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Lymphoma, Diffuse Large-Cell B-cellPhase 1/2NCT01415765

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

A Phase 1/2 study testing MLN4924, Etoposide and Prednisone in people with Lymphoma, Diffuse Large-Cell B-cell and Diffuse, Large B-cell Lymphoma, run by National Cancer Institute (NCI).

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 99 years
What is being tested?
MLN4924, Etoposide and Prednisone
How many people
0 participants
Where
No sites listed yet
Study dates
15 Jul 2011to 7 Jan 2014
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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.
  • -Both men and women and members of all races and ethnic groups are eligible for this trial.

Who cannot join

  • 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
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  • 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.

About this study

Official title: Phase I/II Study of MLN4924 Alone Followed by Dose-Adjusted EPOCH-Rituximab + MLN4924 With Gene Expression Profiling and Mutational Analysis in Relapsed/Refractory de Novo Diffuse Large B-Cell Lymphoma

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.
Read more

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.
Read the detailed description

Background:

  • Diffuse large B-cell lymphomas (DLBCL) have been molecularly sub-classified into germinal center like B-cell (GCB) and activated B-cell like (ABC) DLBCL.
  • Clinically, the ABC subtype has a significantly higher rate of drug resistance and lower survival. The ABC subtype has constitutive activation of the NF-KappaB pathway which may account for the drug resistance.
  • The ability of NF-KappaB to inhibit responses to cancer therapeutic agents may also contribute to the refractory clinical behavior of ABC subtype, and inhibition of NF-KappaB can synergize with chemotherapy to kill tumor cells.
  • Because a phase II randomized design is not clinically or technically practical at this early stage to address the scientific endpoints, we have designed a novel endpoint based on relative efficacy of DA-EPOCH-R + MLN 4924 (DA-EPOCH-RN) in ABC and GCB DLBCL. Based on our study that shows that survival of relapsed ABC and GCB DLBCL are comparable and poor following initial R-CHOP, we hypothesize that significantly improved survival of ABC compared to GCB DLBCL after DA-EPOCH-RN is strongly indicative of preferential activity of MLN4924 in ABC DLBCL.

Objectives:

  • Assess response of MLN4924 in relapsed/refractory DLBCL
  • Assess toxicity and safe tolerated dose of MLN4924 and DA-EPOCH-R
  • Assess difference in response (CR/PR) and OS in ABC and GCB DLBCL

Eligibility:

  • Relapsed/refractory de novo DLBCL greater than or equal to 18 years.
  • No PMBL DLBCL
  • No patients with active CNS lymphoma.
  • No pregnant or breast-feeding women.
  • Adequate organ function (as defined in protocol).

Study Design:

  • This is a single center with a sequential treatment design. The study is divided into two parts (A and B). Clinical end points are to assess the activity of MLN4924 alone (Part A) and in combination with DA-EPOCH-R (Part B), and to assess the toxicity and MTD of DA-EPOCH-RN.
  • In Part A, MLN4924 will be given alone for 6 cycles.
  • In Part B, MLN4924 will be initially escalated to determine the maximum tolerated dose (MTD) in combination with DA-EPOCH-R at dose levels (to be determined) and schedule every 21 days. Responding or stable patients may receive up to 6 cycles of DAEPOCH-RN.
  • Patients will be restaged every 2 cycles during treatment, and every 3, 4 and 6 months during years one, two and three respectively, thereafter. Standard response criteria will be applied.
  • A total of 56 patients will be enrolled depending on the relative differences in response observed between the ABC and GCB subtypes to MLN4924.
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
Medical subject headings
Lymphoma, Large B-Cell, Diffuse, Dendritic Cell Sarcoma, Interdigitating, Acromesomelic dysplasia, Maroteaux type, Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MLN4924Drug

    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

  • EtoposideDrug

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

  • PrednisoneDrug

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

  • VincristineDrug

    CIV on days 1-4 of every 21 day cycle

  • CyclophosphamideDrug

    IV on day 5 of each 21 day cycle

  • DoxorubicinDrug

    CIV on days 1-4 of each 21 day cycle

  • RituximabDrug

    IV on day 1 of each 21 day cycle

  • FilgrastimDrug

    Subcutaneously beginning Day 6 of each 21 day cycle

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Assess response of MLN4924 in relapsed/refractory DLBCL

    Measured: 4 years

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

    Measured: 4 years

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

    Measured: 4 years

Secondary outcomes (3)

  1. Analyze molecular subtype (ABC and GCB)

    Measured: 4 years

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

    Measured: 4 years

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

    Measured: 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Aug 2011 (estimated)
  2. Study start15 Jul 2011
  3. Primary completion7 Jan 2014
  4. Study completion7 Jan 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01415765
Sponsor's protocol ID
110216
Other IDs
11-C-0216
Status last verified
7 Jan 2014
First submitted
11 Aug 2011
Last updated
17 Dec 2019
Results posted
No

Publications

  • 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.

    PubMed 11807147

  • 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.

    PubMed 12075054

  • 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.

    PubMed 20054396

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing MLN4924, Etoposide and Prednisone in people with Lymphoma, Diffuse Large-Cell B-cell and Diffuse, Large B-cell Lymphoma, run by National Cancer Institute (NCI).

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 17 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Assess response of MLN4924 in relapsed/refractory DLBCL (time frame: 4 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01415765, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2019.

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