Selumetinib in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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This phase II clinical trial is studying how well selumetinib works in treating patients with relapsed or refractory diffuse large B-cell lymphoma. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the overall response rate (combined complete remission [CR] and partial remission [PR]) of AZD6244 hyd-sulfate anti-MEK (selumetinib) therapy for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of MEK inhibitor therapy. II. To determine the progression-free survival, time to treatment failure, duration of response, and overall survival with AZD6244 hyd-sulfate therapy. III. To examine biomarkers through down-regulation of phosphorylated extracellular signal-related kinase (pERK) and several relevant target substrates (e.g., monocarboxylate transporter-1 [MCT-1], Menkes disease-associated protein [MNK], ELK, c-v-myc avian myelocytomatosis viral oncogene homolog [c-MYC], and hypoxia-inducible factor-1alpha [HIF-1a]) in peripheral blood studies. OUTLINE: This is a multicenter study. Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample and tumor tissue collection at baseline and at day 15 of course 1 for biomarker studies. After completion of study therapy, patients are followed up every 3 months for up to 3 years.

Official Title
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A Single-Arm Phase II Clinical Trial With the Novel MEK Inhibitor AZD-6244 for the Treatment of MCT-1 Related Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Conditions
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Recurrent Adult Diffuse Large Cell Lymphoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Selumetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care Relapsed or refractory diffuse large B-cell lymphoma (transformed large cell lymphomas are allowed to enroll) Patients must have received at least one previous therapeutic regimen, and no more than 6 previous therapeutic regimens Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Life expectancy > 3 months No chemotherapy, radiation therapy, immunotherapy, or experimental anticancer therapy within 28 days before beginning study treatment Human immunodeficiency virus (HIV)-positive patients are eligible if: the cluster of differentiation (CD)4 count is > 400, have no acquired immune deficiency syndrome (AIDS)-defining illnesses (other than non-Hodgkin lymphoma [NHL]), and they are not taking combination antiretroviral therapy (cART) at the time of study entry that would interfere with cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP4503A4) No other active infection Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, or abstinence) prior to study entry, for the duration of study participation, and for 4 weeks after dosing with AZD6244 hyd-sulfate ceases; women of child-bearing potential must have a negative pregnancy test prior to entry; should a woman become pregnant or suspect she is pregnant while she or her partner participating in this study, the patient should inform her treating physician immediately; please note that the AZD6244 hyd-sulfate manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD6244 hyd-sulfate Patients may have received prior autologous, but not prior allogeneic stem cell transplant; however, patients who are eligible for potentially curative treatment with bone marrow transplant should not be entered on this investigational trial, unless they refuse the transplant option (or are not eligible for transplantation) Exclusion Criteria: Any prior exposure to mitogen-activated protein kinase kinase (MEK), Ras, or v-raf murine sarcoma 3611 viral oncogene homolog (Raf) inhibitors Patients with any active central nervous system (CNS) involvement by lymphoma are excluded Patients that are taking drugs that alter CYP450 3A4 (or cannot be changed to drugs that do not alter CYP450 3A4) are excluded Cardiac conditions as follows: Uncontrolled hypertension (blood pressure [BP] >= 150/95 despite optimal therapy) Heart failure New York Heart Association (NYHA) class II or above Prior or current cardiomyopathy Baseline left ventricular ejection fraction (LVEF) =< 50% Atrial fibrillation with heart rate > 100 beats per minute (bpm) Unstable ischemic heart disease (myocardial infarction [MI] within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly) Patients are excluded if there is corrected QT (QTc) interval > 450 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) Patients are excluded if they are taking any drugs that may significantly prolong the QTc; these drugs are prohibited during the study; if the patient is taking one or more of these medications, they may enroll if all pertinent medications are stopped with the associated wash out periods Absolute neutrophil count (ANC) < 1.5 x 10^9/L (1500 per mm^3) Platelets < 100 x 10^9/L Hemoglobin (Hgb) < 8.0 g/dL Serum bilirubin >= 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) >= 2.5 x ULN (>= 5 ULN in presence of liver metastases) There should be a minimum of a 1 month wash-out interval from another investigational product to AZD6244 hyd-sulfate dosing start plus recovery from side effects of investigational product There should be a minimum of a 1 month wash-out interval from the end of previous systemic treatment and radiotherapy Patients are excluded if there is a history of a serious medical or psychiatric illness likely to interfere with participation in this clinical study Patients may not have recent history of refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption

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 (selumetinib)<br>Patients receive selumetinib PO BID on days 1-28. Treatment repeats every 28 days for 8 courses in the absence of disease progression or unacceptable toxicity | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Selumetinib<br>* Given PO<br>* Other names: MEK Inhibitor AZD6244;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Complete Response [CR] and Partial Response [PR]) in Patients Treated With Selumetinib | Estimates of the response rate based on best response (CR and PR) with the exact two-sided 95% confidence intervals. Response for this lymphoma clinical study was measured utilizing Non-Hodgkins Lymphoma Response Criteria. These criteria are based upon the criteria from the Revised Response Criteria for Malignant Lymphoma, (Cheson et al.), Journal of Clinical Oncology, 2007, Vol. 25:579-586. | Up to 3 years | 
| Disease Control Rate (Complete Response [CR], Partial Response [PR], and Stable Disease [SD]) in Patients Treated With Selumetinib | Estimates of the disease control rate with the exact two-sided 95% confidence intervals. Response was measured utilizing Non-Hodgkins Lymphoma Response Criteria. These criteria are based upon the criteria from the Revised Response Criteria for Malignant Lymphoma, (Cheson et al.), Journal of Clinical Oncology, 2007, Vol. 25:579-586. Using these criteria, 'disease control rate' encompassed patients who had either a CR, PR, and SD. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | The Kaplan-Meier procedure will be used to characterize the duration of response. Median time-to-event and the corresponding two-sided 95% confidence intervals will be provided. | From the documented beginning of response (CR or PR) to the time of relapse, assessed up to 3 years | 
| Incidence of Adverse Events Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Percentage of patients experiencing any grade 3 or higher adverse event at least possibly attributed to the study drug. (Additional adverse event reporting will appear in the AE outcomes module.) | Up to 3 years | 
| Overall Survival | The Kaplan-Meier procedure will be used to characterize the survivorship function. Median time-to-death and the corresponding two-sided 95% confidence intervals will be provided. | Date of study entry to the date of death, assessed up to 3 years | 
| Progression-free Survival | The Kaplan-Meier procedure will be used to characterize the survivorship function. Median time-to-event and the corresponding two-sided 95% confidence intervals will be provided. | Time from entry onto study until lymphoma progression or death from any cause, assessed up to 3 years | 
| Time to Treatment Failure | The Kaplan-Meier procedure will be used to characterize the survivorship function. Median time-to-event and the corresponding two-sided 95% confidence intervals will be provided. | Time from study entry to treatment failure, defined as lymphoma progression or withdrawal from treatment due to adverse events, assessed up to 3 years. Patients who die without progression while still on therapy will be censored as of the time of death. |