Ixazomib Citrate in Treating Patients With Chronic Graft-versus-Host Disease

Study Overview
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Brief Summary
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This phase II trial studies how well ixazomib citrate works in treating patients with chronic graft-versus-host disease. Chronic graft-versus-host disease is a complication of a donor bone marrow or blood cell transplant, usually occurring more than three months after transplant, in which donor cells damage the host tissue. Ixazomib citrate may be an effective treatment for chronic graft-versus-host disease.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the proportion of subjects with treatment failure by 6 months of ixazomib (ixazomib citrate) treatment for chronic graft-versus-host disease (GVHD). SECONDARY OBJECTIVES: I. Determine 3 month overall (complete + partial), and complete response rate. II. Determine 6 month overall (complete + partial), and complete response rate. III. Report overall survival, non-relapse mortality, primary malignancy relapse, failure-free survival, treatment success, and discontinuation of immune-suppressive therapy at 6 months and 1 year. IV. Examine functional outcome (2-minute walk test) and patient-reported outcomes (Lee Chronic GVHD Symptom Scale, quality of life [Short Form Health Survey (SF)-36, Functional Assessment of Cancer Therapy Bone Marrow Transplant (FACT-BMT)], Human Activity Profile [HAP]) at study enrollment, 6 months, and 1 year. V. Study biologic effects of proteasome inhibition. OUTLINE: Patients receive ixazomib citrate orally (PO) once weekly on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with complete response, partial response, or stable disease may receive an additional 6 courses of ixazomib citrate. After completion of study treatment, patients are followed up for 6 months.

Official Title
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Ixazomib for Treatment of Chronic Graft vs. Host Disease

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Drug: Ixazomib Citrate
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR Agree to practice true abstinence or exclusively non-heterosexual activity when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: Agree to practice two effective contraception measures during the entire study treatment period and through 90 days after the last dose of study drug, OR Agree to practice true abstinence or exclusively non-heterosexual activity when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) Patients must have a diagnosis of a chronic GVHD according to the National Institute of Health (NIH) Consensus Criteria Patients must have failed at least one prior line of systemic immune suppressive therapy for management of chronic GVHD Absolute neutrophil count (ANC) >= 1,000/mm^3 Platelet count >= 75,000/mm^3; platelet transfusions are not allowed within 3 days before study enrollment Total bilirubin =< 1.5 x the upper limit of the normal range (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN Calculated creatinine clearance >= 30 mL/min Exclusion Criteria: Female patients who are lactating or have a positive serum pregnancy test during the screening period Major surgery within 14 days before enrollment Does not include placement of venous access device, bone marrow biopsy, GVHD diagnostic biopsy, or other routine procedures in chronic GVHD or post-transplantation care Uncontrolled infection within 14 days before study enrollment Infection treated with appropriate antimicrobial therapy and without signs of progression/treatment failure does not constitute an exclusion criterion Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months Chronic hypertension on medical therapy does not constitute an exclusion criterion Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent Non-hematologic malignancy within the past 2 years with the exception of: Adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer Carcinoma in situ of the cervix or breast Prostate cancer of Gleason grade 6 or less with stable prostate-specific antigen levels Cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period Treatment with non-Food and Drug Administration (FDA) approved drug within 21 days of start of this trial New systemic immune suppressive agent added for the treatment of chronic GVHD within 2 weeks prior to enrollment Addition of a new systemic immune suppressive treatment simultaneously with ixazomib is also prohibited Evidence of recurrent or progressive underlying malignant disease Karnofsky performance status < 70% Life expectancy less than 6 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ixazomib citrate)<br>Patients receive ixazomib citrate PO once weekly on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with complete response, partial response, or stable disease may receive an additional 6 courses of ixazomib citrate. | Drug: Ixazomib Citrate<br>* Given PO<br>* Other names: Ninlaro;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 | Up to 30 days following completion of study treatment | 
| Probability of Treatment Failure at 6 Months | Kaplan-Meier estimate assessed at 6 months for probability of treatment failure, defined as addition of a line of systemic immune-suppressive therapy, recurrent malignancy, or death. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biologic Studies | The biologic impact of proteasome inhibition in the treatment of chronic GVHD will be assessed. | Up to 6 months | 
| Complete Response (CR) Rate | Response will be determined by both clinician-defined, as well as separately calculated according to the proposed response definitions of the NIH Consensus Conference. | 6 months | 
| Probability of Non-relapse Mortality at 1 Year | Kaplan-Meier estimate assessed at 1 year for probability of non-relapse mortality, defined as death in the absence of primary malignancy relapse after transplant. | 1 year | 
| Cumulative Incidence of Primary Malignancy Relapse | Defined as hematologic relapse or any unplanned intervention to prevent progression of disease in patients with evidence (molecular, cytogenetic, flow cytometric, radiographic) of malignant disease after transplantation. | 1 year | 
| Probability of Failure-free Survival at 1 Year | Kaplan-Meier estimate assessed at 1 year for failure-free survival, defined as the absence of death from any cause, relapse or addition of secondary immune suppressive agents. | 1 year | 
| Incidence of Discontinuation of All Systemic Immune Suppressive Therapies | The incidence of complete discontinuation of all systemic immune-suppressive therapies will be determined at 1 year. | 1 year | 
| Overall Response Rate (ORR) (Complete Response + Partial Response) | ORR at 6 months will be determined by both clinician-defined categories of complete response and partial response, as well as separately calculated according to the proposed response definitions of the NIH Consensus Conference. | 6 months | 
| Probability of Overall Survival at 1 Year | Kaplan-Meier estimate assessed at 1 year for overall survival, defined as absence of death from any cause. | 1 year | 
| Treatment Success | Treatment success will be estimated at 1 year with a composite outcome of complete resolution of all reversible chronic graft-versus-host disease (GVHD) manifestations, discontinuation of all systemic immune suppressive agents, and freedom from death or primary malignancy relapse after transplant. | 1 year | 
| Use of Additional Systemic Immune Suppressive Therapies | Addition of therapy after ixazomib constitutes failure, could occur at any time from baseline to 12mo. | 1 year | 
| Symptoms as Measured by Patient Self-report--Short Form-36 (SF-36) | SF-36 subscales have min=0 and max=100; results given are actual scores at 12mo, with higher scores indicating higher quality of life. | 1 year | 
| Symptoms as Measured by Patient Self-report--Functional Assessment of Chronic Illness Therapy (FACT) | FACT-BMT subscales have various min/max, see below; results given are actual 12mo scores, with higher scores indicating better functioning. FACT physical well-being (0-28) FACT social/family well-being (0-28) FACT emotional well-being (0-24) FACT functional well-being (0-28) FACT Bone Marrow Transplant (BMT) subscale (0-40) FACT trial outcome index (0-96) FACT-General (G) (0-108) FACT-BMT total (0-148) | 1 year | 
| Symptoms as Measured by Patient Self-report--Human Activities Profile (HAP) | HAP subscales have min=0 and max=94; results given are actual 12mo scores, with higher scores indicating better functioning. Maximum Activity Score (MAS) is highest item number answered still doing. Represents highest oxygen demanding activity that respondent still performs. Adjusted Activity Score (AAS) is MAS minus total number of stopped doing responses below MAS. A measure of usual daily activities. Modified AAS is MAS minus total number of stopped doing responses below MAS but not penalized for not doing activities not permitted post transplant. The following items are not counted against the score:11,15,19,20,22,25,34,41,42,47,49,50,52,53,54,57,72,73,77,78. | 1 year | 
| Symptoms as Measured by Patient Self-report--Lee Chronic GVHD Symptom Scale | Lee symptom scale (LSS) has subscales with min=0, max=100; results given are 12mo scores, with higher numbers indicating higher symptom burden. | 1 year |