A Phase 2 Open-Label Pilot Study of the Safety and Tolerability of Ixazomib Administered Orally to Patients With Scleroderma-Related Interstitial Lung Disease
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Treatment-emergent Adverse Event (AE)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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, .
研究组 & 干预措施
Ixazomib in patients with scleroderma-interstitial lung disease (ILD)
Participants will be administered oral ixazomib for six cycles (each cycle is 28 days duration).
干预措施: Ixazomib (Drug)
结局指标
主要结局
Treatment-emergent Adverse Event (AE)
时间窗: 7 months
The number of participants with at least one treatment-emergent adverse event. Defined as any of the following: Treatment-emergent AEs; Treatment-emergent serious adverse events (SAEs); Treatment-emergent treatment-related AEs; or Treatment-emergent treatment-related SAEs.
Adverse Events Leading to Ixazomib Dose Modifications
时间窗: 7 months
Number of participants with treatment-emergent AEs leading to ixazomib dose modifications.
Adverse Events Leading to Ixazomib Early Discontinuation
时间窗: 7 months
Number of participants with treatment-emergent AEs leading to ixazomib early discontinuation.
Change in the UCLA Scleroderma Clinical Trials Consortium Gastrointestinal 2.0 (UCLA SCTC GIT 2.0) Questionnaire Score
时间窗: Baseline, 7 months
The UCLA SCTC GIT 2.0 is a self-administered survey consisting of 34 questions (Reflux 1 to 8, Distention/Bloating 9 to 12, Fecal Soilage 13, Diarrhea 14 to 15, Social functioning 16 to 21, Emotional well-being 22 to 30, Constipation 31 to 34). The items are scored on a scale from 0 to 3, where 0 indicates better health and 3 indicates worse health, except for questions 15 and 31, which are scored as 0 (better health) and 1 (worse health). Scores from all scales except the constipation scale are averaged to form a total GIT score from 0 (no gastrointestinal problems) to 3 (most severe) that captures overall burden of severity of scleroderma-associated gastrointestinal involvement.
次要结局
- Change in Physician Global Assessment of Disease Activity (MDGA)(Baseline, 24 weeks)
- Change From Baseline in Modified Rodnan Skin Score (MRSS)(Baseline, 24 weeks)
- Change From Baseline in High Resolution Chest CT Scan Goh Score(Baseline, 24 weeks)
- Change in Forced Vital Capacity (FVC) % Predicted.(Baseline, 7 months)
- Change in Total Lung Capacity (TLC) % Predicted(Baseline, 24 weeks)
- Severity of Dyspnea at Baseline (Mahler Baseline Dyspnea Index)(Baseline)
- Dyspnea Status Rating (Mahler Transitional Dyspnea Index)(12 weeks, 24 weeks)
- Change in Scleroderma Health Assessment Questionnaire (SHAQ) Score(Baseline, 24 weeks)
- Change in Patient Global Assessment of Disease Activity (PtGA)(Baseline, 24 weeks)
- Change in American College of Rheumatology Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (ACR CRISS)(Baseline, 24 weeks)
- Change in Diffusion Capacity (DLCO) % Predicated(Baseline, 7 months)
研究者
Michael M. Pham
Regulatory Sponsor and Principal Investigator
Mayo Clinic