Advances in Hematologic Malignancies Issue 1, Spring 2013
The Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC)
Adult Lymphoma Program operates a large and growing
research program. We now have over 25 clinical trials actively enrolling patients for the treatment of both de novo and relapsed/refractory lymphomas. This includes
trials in B- and T-cell non-Hodgkin lymphoma (NHL),
trials in Hodgkin lymphoma, and
trials in chronic lymphocytic leukemia (CLL).
While we are testing many exciting and active drugs, we are particularly interested in highlighting two clinical trials here, as they draw on recent advances in oncology: antibody-cytotoxic drug conjugates and "immunomodulatory" drugs.
Antibody-cytotoxic drug conjugates are highly effective therapies, as evidenced by the success of brentuximab for CD30+ T-cell and Hodgkin lymphoma, gemtuzumab ozogamicin for acute promyelocytic leukemia, and T-DM1 (trastuzumab emtansine) for Her2-positive breast cancer. ImmunoGen has developed an anti-CD37 antibody conjugated to maytansinoid, also known as DM1, the same microtubule inhibitor used in T-DM1.
CD37 is a surface antigen that is specific for pro-B and peripheral-B lymphocytes and highly expressed on malignant B-cells; the anti-CD37 monoclonal antibody allows targeted delivery of the cytotoxic medication to the cancer cell. We are testing this drug in a Phase I clinical trial in relapsed/refractory B-cell NHLs: follicular, marginal zone, mantle cell, and diffuse large B-cell lymphoma. Part 1 is a dose escalation phase to determine the maximally tolerated dose (MTD), and part 2, the expansion phase, is to better characterize the safety, tolerability, and anti-tumor activity of the drug at the MTD. The expansion phase will be limited to patients with CD37+ tumors.
Patients may have received any number of prior regimens, but must have an ECOG performance status of ≤ 2 and measurable disease. Prior chemotherapy and immunotherapy (e.g., rituximab) must have been discontinued for at least three weeks and six weeks, respectively, prior to the first dose of the drug. The drug is administered as an intravenous infusion every three weeks for up to nine cycles or until disease progression, with disease assessment every 12 weeks.
Immune modulation is likewise an increasingly popular and powerful antitumor strategy. Drugs like Ipilimumab, which target the inhibitory T-cell co-receptor CTLA-4, thereby relieving T-cell inhibition and enhancing antitumor immunity, have had success in treating melanoma. Another immunomodulatory target is programmed cell death-1 (PD-1), an inhibitory T- and B-cell co-receptor whose ligands are expressed on macrophage-lineage and endothelial cells, as well as by many tumor cells. Thus, tumor PD-1 ligands may play a role in tumor immune evasion.
Targeting PD-1 with an inhibitory antibody developed by Bristol-Myers Squibb has been a successful strategy in early-phase trials in the solid tumor setting. We are currently studying an anti-PD1 antibody in a phase 1 trial in hematologic malignancies. Patients with any relapsed or refractory hematologic malignancy are eligible, except for patients with myelodysplastic syndromes, polycythemia vera, acute myeloid or acute lymphoid leukemia, chronic myeloid leukemia in blast crisis, T-cell lymphoblastic lymphoma, and Burkitt lymphoma. Prior radiation and drug therapy must be completed 2 and 3 weeks, respectively, prior to the first dose of the drug, and patients must have an ECOG performance status of ≤ 1. The drug is administered as an intravenous infusion every 2 weeks for up to 2 years, or until disease progression, with disease assessment intervals determined by the specific malignancy.
We are excited to share with you the details of these two trials that we feel are emblematic of our innovative clinical research program here at DF/BWCC. We encourage you to
contact us to refer potentially eligible and interested patients for further consultation.
— Caron A. Jacobson, MD, Oncologist in the DF/BWCC Adult Lymphoma Program, with Ann LaCasce, MD, Director of the Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program and Oncologist in the DF/BWCC Adult Lymphoma Program, and Arnold Freedman, MD, Clinical Director of the DF/BWCC Adult Lymphoma Program