MLN4924 Compared With MLN4924 Plus Chemotherapy for Large B-cell Lymphoma
- 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.
- 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.
- Individuals at least 18 years of age who have large B-cell lymphoma that will be treated with chemotherapy.
- 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.
|Lymphoma, Diffuse Large-Cell B-cell Diffuse, Large B-cell Lymphoma Lymphoma, Diffuse Large-Cell Large-Cell Lymphoma, Diffuse||Drug: MLN4924 Drug: Etoposide Drug: Prednisone Drug: Vincristine Drug: Cyclophosphamide Drug: Doxorubicin Drug: Rituximab Drug: Filgrastim||Phase 1 Phase 2|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|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|
- Assess response of MLN4924 in relapsed/refractory DLBCL [ Time Frame: 4 years ]
- Assess toxicity and safe tolerated dose of MLN4924 and DA-EPOCH-R [ Time Frame: 4 years ]
- Assess ORR (CR/PR) and PFS of MLN4924 and DA-EPOCH-R in relapsed/refractory DLBCL [ Time Frame: 4 years ]
- Analyze molecular subtype (ABC and GCB) [ Time Frame: 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 [ Time Frame: 4 years ]
- Analyze mutations of the ITAM motifs, CARD11 and A20 in DLBCL [ Time Frame: 4 years ]
|Study Start Date:||July 15, 2011|
|Study Completion Date:||January 7, 2014|
|Primary Completion Date:||January 7, 2014 (Final data collection date for primary outcome measure)|
- 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.
- 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
- 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).
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01415765
|Principal Investigator:||Wyndham H Wilson, M.D.||National Cancer Institute (NCI)|