg/dL
Albumin ≥ 3.0 g/dL
Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT]) 1.5 X upper limit of normal (ULN)

In the event one or more of the above laboratory criteria is not satisfied, subjects may have repeat assessments performed one time during the Screening Phase. If the result(s) is confirmed, subjects will be ineligible to enroll in the study and will be considered screen failures.

Pregnancy

12. Females of childbearing potential (FCBP)* must undergo pregnancy testing based on the frequency outlined in Appendix F and pregnancy results must be negative.
13. Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods as specified in Appendix F.
14. Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP as specified in Appendix F.
15. Males must agree not to donate semen or sperm during the duration specified in Appendix F.
16. All subjects must:
Understand that the IP could have a potential teratogenic risk.
Agree to abstain from donating blood while taking IP and following discontinuation of investigational product (see Appendix F).
Agree not to share IP with another person.
Other than the subject, FCBP and males able to father a child should not handle the IP or touch the capsules, unless gloves are worn.
Be counseled about pregnancy precautions and risks of fetal exposure (see Appendix F).

Concomitant Therapies

17. Use of concomitant medications for the treatment of SSc-related symptoms is permitted. These include:
Proton pump inhibitors or other gastroesophageal reflux disease (GERD) therapies
Angiotensin receptor blocker (ARB) therapies
Angiotensin-converting enzyme inhibitor (ACEI) therapies
Selective serum reuptake inhibitors (SSRIs)
Calcium channel blockers
Non-sedating oral or intranasal antihistamine agents (intermittent usage)
PDE5 inhibitors (if not being taken for pulmonary arterial hypertension [PAH])
≤ 10 mg/day of oral prednisone (or equivalent)
Oral statin agents for hyperlipidemia (if the medication has been taken for ≥ 84 days [12 weeks] prior to Screening)
Analgesic or opioid pain medications
Subjects are required to follow a low-dose aspirin regimen ( 100 mg per day) unless contraindicated (Note: if contraindicated, the Investigator must assess the increased potential risk of thrombosis development versus the potential clinical benefit if the subject participates).
Medication doses and treatment regimens should remain generally stable throughout the course of the study.

EXCLUSION CRITERIA

The presence of any of the following will exclude a subject from enrollment:

Disease-specific
1. Oxygen saturation (SpO2) < 92% (room air [sea level] at rest) at Screening or Baseline
2. Known diagnosis of obstructive lung disease as defined by FEV1/FVC ratio < 0.65
3. Diagnosis of pulmonary arterial hypertension (PAH) requiring treatment
4. Known diagnosis of other significant respiratory disorders (eg, asthma, tuberculosis, sarcoidosis, aspergillosis, chronic bronchitis, neoplastic disease, cystic fibrosis, etc.)

Medical Conditions

5. Any significant medical condition, laboratory abnormality or psychiatric illness that would prevent the subject from participating in the study
6. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
7. Any condition that confounds the ability to interpret data from the study
8. Pregnant or lactating females
9. Current clinical diagnosis of another inflammatory connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, etc.)
10. History of a thromboembolic event (eg, deep vein thrombosis, thrombotic cerebrovascular or cardiovascular events) or hypercoagulable state
11. Family history of genetic disease associated with deep vein thrombosis or thromboembolism
12. History of clinically significant (as determined by the Investigator) endocrinologic, pulmonary (other than SSc-related), GI (other than SSc-related), neurologic, psychiatric, hepatic, renal, hematologic, cardiovascular, immunologic or other major uncontrolled disease
13. History or current diagnosis of peripheral neuropathy
14. History of alcohol or drug abuse
15. History of any of the following cardiac conditions within 6 months of Screening: acute myocardial infarction, acute coronary syndrome, new onset atrial fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery, interventional cardiac catheterization (with or without a stent placement), interventional electrophysiology procedure, presence of implanted permanent pacemaker or presence of implanted defibrillator
16. History of additional risk factors for torsade de pointes (TdP) (eg, heart failure, hypokalemia, family history of Long QT syndrome)
17. Corrected QTcF > 440 msec at Screening or Baseline (pre-dose)
18. Presence of any of the following on 2 of the 3 Screening or Baseline ECGs (pre-dose) at rest:
heart rate < 45 beats per minute
heart rate > 110 beats per minute
PR interval > 220 ms
QRS duration > 110 ms
19. Clinically significant abnormality on any Screening or Baseline ECG
20. History of tuberculosis (TB) (Subjects with a history of TB who have completed a standard course of treatment [documented] are eligible for study entry.
21. History of human immunodeficiency virus (HIV) infection
22. History of congenital and acquired immunodeficiencies (eg, common variable immunodeficiency [CVID])
23. Hepatitis B surface antigen positive or hepatitis B core antibody positive at Screening
24. Antibodies to hepatitis C at Screening
25. History of malignancy (exceptions: excised and cured basal / squamous cell skin carcinomas)

Prior Treatments

26. Use of concomitant medication(s) which could increase the risk for developing deep vein thrombosis, including sex steroid-based contraceptives (oral, injectable or implanted) and hormone replacement therapies, if use of a low-dose aspirin regimen is contraindicated.
27. Use of melphalan within 52 weeks of Screening
28. Use of concomitant medications which prolong the QT/QTc interval (see Appendix G)
29. Use of any anti-coagulant or anti-thrombotic medications (other than low dose-aspirin [( 100 mg/day)
30. Use of any cytotoxic/immunosuppressive agent (other than prednisone ≤ 10 mg/day [mean dose] or equivalent), including but not limited to azathioprine, cyclophosphamide, methotrexate, mycophenolate and cyclosporine within 84 days of Screening
31. Use of prostaglandin analogues (eg, misoprostol, epoprostenol, iloprost, treprostinil) within 28 days (4 weeks) of Screening
32. Use of any biologic agent within 84 days (12 weeks) or 5 half-lives of Screening. In the case of rituximab, use within 168 days (24 weeks) of Screening or no recovery of CD19-positive B lymphocytes if the last dose of rituximab has been more than 168 days (24 weeks) prior to Screening
33. Use of endothelin-1 inhibitors (eg, bosentan) within 84 days (12 weeks) of Screening
34. Use of medications (eg, D-penicillamine, Potaba) with putative scleroderma disease-modifying properties within 28 days (4 weeks) of Screening

Other

35. Smoking of cigars, pipes or cigarettes within 168 days (24 weeks) of Screening
36. Ingestion of grapefruit, grapefruit juice or grapefruit-containing products within 14 days (2 weeks) of randomization
37. Use of any investigational drug within 28 days (4 weeks) of Screening or 5 PD/PK half-lives if known (whichever is longer)