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

Recurrent Adult Diffuse Large Cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01278615
• Other study ID #: NCI-2011-02558
• Secondary ID: NCI-2011-02558NU
• Status: Terminated
• Phase: Phase 2
• First received: January 15, 2011
• Last updated: January 4, 2016
• Start date: December 2010
• Est. completion date: May 2014

Study information

• Verified date: July 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: May 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Recurrent Adult Diffuse Large Cell Lymphoma

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Selumetinib
Given PO

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Tufts Medical Center	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	M D Anderson Cancer Center	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Weill Medical College of Cornell University	New York	New York
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Saint John's Mercy Medical Center	Saint Louis	Missouri
United States	Southern Illinois University	Springfield	Illinois
United States	University of Massachusetts Memorial Health Care	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	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.	No