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
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Assess response of MLN4924 in relapsed/refractory DLBCL
Wyndham H Wilson, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|