A Study to Evaluate the Safety and Tolerability of Oral Ixazomib in Scleroderma-related Lung Disease Patients

Michael M. Pham

Status and phase

Terminated

Phase 2

Conditions

Progressive Systemic Sclerosis

Diffuse Cutaneous Scleroderma

Diffuse Cutaneous Systemic Sclerosis

Scleroderma With Pulmonary Involvement

Systemic Sclerosis, Diffuse

Scleroderma, Systemic

Systemic Sclerosis With Lung Involvement

Progressive Scleroderma

Systemic Sclerosis

Systemic; Sclerosis, Progressive

Systemic Sclerosis Pulmonary

Interstitial Lung Disease

Diffuse Systemic Sclerosis

Pulmonary Fibrosis Interstitial

Diffuse Scleroderma

Scleroderma

Scleroderma;Progressive

Scleroderma, Diffuse

Scleroderma of Lung

Treatments

Drug: Ixazomib

Study type

Interventional

Funder types

Other

Identifiers

NCT04837131

20-004201

Details and patient eligibility

About

The purpose of this research study is to learn about the effects of the medication ixazomib in participants with scleroderma/systemic sclerosis including its safety and tolerability, its effects on skin, lungs and other organs, and its effects on overall health and quality of life.

Full description

The primary objective of this study is to assess the safety and tolerability of oral ixazomib taken on days 1, 8, and 15 of each 28-day treatment cycle for 6 cycles in 12 participants having diffuse systemic sclerosis/scleroderma of less than 5 years duration with non-severe interstitial lung involvement as identified from chest CT scan completed within the preceding 3 months or at study screening visit. All 12 participants will receive oral ixazomib. Reflecting the common use of mycophenolate in the management of scleroderma with complicating interstitial lung disease, 6 of 12 participants who will be enrolled will be already taking mycophenolate at a stable dose for the preceding 3 months and will be allowed to continue taking mycophenolate throughout the entire study prescribed as routine care. Ixazomib will be added to their medications. The remaining 6 of 12 participants meeting the same eligibility criteria will not be using mycophenolate or any other treatment for scleroderma interstitial lung disease at the time of enrollment and will subsequently take ixazomib study medication during participation in this study. Ixazomib dose modification or interruption is allowed for safety and tolerability reasons at any time during the study.

The secondary objective of this study is to assess the effect of ixazomib on scleroderma skin tightness/thickening and its effect on scleroderma interstitial lung disease.

The study includes approximately 13 clinic visits over up to approximately 10 months. Study procedures include medical examinations, blood tests, chest CT scans, pulmonary function tests, echocardiogram, EKG, skin biopsies, and questionnaires.

There is no cost for participation in this study.

Enrollment

4 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Male and female patients, age ≥18 years at time of signing informed written consent
Confirmed diagnosis of diffuse cutaneous systemic sclerosis/scleroderma
Disease duration not longer than 60 months defined as the time from the first non-Raynaud phenomenon manifestation
Scleroderma skin thickness score (modified Rodnan skin score) between 15 and 45
Evidence of scleroderma-related lung involvement on chest CT scan completed within the preceding 3 months or at screening study visit
Pulmonary function testing demonstrating FVC ≥45% predicted and DLCO ≥40% predicted at screening study visit
Resting transthoracic echocardiogram within the preceding 6 months or at screening study visit without evidence of pulmonary artery hypertension
Stable mycophenolate dose during the preceding 3 months for those who are taking mycophenolate. Mycophenolate use is not an eligibility requirement to participate; but those participants already using mycophenolate at screening study visit will continue taking the medication throughout the entire study.
Willingness to undergo supervised withdrawal during the first 90 days of the study of any other medication besides mycophenolate used specifically as treatment of scleroderma-related interstitial lung disease with confirmed stable pulmonary status.
Willingness to undergo supervised withdrawal during the first 90 days of the study of any other prohibited medications with confirmed stable status.
Able to understand and sign a written informed consent form
Able to understand the importance of adhering to study treatment and the study protocol, and willing and able to follow all study requirements, including the concomitant medication restrictions, throughout the study
Practice birth control requirements for sexually active female participants including option of abstinence for the entire study and for at least 90 days after the last dose of study medication
Practice birth control requirements for sexually active male participants or partners including option of abstinence for the entire study and for at least 90 days after the last dose of study medication

Exclusion criteria

Pulmonary artery hypertension under treatment
Evidence of clinically significant pulmonary hypertension or left ventricular dysfunction with left ventricular ejection fraction < 40% from either prior heart catheterization or resting transthoracic echocardiography within the preceding 6 months.
Evidence of significant gastrointestinal involvement by scleroderma as assessed by the University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Tract multi-item questionnaire, 2.0 ([UCLA SCTC GIT 2.0) at screening study visit.
Known esophageal stricture sufficient to limit the ability to swallow oral medication
Prior history of scleroderma renal crisis
Another connective-tissue disorder (eg, rheumatoid arthritis, systemic lupus erythematosus)
Any other significant pulmonary disorder (e.g., chronic obstructive pulmonary disease, emphysema, adult moderate to severe asthma)
Significant environmental exposure known to cause pulmonary fibrosis including, but not limited to, drugs (e.g., amiodarone), asbestos, beryllium, radiation, or domestic birds or other exposures associated with hypersensitivity pneumonitis
Unstable or deteriorating cardiac disease within the preceding 6 months including but not limited to unstable angina pectoris, myocardial infarction (heart attack), heart failure requiring hospitalization, poorly controlled heart arrhythmia, or significant pericardial effusion/fluid collection around the heart
Known liver disease (e.g., chronic hepatitis or cirrhosis)
Significant abnormality of liver function tests
Significant kidney function impairment of any cause as evidenced by creatinine clearance <30 mL/min
Known active or suspected peptic (stomach) ulcer
Known active hematologic blood-related disorder other than anemia of chronic disease or iron deficiency anemia
Significant abnormality of blood count including hemoglobin ≤ 8.0 gm/dl, absolute neutrophil count ≤ 1000, or platelet count ≤ 75,000
Known hematologic blood-related malignancy
Prior stem cell or bone marrow transplant
History of any malignancy within the last 5 years other than non-melanoma skin cell cancer cured by local resection or a carcinoma-in-situ
Any condition likely to result in death within 12 months.
Any condition which might be significantly worsened by the known side effects associated with ixazomib including known ≥ grade 2 peripheral neuropathy
Tobacco smoking within 3 months of screening study visit or unwillingness to avoid smoking throughout the study (e.g., cigarette, pipe, or cigar)
History of alcohol or substance abuse in the previous 2 years
Any active infection including, but not limited to, bronchitis, pneumonia, sinusitis, or urinary tract infection
Pregnancy or lactation/breast feeding
Expectation of study participation being interrupted on account of a foreseeable medical or surgical event
Prior use of ixazomib or other proteasome inhibitor medication
Suspected intolerance, allergy, or hypersensitivity to ixazomib or any of its excipients
Any prior use of rituximab
Any prior use of cyclophosphamide
Ongoing use within the preceding 28 days or expected use of an investigational drug (an investigational drug is defined as any drug that has not been FDA approved for marketing)
Ongoing use or expected use of any of the following therapies: Strong inducers of a cytochrome drug metabolizing enzyme in the liver (CYP3A ). (e.g. rifampin, rifapentine, rifabutin, carbamazepine, enzalutamide, phenytoin, fosphenytoin, phenobarbital, St. John's wort)
Ongoing use or expected use of any of the following medications: cyclophosphamide, rituximab, abatacept, nintedanib, tocilizumab, intravenous immunoglobulin (IVIG), methotrexate, leflunomide, azathioprine, sirolimus, tacrolimus, oral corticosteroids at a dose >10 mg/d prednisone equivalent, D-penicillamine, minocycline, interferon-γ, bosentan, ambrisentan, macitentan, phosphodiesterase inhibitors (sildenafil or tadalafil for uses other than erectile dysfunction or Raynaud phenomenon), riociguat, tumor necrosis factor-α (TNF-α) inhibitors (infliximab, etanercept, adalimumab, certolizumab, golimumab), and cyclosporine, .