FDA Approves First-Ever Targeted Marginal Zone Lymphoma Treatment

On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).

MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.

Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.

The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.

The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.

Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.

At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.


Lymphoma Program to Collaborate with Mayo Clinic in Nationwide, Multi-Instutional Grant on Survivorship in Non-Hodgkin Lymphoma

Last week the Mayo Clinic received an $11 million grant from the National Cancer Institute (NCI) to support research addressing the current and long-term unmet healthcare needs of patients with non-Hodgkin lymphoma. This NCI funded, multi-institutional project is known as the “Lymphoma Epidemiology of Outcomes Cohort Study”. At the Weill Cornell site, Dr. Peter Martin will serve as the Principal Investigator, and Dr. John Leonard will be a participating investigator.

As Principal Investigator at the Weill Cornell site, Dr. Martin, who is the Charles, Lillian, and Betty Neuwirth Clinical Scholar in Oncology, will be overseeing the recruitment of participants and reporting of outcomes. “The LEO Collaboration will be the largest study of it’s kind anywhere in the world and will undoubtedly lead to important, impactful discoveries. We look forward to enrolling participants at Weill Cornell as we seek avenues to increase long-term prognosis and survivorship for those living with NHL,” says Dr. Martin.

Working with participating investigators, Dr. John Leonard and Dr. Giorgio Inghirami (Pathology, Weill Cornell Medical College). “This multi-institutional collaborative study group, supported by the NCI, has a highly productive track record. We are very happy to be a part of it,” says Dr. Leonard.

Look to this space for further information about this study, and other Hodgkin lymphoma related trials. A full listing of our non-Hodgkin lymphoma trials can be found here.


New Clinical Trial: Efficacy of ACP-196 in Patients with Relapsed or Refractory de Novo Activated B-cell (ABC) Subtype of Diffuse Large B-Cell Lymphoma (DLBCL)

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with diffuse large B-cell lymphoma. The study sponsor is Acerta Pharma BV, and the principal investigator at Weill Cornell is Dr. Jia Ruan. 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 greater than or equal to 18 years of age
  • Confirmed de novo ABC DLBCL, and subjects must have archival tissue available for central pathology review
  • Recurrence of disease after a complete response or progressive disease at the completion of the treatment regimen preceding entry to the study
  • Detailed eligibility will be reviewed when you contact the study team

Study Details

The purpose of this study is to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of ACP-196 in treating subjects relapsed or refractory de novo ABC diffuse large B-cell lymphoma (DLBCL).

Clinical Studies have shown that targeting the B-cell receptor (BCR) signaling pathway by inhibiting Bruton tyrosine kinase (Btk) produces significant clinical benefit in patients with non-Hodgkin lymphoma. Acerta Pharma BV has developed a novel second generation Btk inhibitor, ACP-196, that achieves significant oral bioavailability and potency.

Treatment Plans

This study is a multi-center, open-label, randomized, parallel group study. No placebo will be administered during this study. Twenty subjects, 10 refractory and 10 relapsed, will be enrolled and will take 100 mg of ACP-196 twice per day.

Treatment will occur for 5 cycles with a 30 day follow-up period following the last dose. Treatment with ACP-196 may be continued for more than 28 days until disease progression or an unacceptable drug-related toxicity occurs. Subjects with disease progression will be removed from the study. All subjects who discontinue study drug will have a safety follow-up visit 30 (±7) days after the last dose of study drug unless they have started another cancer therapy within that time frame.

 


FDA Announces Approval for Beleodaq in Treatment of Peripheral T-cell Lymphoma

Earlier today the US FDA announced the approval of Beleodaq (belinostat) for the treatment of non-Hodgkin lymphoma patients with relapsed or refractory peripheral T-cell lymphoma.  Beleodaq has previously received the FDA orphan product designation due to its utility in treating this rare disease. Beleodaq functions by inhibiting the enzymes that contribute to T-cell growth. During clinical trials:

“The safety and effectiveness of Beleodaq was evaluated in a clinical study involving 129 participants with relapsed or refractory PTCL. All participants were treated with Beleodaq until their disease progressed or side effects became unacceptable. Results showed 25.8 percent of participants had their cancer disappear (complete response) or shrink (partial response) after treatment.”

“The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever (pyrexia), low red blood cells (anemia), and vomiting.”

Look to this blog and our clinical trials page for further developments regarding the use of Beleodaq in the treatment of peripheral T-cell lymphoma.


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.


ASCO 2013: Ibrutinib Combined with R-CHOP Shows Positive Results in Patients with CD20-positive, B-cell non-Hodgkin Lymphoma

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By Jia Ruan, MD, PhD

Ibrutinib is a first-in-class oral Bruton’s tyrosine kinase inhibitor that has shown promise in treating a variety of relapsed and refractory B-cell malignancies. At the 2013 meeting of the American Society of Clinical Oncology in Chicago, Dr. Anas Younes of the MD Anderson Cancer Center presented results from a recent phase 1b trial combining ibrutinib with standard doses of R-CHOP in patients with previously untreated CD20 positive NHL (NCT01569750).

A total of seventeen patients were enrolled, including those with subtypes of diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma. The recommended phase 2 dose of ibrutinib was established at 560 mg daily in combination with standard doses of R-CHOP given every 21 days.  The overall response rate of treatment was 100% with 7 complete and 3 partial responses in 10 evaluable patients. The most common adverse events were neutropenia (77%), thrombocytopenia (65%), vomiting (59%), anemia (53%), nausea (47%), fatigue (35%), headaches (29%), constipation (24%), diarrhea (24%), and dizziness (24%).

The study concluded that this novel combination of Ibrutinib and R-CHOP has an acceptable and expected safety profile.  An expansion cohort 560 mg ibrutinib is being opened to further explore the safety and efficacy of IR-CHOP in patients with newly diagnosed diffuse large B-cell lymphomas.

For a full listing of all current clinical trials underway in the Lymphoma Program, please click here.


ASCO 2013: Post-therapy Surveillance Imaging has Limited Use in Detection of Relapse of Non-Hodgkin Lymphoma

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By Peter Martin, MD

Despite the frequent use of routine post-therapy imaging as a means of early detection of lymphoma relapse, there is limited evidence that regular scanning improves patient outcomes. Two groups reported on their experience with surveillance imaging at the recent annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Quoc Van Truong of the West Virginia School of Medicine retrospectively evaluated 77 patients with non-Hodgkin lymphoma that had relapsed after achieving a complete response with initial treatment. Despite the frequent use of routine imaging, nearly 80% of relapses were detected by patient-reported symptoms and not surveillance imaging. Overall, there was no survival difference between the groups of patients whose relapse had been detected by scans versus those reporting additional symptoms. Additionally, surveillance imaging led to 2 false positive scans resulting in unnecessary invasive procedures.

Dr. Carrie A. Thomas of the Mayo Clinic reported on an analysis of 644 patients with DLBCL seen at the Mayo Clinic or University of Iowa between 2002 and 2009. A total of 537 patients entered post-treatment observation, and 109 of these patients relapsed while 41 died from other causes. At the time of relapse, 68% were symptomatic, 42% had an abnormal physical exam, 55% elevated LDH, and 87% had more than one of these features. Of the 38 patients whose relapse was detected during a planned visit, 26 displayed clinical features of relapse, while the relapse of the other 12 patients was detected by planned surveillance scan. Of these 12 relapses exclusively detected by the planned surveillance scan; 4 presented a low-grade or other subtype and 8 had DLBCL (4 of whom had equivocal/positive scans at the end of treatment). The authors concluded that post-therapy surveillance scans have little value in detecting DLBCL relapse.

These studies add to the growing body of literature suggesting that lymphoma patients that achieve a complete remission from first-line therapy may not benefit from routine imaging. We recommend that patients discuss plans for post-treatment surveillance with their physician.