Trial of Ixazomib, Dexamethasone and Rituximab in Patients With Untreated Waldenstrom's Macroglobulinemia

Study Overview
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Brief Summary
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This research study is evaluating a drug called ixazomib (also known as MLN9708) in combination with dexamethasone and rituximab (the regimen is called IDR) as a possible treatment for Waldenstrom's Macroglobulinemia (WM).

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational regimen, IDR, to learn whether IDR works in treating a specific cancer. Investigational means that IDR is still being studied and that research doctors are trying to find out more about it-such as the safest dose to use, the side effects it may cause, and if IDR is effective for treating different types of cancer. It also means that the FDA (the U.S. Food and Drug Administration) has not yet approved IDR for use in participants with your type of cancer. Ixazomib is a drug that may kill or stop cancer cells from growing by blocking the proteasome within the cell, which is responsible for degrading or breaking down a variety of proteins. This type of drug is called a proteasome inhibitor. Rituximab is a type of protein called an antibody that attacks the cluster of differentiation 20 (CD20), a protein found on B-cells like WM. Rituximab is approved by the FDA for treating non-Hodgkin lymphoma (NHL). Dexamethasone is a steroid and is similar to the hormones naturally produced by the adrenal glands; it prevents the release of substances that cause inflammation. Rituximab and dexamethasone are often used to treat WM, alone or in combination with other drugs. Combinations with rituximab, dexamethasone and other proteasome inhibitors have shown good response rates in WM participants. Ixazomib is a proteasome inhibitor; thus the investigator swill investigate if the combination of Ixazomib, Rituximab, and Dexamethasone is also active in WM. In this research study, the investigators are combining a new treatment ixazomib with a standard regimen, rituximab and dexamethasone, to determine whether this combination (IDR) is effective and safe for participants with previously untreated WM.

Official Title
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Phase II Trial of Ixazomib, Dexamethasone and Rituximab in Patients With Untreated Waldenstrom's Macroglobulinemia

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: Ixazomib
* Drug: Dexamethasone
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients 18 years or older. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that the patient may withdraw consent 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, AND Agree to practice true abstinence 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 effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR Agree to practice true abstinence 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.) Clinicopathological diagnosis of WM (Owen 2003), with symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on WM (Kyle 2003), and measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level of >2 times the upper limit of normal. Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients must meet the following clinical laboratory criteria Absolute neutrophil count ≥1,000/mm3 and platelet count ≥75,000/mm3. Platelet transfusions to help patients meet eligibility criteria 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. Central nervous system involvement. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. 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. Systemic treatment, within 14 days before the first dose, with strong inhibitors of cytochrome P (CYP) 1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginkgo biloba or St. John's wort. Known hepatitis B or C virus, or HIV infection. 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. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing. Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.

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: IDR<br>- IDR The study treatment will consist on an induction and a maintenance phase. Dose modification will be permitted for toxicity Induction cycles will be 4 weeks long, Maintenance cycles 8 weeks long. Ixazomib- administered orally on predetermined days and dosage during Induction and Maintenance Phase Dexamethasone- administered via IV or orally on predetermined days and dosage during Induction and Maintenance Phase Rituximab- administered via IV on predetermined days and dosage during Induction and Maintenance Phase | Drug: Ixazomib<br>* Doses given on Days 1, 8, and 15 in induction and maintenance cycles.<br>* Other names: MLN9708;Drug: Dexamethasone<br>* Doses given on Days 1, 8, and 15 in induction and maintenance cycles.<br>* Other names: Maxidex;Drug: Rituximab<br>* Doses given on Day 1 of induction and maintenance cycles.<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Very Good Partial Response Rate (VGPR) for IDR | Rate of very good partial response or better in patients treated with IDR. VGPR is defined as a >90% reduction in serum IgM levels from baseline. | 76 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response includes the rate of complete response (CR), partial response (PR), minimal response (MR), stabl disease (SD) and progressive disease (PD). Minor response is >25%-50% reduction in serum IgM from baseline. Partial Response is (>50-90% reduction in serum IgM from baseline. Very Good Partial Response is >90% reduction in serum IgM from baseline. Complete Response is resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly. | 2 Years | 
| Progression-free Survival (PFS) | Duration of time from start of treatment to disease progression. Progressive disease is defined as occurring when a >25% increase in serum IgM and an absolute 500mg/dL increase in IgM level occurs from the lowest attained response value, or progression of clinically significant disease related symptoms. | From start of treatment to time of disease progression, assessed up to 4 years after treatment start | 
| Overall Response Rate by MYD88 L265P and CXCR4-WHIM Status | To evaluate the overall response rate of participants by MYD88 L265P and CXCR4-WHIM mutations in WM. Overall response is defined as achieving at least a minor response, or >25% reduction in serum IgM from baseline. | 2 Years | 
| Time to Progression (TTP) | Duration of time from start of treatment to time of disease progression. | From start of treatment to time of disease progression, assessed up to 4 years after treatment start | 
| Duration of Response (DOR) | The duration of response is measured from the time a participant achieved a response until the date of progression. | From the time each participant achieved a response to time of disease progression, assessed up to 4 years after treatment start | 
| Time to Next Therapy (TTNT) | Duration from start of protocol treatment to time of initiation of new therapy. | From start of treatment until the participant begins a new therapy, assessed up to 4 years after treatment start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Waldenstrom's Macroglobulinemia