Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a dose-escalation, phase I study.

Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.

18F-FDG PET for Measurement of Response and Prediction of Outcome to Relapsed or Refractory Mantle Cell Lymphoma Therapy with Bendamustine-Rituximab.

In a single-arm, phase 2 clinical trial, bendamustine-rituximab (BR) demonstrated an overall response rate of 82% among 45 patients with relapsed or refractory mantle cell lymphoma (MCL), with manageable tolerability. A prespecified 18F-FDG PET analysis was conducted to assess the predictive value of the metabolic response to BR compared with the response by International Working Group (IWG) criteria. METHODS: Adult patients with relapsed or refractory MCL underwent 18F-FDG PET at screening and after 6 cycles of BR therapy. Scans were reviewed by a central facility and scored using the 5-point Deauville scale, comparing uptake to the liver and mediastinum in up to 6 lesions, to determine metabolic response rates, indicated by negative posttreatment scans. Metabolic responses were compared with study outcomes assessed by IWG criteria. RESULTS: Complete 18F-FDG PET data were available for 32 of 45 patients. All patients had positive baseline scans, with baseline scores ranging from 4 to 5. Complete metabolic responses (CMR) were observed in 24 (75%) patients after 6 cycles of BR. Patients attaining a CMR had a 96% overall response rate by IWG criteria, with 62.5% achieving a complete response. Of the 8 patients not attaining a CMR, 6 responded to BR but none achieved a complete response. CMR was associated with a greater 1-y progression-free survival of 91.5%, compared with 12.5% without CMR; a longer median duration of response of 20.6 mo, compared with 7.8 mo; and improved overall survival at 1 y. 18F-FDG PET data from patients with refractory or advanced disease demonstrated CMR in more than half. CONCLUSION: Compared with positive end-of-treatment 18F-FDG PET, negative scans, indicating a CMR, were predictive of improved 1-y survival, duration of response, and overall survival for patients with relapsed or refractory MCL receiving BR.

Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma.

PURPOSE: Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine's effect on cardiac repolarization in treatment-naïve adults with advanced indolent NHL/mantle cell lymphoma (MCL). METHODS: In this multicenter, open-label, phase 3 study, patients received 6-8 28-day cycles of bendamustine (90 mg/m(2), days 1 and 2) and rituximab (375 mg/m(2), day 1). Exclusions included a history of cardiac conditions with potential for QT prolongation. The primary endpoint was change in Fridericia-corrected QT (QTcF; 3 electrocardiograms per time point) on day 2 of cycle 1, from just before infusion to end of infusion (immediately postinfusion, coinciding with maximum plasma concentration of bendamustine). Change 1 h postinfusion was also measured. Exploratory assessments included specific QTcF outlier analyses (new QTcF >500 ms, change >60 ms) and morphological changes. RESULTS: Of the 54 enrolled patients (mean age, 62.9 years), 53 received ≥1 dose; 49 completed ≥6 cycles. Mean QTcF change from baseline was 6.7 ms at end of infusion; no mean changes >20 ms were detected ≤1 h postinfusion. No patients met specific outlier criteria at end of infusion or 1 h postinfusion. No morphological changes were detected. CONCLUSIONS: In this small treatment-naïve population with advanced NHL/MCL, bendamustine did not produce a clinically relevant increase in mean QTcF on the second infusion day. The potential for delayed effects on QT interval after 1 h was not evaluated.

An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

PURPOSE: Bendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug-drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma. METHODS: Data were derived from a bendamustine-rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration-time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy. RESULTS: The established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration-time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate. CONCLUSIONS: Neither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors.

PURPOSE: A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. RESULTS: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. CONCLUSIONS: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.