Hodgkin lymphoma

A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.

A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.

Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.

“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.

Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.

“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”

Patient and treatment characteristics

Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.

The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).

Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.

Safety

The maximum tolerated doses were 110 mg/m² and 196 mg/m² on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.

On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).

On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).

Efficacy

Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.

Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.

“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.

“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”

Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.

Inhibitor exhibits ‘modest’ activity in lymphoma