FDA Approves Bortezomib for Patients with Previously Untreated Mantle Cell Lymphoma

Late last week the FDA announced the approval of bortezomib (VELCADE) for injection for patients with previously untreated mantle cell lymphoma (MCL). This approval was based on results from a head to head Phase III clinical trial. The study found that,

“…previously untreated patients receiving a VELCADE-containing combination (VcR-CAP) experienced a 59 percent relative improvement in the study’s primary endpoint of progression-free survival (PFS) compared to those who were administered the standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) regimen (median 25 vs. 14 months; Hazard Ratio [HR] 0.63; P<0.001) at a median follow up of 40 months. An Independent Review Committee (IRC) assessed the primary efficacy endpoint of PFS. The complete response (CR) rate for patients receiving VcR-CAP vs. R-CHOP was 44 percent vs. 34 percent.”

The full press release can be found here.

The full listing of MCL trials at WCMC is available on the clinical trials website. Look to this space for further news concerning  bortezomib trials for MCL patients at WCMC.

ASCO 2014: Selected Abstracts of Interest

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By Peter Martin, MD

The 50th annual meeting of the American Society of Clinical Oncology took place from May 30-June 3 in Chicago. Over 100 abstracts containing exciting new data were presented. Below is a brief summary of a few abstracts that I found interesting.

 

KPT-330 (selinexor) appears to be safe and active in patients with heavily pretreated non-Hodgkin lymphoma

Selective inhibitors of nuclear export (SINE) are a new class of cancer drugs that function by suppressing export of proteins and RNA from the cell nucleus into the cell cytoplasm. The accumulation of these molecules in the nucleus results in a multitude of changes that ultimately promote the death of cancer cells, while largely sparing normal cells. Selinexor is a first in class, oral SINE that has been under investigation in multiple hematologic malignancies and solid tumors. Dr. Martin Gutierrez of the John Theurer Cancer Center, presented results from a phase I study of selinexor in patients with heavily pretreated non-Hodgkin lymphoma. This study’s primary objective was to identify an appropriate dose of selinexor for future studies, to evaluate possible side effects, and to evaluate the activity of the drug. At the time of the abstract, 32 patients had received KPT-330 at multiple dose levels over a 28-day cycle. Selinexor was generally well tolerated (side-effects included nausea, loss of appetite, and fatigue) and could be administered over prolonged periods. Importantly, selinexor demonstrated signs of activity in aggressive B-cell and T-cell lymphomas that had otherwise responded poorly to prior therapies. This study is ongoing and is open at WCMC and future trials are planned in DLBCL and patients with CLL and Richter’s transformation.

Bortezomib plus rituximab is well tolerated therapeutic regime that approximates prior long term survival rates for indolent non-Hodgkin lymphoma patients with a high tumor burden

Dr. Andrew M. Evens of Tufts Medical Center, presented results from a phase II trial of bortezomib plus rituximab as a first-line therapy for patients with high tumor burden indolent non-Hodgkin lymphoma. A total of 42 patients with histologies that included follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s Macroglobulinemia were enrolled. Therapy was well tolerated with few significant side effects, and an overall response rate of 70% (including a complete remission rate of 40%) was observed. Forty-four percent of patients continued to benefit at 4 years, a rate comparable to prior series with rituximab plus cytotoxic chemotherapy. These results suggest that proteasome inhibitors, like bortezomib, have clear activity in follicular lymphoma, a fact that has likely been under appreciated in the past. Nonetheless, whether bortezomib offers any clear benefit over standard chemotherapy remains unclear. Novel proteasome inhibitors that appear to be better tolerated than bortezomib are under evaluation, including this study with oral ixazomib at WCMC.

Bortezomib appears to improve outcomes in patients receiving front-line treatment for mantle cell lymphoma

Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) remains one of the most common therapies for patients with newly diagnosed mantle cell lymphoma (MCL). In 2006, bortezomib was approved by the FDA for treatment of patients with relapsed MCL. We previously demonstrated that bortezomib could be added to R-CHOP with promising effects . Based on these and other data, investigators in Europe initiated a phase III trial to compare R-CHOP to rituximab, cyclophosphamide, doxorubicin, bortezomib, prednisone (VR-CAP) in patients with previously untreated MCL not eligible for more aggressive therapy. Dr. Franco Cavalli from the Oncology Institute of Southern Switzerland presented the results from this study. A total of 487 patients with treatment naïve, stage II-IV MCL were randomized to receive six to eight cycles R-CHOP or VR-CAP. Patients randomized to treatment with bortezomib achieved significantly longer remission duration with no significant change in side effects. This concept is currently under evaluation in North America in the E1411 trial open at WCMC.

ABT-199 monotherapy shows promise in range of relapsed or refractory non-Hodgkin lymphoma subtypes

ABT-199 is a novel, orally bioavailable, small molecule Bcl-2 inhibitor that has shown promise in the treatment of non-Hodgkin lymphoma (NHL) patients. Dr. Matthew Davids of the Dana-Farber Cancer Institute presented results from a phase I study evaluating the safety and pharmacokinetics profile of ABT-199 in patients with relapsed/refractory NHL. ABT-199 displayed anti-tumor activity across a range of NHL subtypes, most notable in MCL and WM, and at higher doses in DLBCL and FL. Dose escalation is continuing in the phase I study, while subsequent phase II studies are already ongoing in selected histologies.

New Clinical Trial: Rituximab,Bendamustine Hydrochloride & Bortezomib Followed by Rituximab & Lenalidomide in Older Patients with Untreated Mantle Cell Lymphoma

E1411: Intergroup Randomized Phase II Four Arm Study In Patients > 60 With Previously Untreated Mantle Cell Lymphoma Of Therapy With: Arm A = Rituximab+ Bendamustine Followed By Rituximab Consolidation (RB → R); Arm B = Rituximab + Bendamustine + Bortezomib Followed By Rituximab Consolidation (RBV→ R), Arm C = Rituximab + Bendamustine Followed By Lenalidomide + Rituximab Consolidation (RB → LR) or Arm D = Rituximab + Bendamustine + Bortezomib Followed By Lenalidomide + Rituximab Consolidation (RBV → LR)

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men women age 60 and older with mantle cell lymphoma (MCL) that has not been previously treated. The study sponsor is the Eastern Cooperative Oncology Group. The principal investigator at Weill Cornell is Dr. Peter Martin. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 60 and older
  • Mantle cell lymphoma (MCL)
  • No prior therapy for MCL
  • Detailed eligibility reviewed when you contact the study team

Study Details

The study has two steps of treatment:

Step 1: The purpose of Step 1 is to determine the effectiveness of the addition of bortezomib (also called Velcade) to rituximab plus bendamustine, compared to rituximab plus bendamustine alone.

Step 2: The purpose of Step 2 is to determine the effectiveness of continuing treatment after Step 1 with lenalidomide plus rituximab, compared to continuing with rituximab alone.

Study participants will be randomly assigned to one of four treatment regimens:

  • Group 1: Step 1 rituximab plus bendamustine, followed by Step 2 rituximab for up to 2 years
  • Group 2: Step 1 bortezomib plus rituximab and bendamustine, followed by Step 2 rituximab for up to 2 years
  • Group 3: Step 1 rituximab plus bendamustine, followed by Step 2 lenalidomide plus rituximab for up to 2 years
  • Group 4: Step 1 bortezomib plus rituximab and bendamustine, followed by Step 2 lenalidomide plus rituximab for up to 2 years

Although each of the drugs used in the study are FDA-approved to treat blood cancers, the combinations used in this study have not been FDA-approved and are considered experimental.

Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as bendamustine, also work in different ways to kill cancer cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab together with bendamustine and bortezomib is more effective than rituximab and bendamustine, followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.

Treatment Plan

Participants will be asked to take 6 cycles (6 months) of chemotherapy in Step 1. Participants in Groups 1 and 2 will take rituximab every 8 weeks for 2 years. Participants in Groups 3 and 4 will take 24 cycles (2 years) of lenalidomide plus rituximab.