Brentuximab vedotin

Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study.

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Summary

Background

Roughly 70–80% of patients with advanced stage Hodgkin’s lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin’s lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin’s lymphoma.

Methods

We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin’s lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m2 doxorubicin, 10 units/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.

Findings

Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vstwo [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).

Interpretation

Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin’s lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin’s lymphoma.

Source:http://www.thelancet.com

Brentuximab vedotin doubles PFS in unfavourable-risk Hodgkin’s lymphoma after ASCT

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Brentuximab vedotin, the first new drug for Hodgkin’s lymphoma in more than 30 years, doubles progression-free survival (PFS) in patients with unfavourable-risk disease when used as early consolidation therapy after autologous stem cell transplantation (ASCT), the phase III AETHERA study has shown.

In patients randomized to receive brentuximab vedotin (1.8 mg/kg intravenously every 3 weeks for 16 cycles) starting 30 to 45 days after ASCT, median PFS by independent review was 42.9 months compared with 24.1 months in patients receiving placebo (hazard ratio [HR], 0.57; p=0.0013). [Lancet 2015, doi: http:dx.doi.org/10.1016/S0140-6736(15)60165-9]

“At 2 years, 63 percent of patients in the brentuximab vedotin group were progression free, compared with 51 percent in the placebo group,” said lead study author Professor Craig Moskowitz of the Memorial Sloan Kettering Cancer Centre, New York, NY, US.

“Nearly all patients who are progression free at 2 years are likely to be cured, since relapse 2 years after a transplant is unlikely,” he explained.

A consistent PFS benefit of brentuximab vedotin was observed across different subgroups of patients.

“The study met its primary endpoint. No medication available today has had such dramatic results in patients with hard-to-treat Hodgkin’s lymphoma,” said Moskowitz.

Brentuximab vedotin is an antibody-drug conjugate comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. The therapy is approved for relapsed or refractory CD30+ Hodgkin’s lymphoma in 50 countries, including Hong Kong, Japan and Singapore.

 

The antibody-drug conjugate was generally well tolerated in the AETHERA study of 329 patients with unfavourable-risk, relapsed or primary refractory classic Hodgkin’s lymphoma who had been treated with high-dose chemotherapy and ASCT. The most common side effects were peripheral sensory neuropathy (56 percent vs 16 percent with placebo) and neutropenia (35 vs 12 percent).

“AETHERA is a positive study establishing a promising new treatment approach for patients with Hodgkin’s lymphoma at high risk for relapse. However, with a PFS [rate] of about 50 percent at 24 months in the placebo group, whether this patient population is indeed high risk could be debated,” wrote Professor Andreas Engert of the Universtiy Hospital of Cologne, Germany, in a linked comment. [Lancet 2015, doi: http://dx.doi.org/10.1016/S0140-6736(15)60583-9]

“An international consortium is currently reassessing the effect of risk factors in patients with relapsed Hodgkin’s lymphoma to define a high-risk patient population in need of consolidation treatment,” he continued. “We look forward to a better definition of patients with relapsed Hodgkin’s lymphoma who should receive consolidation treatment with brentuximab vedotin.”

Although high-dose chemotherapy followed by ASCT is the standard of care for patients who relapse after or do not respond to initial chemotherapy or radiotherapy, only about 50 percent of patients are cured after ASCT. Prognosis for those who relapse after ASCT is poor, with a median PFS of 1.3 years.

Scripps Research Institute Scientists Invent a Better Way to Make Antibody-Guided Therapies

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Chemists at The Scripps Research Institute (TSRI) have devised a new technique for connecting drug molecules to antibodies to make advanced therapies.

Antibody-drug conjugates, as they’re called, are the basis of new therapies on the market that use the target-recognizing ability of antibodies to deliver drug payloads to specific cell types—for example, to deliver toxic chemotherapy drugs to cancer cells while sparing most healthy cells. The new technique allows drug developers to forge more stable conjugates than are possible with current methods.

“A more stable linkage between the drug molecule and the antibody means a better therapy—the toxic drug is less likely to fall off the antibody before it’s delivered to the target,” said Carlos F. Barbas III, the Janet and Keith Kellogg II Chair at TSRI.

Barbas and two members of his laboratory, Research Associates Narihiro Toda and Shigehiro Asano, report the finding in the chemistry journal Angewandte Chemie, where their paper was published recently online ahead of print and selected as a “hot” contribution.

A Popular Approach with Limitations

The new method for making more stable antibody-drug conjugates comes as the first generation of these powerful therapies are entering the market. Two such conjugates are now in clinical use. Brentuximab vedotin (Adcetris®), approved by the FDA in 2011, has shown powerful effects in clinical trials against otherwise treatment-resistant lymphomas. It uses an antibody to deliver the cell-killing compound monomethyl auristatin E to cells that bear the CD30 receptor, a major marker of lymphoma. The other conjugate, ado-trastuzumab emtansine (Kadcyla®), approved just this year for metastatic breast cancer, delivers the toxic compound mertansine to breast cancer cells that express the receptor HER2.

The success of these antibody-drug conjugates and the broad potential of the technology have made them popular with drug companies, particularly those trying to develop new anticancer medicines. “The current development pipeline is full of antibody-drug conjugates,” says Barbas.

Yet the chemical method that has been used to make these conjugates has significant limitations. The method involves the use of compounds derived from maleimide, which can be easily added to small drug molecules. The maleimide molecule acts as a linker or bridge, making strong bonds with cysteine amino acids that can be engineered into an antibody protein. In this way, a single antibody protein can be tagged with one or more maleimide-containing drug molecules. The main problem is that these maleimide-to-cysteine linkages are susceptible to several forms of degradation in the bloodstream. When such a cut occurs, the disconnected “payload” drug-molecule—typically a highly toxic compound—is liable to cause unwanted collateral damage to the body, like a “smart bomb” gone astray. This instability of current maleimide-based conjugates probably accounts for at least some of their considerable toxicity.

A more stable linkage would mean less toxicity and higher efficacy for antibody-drug conjugates, and for the past several years research chemistry laboratories around the world have been looking for a way to achieve this.

Improved Linkages

Now Barbas and his colleagues appear to have found one in the form of a novel Thiol-Click reaction. In their new paper, they have described a way to make improved linkages using compounds based on methylsulfonyl-substituted heterocycles instead of maleimides. “This method turns out to enable more stable linkages to an antibody protein, as well as more specific linkages, so the drug attaches to the right place on the right protein,” said Barbas.

Coincident with the report of the new linking compounds in Angewandte Chemie, the chemical supplier Sigma-Aldrich Corporation will begin selling the compounds, so that pharmaceutical companies can start working with them to make more stable antibody-drug conjugates. Under a recent agreement (see http://www.scripps.edu/news/press/2013/20130718sigma.html), Sigma-Aldrich markets new chemical reagents from Barbas’s and several other TSRI laboratories as soon as the papers describing them are released.

“Improved antibody–drug conjugate technologies are a top-priority research area in the pharmaceutical industry and exactly the type of fundamental research issue that our partnership with Scripps will continue to address,” said Amanda Halford, vice president of academic research at Sigma-Aldrich.

Although linking drug molecules to target-homing antibodies is the best-known therapeutic application of the new method, Barbas emphasized its broad relevance. “It should be useful for many types of protein conjugation,” he said. These include the conjugation of proteins to fluorescent beacon molecules for laboratory experiments, as well as the linkage of drug compounds to polyethylene glycol molecules—“pegylation”—to slow their clearance from the body and thus keep them working longer.

JC Virus in Natalizumab Users: Test for Virus Exposure Approved.

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Commercial availability of a JC virus antibody assay will change practice in caring for patients with MS.

Patients with multiple sclerosis (MS) or Crohn disease who are taking natalizumab face an increased risk for progressive multifocal leukoencephalopathy (PML) if they have been exposed to JC virus, the FDA warned in January. The agency also announced approval of a new blood test to detect JC virus antibodies.

JC virus is common and usually harmless, the agency said, but its presence can be dangerous in patients taking immunomodulating drugs like natalizumab. Other risk factors associated with developing PML while on natalizumab are treatment with natalizumab for longer than 2 years and previous treatment with immunosuppressant drugs such as methotrexate or cyclophosphamide (but not prior use of first-line injectable immunomodulatory agents, interferon-beta, or glatiramer acetate).

The FDA estimates that patients with all three risk factors face about a 1% risk for PML with natalizumab therapy (11 cases per 1000 patients treated).

Natalizumab’s label will be changed to reflect the new information.

Comment: Commercial availability of a JC virus antibody assay will change practice in caring for patients with MS. The risk for PML with natalizumab was previously said to be about 1 in 1000, but recent safety data provided by the manufacturer indicate that the overall incidence of PML is more than double that (2.11 per 1000 as of February 2012). The major advance for patient safety is recognition that the PML risk can be stratified by three risk factors (treatment duration >2 years, prior immunosuppressant use, and JC virus antibody seropositivity). As highlighted by the FDA, in patients with all three risk factors, the risk for PML is very high (>1 in 100). On the other end of the spectrum, the PML risk with natalizumab appears to be quite low in patients who are JC virus–seronegative. For these patients, the manufacturer estimates the PML risk to be about 1 in 10,000, with a 95% confidence interval potentially as high as 1 in 2000 and as low as zero, based on the lack of observed PML cases in JC virus–seronegative patients to date and the false-negative rate of the assay (3%). The seroconversion rate for JC virus in MS patients is about 2% per year; the optimal frequency of testing for the virus in patients taking natalizumab remains to be defined. This is a fast-moving field, so further refinement of these numbers is likely as more safety data become available.

Source: Journal Watch Neurology