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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01278615
• Collaborator: (none)
• Enrollment: 16
• Locations: 16
• Arm: 1
• Duration (Months): 41
• Patient Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Adult Diffuse Large Cell Lymphoma	Other: Laboratory Biomarker Analysis; Drug: Selumetinib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (selumetinib) 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; Correlative studies; Drug: Selumetinib; Given PO; Other Names: ARRY-142886 AZD6244 MEK Inhibitor AZD6244

Outcome Measures

Primary Outcome Measures

1. Response Rate (Complete Response [CR] and Partial Response [PR]) in Patients Treated With Selumetinib [Up to 3 years]

   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.

2. Disease Control Rate (Complete Response [CR], Partial Response [PR], and Stable Disease [SD]) in Patients Treated With Selumetinib [Up to 3 years]

   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.

Secondary Outcome Measures

1. Duration of Response [From the documented beginning of response (CR or PR) to the time of relapse, assessed up to 3 years]

   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.

2. Incidence of Adverse Events Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [Up to 3 years]

   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.)

3. Overall Survival [Date of study entry to the date of death, assessed up to 3 years]

   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.

4. Progression-free Survival [Time from entry onto study until lymphoma progression or death from any cause, assessed up to 3 years]

   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.

5. Time to Treatment Failure [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.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
3	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
4	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
5	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
6	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
7	Southern Illinois University	Springfield	Illinois	United States	62702
8	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
9	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
10	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
11	Tufts Medical Center	Boston	Massachusetts	United States	02111
12	University of Massachusetts Memorial Health Care	Worcester	Massachusetts	United States	01605
13	University of Michigan	Ann Arbor	Michigan	United States	48109
14	Saint John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
15	Weill Medical College of Cornell University	New York	New York	United States	10065
16	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Leo Gordon, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01278615
• Other Study ID Numbers: NCI-2011-02558; NCI-2011-02558; NU-10H03; CDR0000690641; 12-0110; 8611; N01CM00071; N01CM62201; P30CA014599
• First Posted: Jan 19, 2011
• Last Update Posted: Feb 3, 2016
• Last Verified: Jul 1, 2014

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Large B-Cell, Diffuse

Study Results

Participant Flow

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Period Title: Overall Study
STARTED	16
COMPLETED	14
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Overall Participants	16
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	70
Sex: Female, Male (Count of Participants)
Female	7 43.8%
Male	9 56.3%

Outcome Measures

1. Primary Outcome

Title	Response Rate (Complete Response [CR] and Partial Response [PR]) in Patients Treated With Selumetinib
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	14
Number (95% Confidence Interval) [percentage of response]	0

2. Secondary Outcome

Title	Duration of Response
Description	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.
Time Frame	From the documented beginning of response (CR or PR) to the time of relapse, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to no response.

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	0

3. Secondary Outcome

Title	Incidence of Adverse Events Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Description	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.)
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	16
Number (95% Confidence Interval) [percentage of participants]	37.5 234.4%

4. Secondary Outcome

Title	Overall Survival
Description	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.
Time Frame	Date of study entry to the date of death, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	14
Median (95% Confidence Interval) [days]	129

5. Secondary Outcome

Title	Progression-free Survival
Description	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 Frame	Time from entry onto study until lymphoma progression or death from any cause, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	14
Median (95% Confidence Interval) [days]	34

6. Secondary Outcome

Title	Time to Treatment Failure
Description	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 Frame	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	14
Mean (95% Confidence Interval) [days]	34

7. Primary Outcome

Title	Disease Control Rate (Complete Response [CR], Partial Response [PR], and Stable Disease [SD]) in Patients Treated With Selumetinib
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
Measure Participants	14
Number (95% Confidence Interval) [percentage of disease control]	14.3

Adverse Events

Arm/Group Title	Treatment (Selumetinib)
Arm/Group Description	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 Laboratory Biomarker Analysis: Correlative studies Selumetinib: Given PO
All Cause Mortality
	Treatment (Selumetinib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Selumetinib)
	Affected / at Risk (%)	# Events
Total	7/16 (43.8%)
Blood and lymphatic system disorders
Anemia	1/16 (6.3%)
Cardiac disorders
Atrioventricular block complete	1/16 (6.3%)
Left ventricular systolic dysfunction	1/16 (6.3%)
Gastrointestinal disorders
Colonic obstruction	1/16 (6.3%)
Gastrointestinal disorders - Other, specify	1/16 (6.3%)
Pancreatic necrosis	1/16 (6.3%)
Small intestinal obstruction	1/16 (6.3%)
General disorders
Death NOS	1/16 (6.3%)
Hypothermia	1/16 (6.3%)
Pain	1/16 (6.3%)
Infections and infestations
Skin infection	1/16 (6.3%)
Injury, poisoning and procedural complications
Fall	1/16 (6.3%)
Injury to kidney	2/16 (12.5%)
Investigations
Lymphocyte count decreased	1/16 (6.3%)
Neutrophil count decreased	2/16 (12.5%)
White blood cell decreased	1/16 (6.3%)
Metabolism and nutrition disorders
Hypoalbuminemia	1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/16 (6.3%)
Muscle weakness lower limb	1/16 (6.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/16 (6.3%)
Psychiatric disorders
Confusion	1/16 (6.3%)
Renal and urinary disorders
Urinary retention	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/16 (12.5%)
Hypoxia	1/16 (6.3%)
Respiratory failure	1/16 (6.3%)
Vascular disorders
Hypotension	1/16 (6.3%)
Thromboembolic event	2/16 (12.5%)
Other (Not Including Serious) Adverse Events
	Treatment (Selumetinib)
	Affected / at Risk (%)	# Events
Total	11/16 (68.8%)
Blood and lymphatic system disorders
Anemia	7/16 (43.8%)
Eye disorders
Blurred vision	1/16 (6.3%)
Gastrointestinal disorders
Constipation	1/16 (6.3%)
Diarrhea	5/16 (31.3%)
Dry mouth	1/16 (6.3%)
Dyspepsia	1/16 (6.3%)
Dysphagia	1/16 (6.3%)
Gastrointestinal disorders - Other, specify	1/16 (6.3%)
Nausea	2/16 (12.5%)
Vomiting	1/16 (6.3%)
General disorders
Edema face	2/16 (12.5%)
Edema limbs	3/16 (18.8%)
Fatigue	7/16 (43.8%)
Fever	2/16 (12.5%)
Hypothermia	1/16 (6.3%)
Infections and infestations
Catheter related infection	1/16 (6.3%)
Investigations
Alanine aminotransferase increased	3/16 (18.8%)
Alkaline phosphatase increased	1/16 (6.3%)
Aspartate aminotransferase increased	7/16 (43.8%)
Blood bilirubin increased	1/16 (6.3%)
Creatinine increased	4/16 (25%)
Electrocardiogram QT corrected interval prolonged	1/16 (6.3%)
Lymphocyte count decreased	3/16 (18.8%)
Neutrophil count decreased	2/16 (12.5%)
Platelet count decreased	4/16 (25%)
Weight gain	1/16 (6.3%)
White blood cell decreased	3/16 (18.8%)
Metabolism and nutrition disorders
Anorexia	4/16 (25%)
Hypercalcemia	2/16 (12.5%)
Hyperglycemia	6/16 (37.5%)
Hypernatremia	1/16 (6.3%)
Hypoalbuminemia	4/16 (25%)
Hypocalcemia	4/16 (25%)
Hypokalemia	1/16 (6.3%)
Hypomagnesemia	3/16 (18.8%)
Metabolism and nutrition disorders Anorexia	4/16 (25%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/16 (6.3%)
Nervous system disorders
Headache	1/16 (6.3%)
Oral dysesthesia	1/16 (6.3%)
Paresthesia	1/16 (6.3%)
Peripheral sensory neuropathy	1/16 (6.3%)
Tremor	1/16 (6.3%)
Psychiatric disorders
Confusion	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/16 (6.3%)
Dyspnea	3/16 (18.8%)
Skin and subcutaneous tissue disorders
Dry skin	3/16 (18.8%)
Pruritus	1/16 (6.3%)
Rash acneiform	1/16 (6.3%)
Skin and subcutaneous tissue disorders - Other, specify	1/16 (6.3%)
Vascular disorders
Hypotension	1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.