Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med

Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
New England Journal of Medicine (Impact Factor: 55.87). 11/2010; 363(19):1812-21. DOI: 10.1056/NEJMoa1002965
Source: PubMed


Hodgkin's lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35).
In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kilogram of body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily Hodgkin's lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation.
The maximum tolerated dose was 1.8 mg per kilogram, administered every 3 weeks. Objective responses, including 11 complete remissions, were observed in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy.
Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase 1 study. Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects. (Funded by Seattle Genetics; number, NCT00430846.).

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    • "Binding of MMAE to tubulin disrupts the microtubule network and induces cell cycle arrest and apoptotic death [7]. Clinical studies indicate that peripheral neuropathy is a frequent complication of treatment (possibly related to the disruption of axonal transport as seen with vinca alkaloids), and in certain trials this represented the most common reason for discontinuation of the agent [6] [7] [8] [9] [10]. In one Phase I study exploring different dosing schedules, there was a significant increase in neuropathy among patients receiving weekly doses compared to those who received the drug every three weeks [8]. "
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    ABSTRACT: The number of available therapies for hematologic malignancies continues to grow at a rapid pace. Unfortunately, many of these treatments carry both central and peripheral nervous system toxicity, potentially limiting a patient’s ability to tolerate a full course of treatment. Neurotoxicity with chemotherapy is common and second only to myelosuppression as a reason to limit dosing. This review addresses the neurotoxicity of newly available therapeutic agents including brentuximab vedotin and blinatumomab as well as classic ones such as methotrexate, vinca alkaloids and platinums. Although peripheral neuropathy is common with many drugs, other complications such as seizures and encephalopathy may require more immediate attention. Rapid recognition of adverse neurologic effects may lead to earlier treatment and appropriate adjustment of dosing regimens. In addition, knowledge of common toxicities may help differentiate chemotherapy-related symptoms from actual progression of cancer into the CNS.
    Preview · Article · Sep 2014 · Blood Reviews
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    • "Interestingly, SGN-35, trade name Brentuximab Vedotin, a CD30 antibody-drug conjugate, was recently approved by the FDA for the treatment of relapsed CD30-positive lymphomas 35-37. To benefit from this targeted therapy, it is critical to establish the status of CD30 biomarker expression on tumor cell and an. in vitro immunostaining of tumor tissues is currently the only method for such analysis. "
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    ABSTRACT: Although several imaging modalities are widely used for tumor imaging, none are tumor type-specific. Different types of cancer exhibit differential therapeutic responses, thus necessitating development of an imaging modality able to detect various tumor types with high specificity. To illustrate this point, CD30-specific oligonucleotide aptamer in vivo imaging probes were conjugated to the near-infrared IRD800CW reporter. Mice bearing xenografted CD30-positive or control CD30-negative lymphoma tumors on contralateral sides of the same mouse were developed. Following a systemic administration of aptamer probes, whole body imaging of tumor-bearing mice was performed. Imaging signal from tumor sites was analyzed and imaging specificity confirmed by tissue immunostaining. The in vivo biodistribution of aptamer probes was also evaluated. Whole body scans revealed that the RNA-based aptamer probes selectively highlighted CD30-expressing lymphoma tumors immediately after systemic administration, but did not react with control tumors in the same mouse. The resultant imaging signal lasted up to 1 hr and the aptamer probes were rapidly eliminated from the body through urinary and lower intestinal tracts. For more sensitive imaging, biostable CD30-specific ssDNA-based aptamer probes were also generated. Systemic administration of these probes also selectively highlighted the CD30-positive lymphoma tumors, with imaging signal detected 4-5 folds higher than that derived from control tumors in the same animal, and lasted for up to 24hr. This study demonstrates that oligonucleotide aptamer probes can provide tumor type-specific imaging with high sensitivity and a long-lasting signal, indicating their potential for clinical applications.
    Preview · Article · Jul 2014 · Theranostics
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    • "Recently, novel agents for the treatment of refractory or relapsed PTCL have emerged, such as brentuximab vedotin, an anti-CD30 antibody-drug conjugate. In a Phase I clinical trial involving 45 patients with relapsed or refractory CD30+ hematopoietic neoplasms that were treated with brentuximab vedotin, 17 patients showed an objective response, and stable disease was reported in 19 patients.16 In a Phase II multicenter study, 58 patients with relapsed or refractory ALCL were treated with brentuximab vedotin (1.8 mg/kg every 3 weeks for up to 16 cycles). "
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    ABSTRACT: Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.
    Full-text · Article · Jun 2014 · OncoTargets and Therapy
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