MLN4924 Compared With MLN4924 Plus Chemotherapy for Large B-cell Lymphoma

NCT01415765 | Withdrawn Phase 1

• 2 other identifiers: 11021611-C-0216
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Background: \- MLN4924 is an experimental cancer drug. It may help kill lymphoma cells and make them more sensitive to chemotherapy. EPOCH R is a combination chemotherapy drug. It has been effective in treating some cases of large B-cell lymphoma. This research will look at two things. The first is the effect of MLN4924 on its own in treating large B-cell lymphoma. The second is the safe dose and effect of MLN4924 and EPOCH-R in combination when treating large B-cell lymphoma. Objectives:

• To study how MLN4924 affects large B-cell lymphoma tumors.
• To compare the effects of MLN 4924 alone and MLN4924 plus standard EPOCH-R chemotherapy. Eligibility: \- Individuals at least 18 years of age who have large B-cell lymphoma that will be treated with chemotherapy. Design:
• Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, tumor samples, and imaging studies.
• Participants will receive MLN4924 for a maximum of six 21-day cycles of treatment. Each cycle involves a dose of MLN4924 twice a week for 2 weeks, followed by a 1-week rest period. Participants will be monitored with frequent blood tests and imaging studies.
• Participants who do not benefit from MLN4924 alone will have MLN4924 along with EPOCH-R chemotherapy for up to six cycles of treatment.

Conditions

Lymphoma, Diffuse Large-Cell B-cell; Diffuse, Large B-cell Lymphoma; Lymphoma, Diffuse Large-Cell; Large-Cell Lymphoma, Diffuse

Keywords

Germinal Center Like B-Cell (GCB) DLBCL; Activated B-Cell Like (ABC) DLBCL; NF-KappaB Pathway; Drug Resistance; Nedd-8 Activating Enzyme Inhibitor; Diffuse Large B-Cell Lymphoma; Lymphoma

Outcome Measures

Primary Outcomes (3)

• Assess response of MLN4924 in relapsed/refractory DLBCL

  4 years

• Assess toxicity and safe tolerated dose of MLN4924 and DA-EPOCH-R

  4 years

• Assess ORR (CR/PR) and PFS of MLN4924 and DA-EPOCH-R in relapsed/refractory DLBCL

  4 years

Secondary Outcomes (3)

• Analyze molecular subtype (ABC and GCB)

  4 years

• Assess difference in response between ABC and GCB subtypes of relapsed/refractory DLBCL/MLN 4924 alone and w/MLN4924 and DA-EPOCH-R

  4 years

• Analyze mutations of the ITAM motifs, CARD11 and A20 in DLBCL

  4 years

Interventions

MLN4924 DRUG

Part A: 150mg/m2 IV (in the vein) on days 1,4,7,11 of each 21 day cycle Part B: variable dose levels IV on days 1,5 each 21 day cycle

Etoposide DRUG

CIV(continuous intravenous infusion) on days 1-4 of every 21 day cycle

Prednisone DRUG

PO (by mouth) twice daily on days 1-5 of every 21 day cycle

Vincristine DRUG

CIV on days 1-4 of every 21 day cycle

Cyclophosphamide DRUG

IV on day 5 of each 21 day cycle

Doxorubicin DRUG

CIV on days 1-4 of each 21 day cycle

Rituximab DRUG

IV on day 1 of each 21 day cycle

Filgrastim DRUG

Subcutaneously beginning Day 6 of each 21 day cycle

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Biopsy-proven relapsed or refractory Large B-cell lymphoma.
• Confirmed pathological diagnosis by the Laboratory of Pathology, NCI.
• Age greater than or equal to 18 years.
• ECOG performance status 0-2.
• Adequate renal function or creatinine clearance \> 50 ml/min/1.73m(2) unless lymphoma related.
• Adequate hepatic and hematological function, as defined by:
• Bilirubin must be less than or equal to ULN, except less than or equal to 2 mg/dl (total) in patients with Gilbert s syndrome (as defined by \> 80% unconjugated hyperbilirubinemia);
• ALT and AST must be less than or equal to Grade 1.
• ANC \> 1000 and platelets \> 75,000 unless lymphoma related.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be less than or equal to 1.5 times the upper limit of the normal range (ULN); except if, in the opinion of the Investigator, the aPTT is elevated because of a positive Lupus Anticoagulant.
• Left ventricular ejection fraction (LVEF) \> 45% as assessed by echocardiogram or MUGA
• 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.
• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
• Male patients must use an appropriate method of barrier contraception (eg, condoms), inform any sexual partners that they must also use a reliable method of contraception (ie, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence), and refrain from blood and semen donation during the study and for 4 months after the last dose of study treatment.

You may not qualify if:

• Female subject pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum Beta-human chorionic gonadotropin (Beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for women without child-bearing potential.
• History of a prior invasive malignancy in past 5 year.
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Patient has greater than or equal to Grade 2 peripheral neuropathy within 14 days before enrollment
• Serious concomitant medical illnesses that would jeopardize the patient s ability to receive the regimen with reasonable safety.
• HIV positive patients
• Systemic cytotoxic therapy within 3 weeks of treatment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• CYP3A inducers within 14 days before the first dose of MLN4924. Moderate and strong CYP3A inhibitors and CYP3A inducers are not permitted during the study. Patients must have no prior history of chronic amiodarone use in the 6 months prior to the first dose of MLN4924.
• Patients currently taking statins who are unwilling or unable to refrain from using statins on the day prior to, day of, and day after each MLN4924 administration
• Diarrhea \> Grade 1, based on the NCI CTCAE categorization despite use of optimal antidiarrheals
• Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
• Clinically uncontrolled central nervous system (CNS) involvement (Patients who have a history of CNS involvement, but no evidence of active CNS disease are not excluded.)
• Ongoing anticoagulant therapy (eg, aspirin, Coumadin, heparin) that cannot be held to permit bone marrow sampling. Patients who require anticoagulant therapy, and can not be maintained on low molecular weight heparin should not be considered for this study.
• Both men and women and members of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Related Publications (3)

• Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. doi: 10.1056/NEJMoa011795.

  PMID: 11807147 BACKGROUND

• Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jun 20;346(25):1937-47. doi: 10.1056/NEJMoa012914.

  PMID: 12075054 BACKGROUND

• Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010 Jan 7;463(7277):88-92. doi: 10.1038/nature08638.

  PMID: 20054396 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Dendritic Cell Sarcoma, Interdigitating; Acromesomelic dysplasia, Maroteaux type; Lymphoma

Interventions

pevonedistat; Etoposide; Prednisone; Vincristine; Cyclophosphamide; Doxorubicin; Rituximab; Filgrastim

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Histiocytic Disorders, Malignant; Histiocytosis

Intervention Hierarchy (Ancestors)

Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors

Study Officials

• Wyndham H Wilson, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2011
• First Posted: August 12, 2011
• Study Start: July 15, 2011
• Primary Completion: January 7, 2014
• Study Completion: January 7, 2014
• Last Updated: December 17, 2019

Record last verified: 2014-01-07