Results from a clinical trial with IMGN529, ImmunoGen’s experimental therapy for B-cell malignancies presented at the American Society of Hematology (ASH) annual meeting being held in San Francisco’s Moscone Center, December 6 – 9, 2014, shows that the trial drug achieved objective responses in four of ten evaluable patients with heavily pretreated diffuse large B-cell lymphoma or DLBCL. The study by Anastasios Stathis, MD (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland), Arnold S. Freedman, MD (Dana-Farber Cancer Institute, Boston, MA), Ian W. Flinn, MD (Sarah Cannon Research Institute, Nashville, TN) and others, includes a complete response at the dose levels evaluated to date. While dose finding is ongoing, and the maximum ASHtolerated dose (MTD) has not yet been established, the results include objective responses at doses that were generally well tolerated. [1]

B-cell lymphoma’s are a type of cancer that forms in B cells. They are either indolent (slow-growing) or aggressive (fast-growing). The majority of B-cell lymphomas are non-Hodgkin lymphomas. There are many different types of B-cell non-Hodgkin lymphomas, including Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma or CLL/SLL, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. Prognosis and treatment depend on the actual type and stage of the particular cancer.

More than 70,000 people will be diagnosed with non-Hodgkin lymphoma (NHL) in the US in 2014.[2] DLBCL is an aggressive lymphoma that represents approximately one third of the new NHL cases diagnosed annually.[2]

Potential new treatment
ImmunoGen’s IMGN529 is a potential new treatment for DLBCL and other non-Hodgkin lymphoma (NHL) subtypes. An antibody-drug conjugate or ADC, IMGN529 comprises a monoclonal antibody that targets CD37, a surface antigen widely expressed on malignant B cells, attached to the maytansinoid DM1, a potent anti-microtubule agent, via the thioether linker N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). Preclinical data shows that the resulting ADC retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery.

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The antibody serves to deliver the DM1 specifically to B cells to kill them and, based on preclinical research, also contributes anticancer activity.[3][4] Furthermore, in normal tissues, CD37 expression is restricted to lymphoid tissues and blood cells, with high levels of expression on B lymphocytes and low levels on non-B lymphoid and myeloid cells.[3]

Dose finding
IMGN529 is currently in the dose-finding portion of a Phase I clinical trial, which assesses increasing doses of this experimental therapy in new groups of patients with relapsed/refractory NHL. Findings with the first doses evaluated were reported previously.[5]

Presented Clinical Data
The IMGN529 dose levels evaluated to date range from 0.1 to 1.4 mg/kg, administered once every three weeks. Its MTD has not yet been established, and evaluation of the 1.4 mg/kg level is ongoing.

Twenty four (24) of the 33 patients enrolled to date were evaluable for efficacy. Ten evaluable patients had DLBCL, which had been heavily pretreated, and four (40%) of these patients had an objective response: one had a complete response (CR) and three had partial responses (PRs). The CR and one of the PRs were among patients treated with 1.0 mg/kg, the highest IMGN529 dose level to complete evaluation to date. Both of these patients had received multiple prior treatments, including autologous stem cell transplant (ASCT). Ten of the 24 evaluable patients had follicular lymphoma and one of these patients also had a PR. This patient, too, had received multiple treatments including ASCT.

Preclinical research
As reported previously by Jutta Deckert, PhD, Jose F. Ponte, PhD, Jennifer A. Coccia and other researchers at ImmunoGen, an early onset, transient drop in neutrophil counts was seen in several patients receiving IMGN529 at low doses. [3] This was believed to be due to a redistribution of the neutrophils – induced by antibody-mediated cytokine release – rather than to bone marrow suppression; subsequent preclinical research supports this hypothesis.

In vitro studies with peripheral blood cells from normal human donors demonstrated that incubation with IMGN529 for 1 hour or 24 hours resulted in significant B-cell depletion with no apparent neutrophil depletion detected, similar to observations after rituximab treatment. In contrast, alemtuzumab treatment in vitro resulted in both B-cell and neutrophil depletion. This is consistent with the high level of CD37 expression on target B cells and the relatively low CD37 expression level on other blood cells. [6]

With the addition of peri-infusional steroids to the treatment protocol, the incidence and severity of neutropenia decreased markedly and dose escalation resumed. As reported previously, the first patients treated with 1.0 mg/kg had delayed onset neutropenia or febrile neutropenia.2 G-CSF was subsequently added to the treatment protocol and there have been no new reports of febrile neutropenia at doses of 1.0 or 1.4 mg/kg; the one incidence of high grade neutropenia seen with 1.4 mg/kg was of short (2 day) duration.

Hematologic side effects are not unexpected in such heavily pretreated patients. Other frequent side effects were fever, fatigue, nausea, and diarrhea, which were typically Grade 1/2.

“It is encouraging that patients with such heavily pretreated disease responded to IMGN529,” commented Charles Morris, MB, ChB, MRCP, Executive Vice President (EVP) and Chief Development Officer. “We are particularly pleased with the responses seen in the patients with diffuse large B-cell lymphoma given the limited treatment options for such patients today, and look forward to advancing IMGN529 into disease-specific testing in 2015.”