Clinical trial NCT01278615: Selumetinib in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Recurrent Adult Diffuse Large Cell Lymphoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2011-01-19
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Response Rate (Complete Response [CR] and Partial Response [PR]) in Patients Treated With Selumetinib
timeFrame: Up to 3 years
measure: Disease Control Rate (Complete Response [CR], Partial Response [PR], and Stable Disease [SD]) in Patients Treated With Selumetinib
timeFrame: Up to 3 years
Secondary outcomes:
measure: Duration of Response
timeFrame: From the documented beginning of response (CR or PR) to the time of relapse, assessed up to 3 years
measure: Incidence of Adverse Events Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
timeFrame: Up to 3 years
measure: Overall Survival
timeFrame: Date of study entry to the date of death, assessed up to 3 years
measure: Progression-free Survival
timeFrame: Time from entry onto study until lymphoma progression or death from any cause, assessed up to 3 years
measure: Time to Treatment Failure
timeFrame: 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.
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Health Care
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Saint John's Mercy Medical Center
state: Missouri
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
Study officials:
affiliation: Northwestern University
name: Leo Gordon
role: PRINCIPAL_INVESTIGATOR
References: