Phase I Study of the Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-Hodgkin's Lymphoma

Division of Oncology, Stanford University Medical Center, 875 Blake Wilbur Dr, Stanford, CA 94305, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2009; 27(26):4371-7. DOI: 10.1200/JCO.2008.21.3017
Source: PubMed

ABSTRACT To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).
In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.
In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.
Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.

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    • "Together, these data support the investigation of agents targeting CD40 as a single agent or in combination with chemotherapy in patients with haematological malignancies. The biological significance of CD40 has led to the development of CD40-directed therapies that range in activity from agonists to antagonists (Schoenberger et al, 1998; Advani et al, 2009; Lewis et al, 2011). Lucatumumab is a fully human antagonistic anti-CD40 mAb. "
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    ABSTRACT: Despite advancements in the treatment of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8-week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa-associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation.
    British Journal of Haematology 11/2013; 164(2). DOI:10.1111/bjh.12630 · 4.96 Impact Factor
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    • "Dacetuzumab, SGN-40, is a humanized IgG1 anti-CD40 mAb that has shown the ability to induce apoptosis and mediate ADCC in vitro (Law et al, 2005). Early phase trials have reported tolerability and efficacy in CLL and relapsed/ refractory NHL (Advani et al, 2009). Additional studies are investigating dacetuzumab in combination with chemotherapeutic agents. "
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    British Journal of Haematology 08/2012; 159(1):3-17. DOI:10.1111/bjh.12002 · 4.96 Impact Factor
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    • "Early clinical trials have evaluated the pharmacokinetics, safety, and efficacy of dacetuzumab monotherapy in patients with relapsed/refractory MM and other B-cell tumors [24] [25]. Phase I data suggest both agents are well tolerated with no immunogenicity and show early evidence of single-agent clinical activity in relapsed and refractory MM and NHL [26] [27]. SGN-40 Phase Ib clinical trials in combination with lenalidomide and dexamethasone/or bortezomib are planned based on enhanced anti- MM activities when combining SGN-40 with lenalidomide [28] "
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