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Ipilimumab for Relapsed Blood Cancers after Stem Cell Transplantation

Matthew Davids, MD (DFCI), is running a Phase 1/1b trial of ipilimumab in hematologic malignancies for patients who have relapsed after allogeneic stem cell transplantation.

October 3, 2013 | eNews

An open and accruing Phase 1/1b clinical trial is testing whether ipilimumab, an FDA approved immunotherapy for melanoma, might rescue the immune response to leukemias, lymphomas and other hematologic malignancies that have relapsed following allogeneic hematopoietic cell transplants.

“Patients who relapse after allo transplantation have few effective treatment options,” says Matthew Davids, MD (DFCI), who leads the new trial. “They often go back on chemotherapy, but infrequently achieve durable disease remission. While there are many trials for promising new drugs for relapsed hematologic malignancies, they usually exclude patients who have had allo transplants. We wanted to design a trial with a strong scientific rationale for patients who relapse after allo transplantation.”

The Rationale for Ipilimumab

Ipilimumab is a humanized monoclonal antibody that blocks Cytotoxic T Lymphocyte Antigen 4 (CTLA-4), which is a negative regulator of the T cell immune response following T cell activation. Tumor cells exploit CTLA-4 to prevent an attack by the immune system. By blocking CTLA-4, ipilimumab in a sense “releases the brake” on T cells and re-engages the immune response against the cancer cells.

The rationale for allo transplantation for patients with hematologic malignancies is that the donor’s T cells may recognize the cancer cells as foreign and kill them, explains Davids. Over time, however, immunological effects such as the CTLA-4 braking mechanism may reduce the anti-cancer immune response, thereby leading to relapse. He hypothesizes that ipilimumab might restore the donor’s T cell response against the malignant cells.

Prior Evidence

In a 2009 pilot study, conducted in part at DFCI, 29 patients with hematologic malignancies who had relapsed after allo transplantation were each given a single, low dose of ipilimumab (0.1-3 mg/kg). The therapeutic dose in melanoma is 10 mg/kg. The pilot study was conservative because of concern that ipilimumab might cause severe graft versus host disease (GVHD), in which the donor cells attack the normal tissues of the body. The treatment was well tolerated, with no significant GVHD observed, and three patients with lymphoid malignancies had excellent responses.

Study Objectives

The current study is an open-label, multicenter Phase 1/1b trial of up to 40 patients with various hematologic malignancies who have relapsed after allo transplantation. The trial’s primary objectives are to determine the maximum tolerated dose (Phase 1) and to characterize toxicity (Phase 1b). Secondary objectives include assessment of efficacy by standard response criteria. Exploratory objectives are to assess the effects of ipilimumab on immune cells and on tumor glucose metabolism using FDG-PET imaging.

Study Design

The trial uses univariate binomial design, with five patients in each cohort, to determine the maximum tolerated dose (MTD). The first cohort began with ipilimumab at 3 mg/kg. If there are no dose-limiting toxicities, the second cohort will receive 10 mg/kg, the FDA-approved dose for melanoma patients. If dose-limiting toxicities occur, the dose will drop back to 5 or 1 mg/kg. After the MTD is established, the phase 1b study will expand patient enrollment at the MTD to further characterize the drug’s toxicity.

The schedule will be the same as that approved for ipilimumab in melanoma. During the induction phase, patients receive one intravenous dose every three weeks for four cycles. During the maintenance phase, they receive one dose every three months for up to a year. After completing treatment, patients will be monitored for progression free and overall survival.

Another Option

“Our goal is to be able to offer an option to these patients who had hoped that they were potentially cured and then unfortunately relapsed,” says Davids. “This strategy of harnessing the immune system may salvage an allo transplant that would otherwise fail. It’s a pretty exciting prospect, but there is still the risk of worsening graft versus host disease and other toxicities. This study allows us to evaluate whether this is a safe therapy for these patients and therefore worthy of exploration in a larger study.”

Phase 1/1b Trial

Title: A Phase I/Ib study of ipilimumab in patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation

Principal Investigator: Matthew Davids, MD (DFCI)

NIH Trial Number: NCT01822509

DF/HCC Protocol Number: 12-537

More Information:

The trial is recruiting patients. Find more information at ClinicalTrials.gov.

Research detailed in this article was funded in part by NIH grants, including CA065164, CA183559-01, and the NIH Cancer Therapy Evaluation Program.


Bashey, Asad, et al. “CTLA4 Blockade with Ipilimumab to Treat Relapse of Malignancy after Allogeneic Hematopoietic Cell Transplantation.” Blood 113, no. 7 (February 12, 2009): 1581–1588.

 — Cathryn Delude