Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma
Despite numerous treatment strategies over the last 20 years failure rates remain 25-30% for pediatric anaplastic large cell lymphoma (ALCL). Two novel agents that have demonstrated high response rates as single agents in ALCL will be studied in this trial. Brentuximab vedotin (previously known as SGN35; currently marketed under the brand name Adcetris) is an antibody-drug conjugate containing an anti-CD30 monoclonal antibody linked to a tubulin inhibitor (monomethylauristatin E). After binding CD30, a transmembrane receptor expressed on all ALCLs, brentuximab vedotin is internalized and the drug is released into the cytoplasm where it causes cell cycle arrest and apoptosis. Tubulin inhibitors are active agents in ALCL as evidenced by responses using vincristine and vinblastine. The response rate of brentuximab vedotin in patients with relapsed/refractory ALCL is impressive and the FDA has approved brentuximab vedotin for the treatment of patients with ALCL that have failed one line of therapy. Crizotinib is an orally bioavailable small molecule inhibitor of receptor tyrosine kinases including anaplastic large cell lymphoma kinase (ALK). ALK plays a central role in the pathogenesis of ALCL due to a chromosomal translocation that results in expression of an oncogenic kinase fusion protein. Crizotinib inhibits ALK phosphorylation resulting in antitumor activity. Crizotinib has also shown impressive response rates in patients with refractory/relapsed ALK positive ALCL.
The primary aim of this pilot phase II study is to determine the toxicity and efficacy of the addition of two novel agents (brentuximab vedotin or crizotinib) to standard chemotherapy (best arm of ALCL99) in children with newly diagnosed ALCL. In this protocol, patients with newly diagnosed ALCL will be randomized to receive standard chemotherapy plus brentuximab vedotin (Arm BV) or standard chemotherapy plus crizotinib (Arm CZ). All patients will initially receive a 5 day prophase followed by 6 cycles of chemotherapy. The novel agent (either brentuximab vedotin or crizotinib) will start with Cycle 1 and be given in all 6 cycles. Each cycle lasts 21 days with the total therapy lasting approximately 19 weeks. Each arm will be evaluated for toxicity. Each arm will independently be evaluated for differences in EFS compared to historical data for ALCL99. A secondary aim of the trial will be to determine if minimal disease at diagnosis and/or minimal residual disease during treatment can identify patients at high risk of recurrence. Minimal disseminated disease (MDD) and minimal residual disease (MRD) will be measured using peripheral blood at 3 separate time points (diagnosis, after prophase, and after Cycle 1). The results from this pilot phase II study will provide necessary information to incorporate these novel agents into future trials and potentially improve the treatment of children with ALCL.