Response Rates in Phase 1 Studies of Hematologic Malignancies Improved Over Time

Blood sample
Response rates have improved as phase 1 studies shifted from chemotherapy to targeted agents for hematologic malignancies.

The following article features coverage from the American Society of Hematology 2020 meeting. Click here to read more of MPR’s conference coverage.

During the past 20 years, phase 1 trials have shifted away from investigating chemotherapy toward evaluating targeted agents for the treatment of hematologic malignancies, which has resulted in improved response rates, according to results of a study presented at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

The National Institute of Cancer (NCI) team conducted a similar study 15 years ago, which showed an overall response rate (ORR) of 10.6% and a rate of grade 5 toxicity of 0.49%. “However, there have been significant changes in investigational agents evaluated in phase 1 studies over the last few decades,” Dai Chihara, MD, PhD, of the National Institute of Health in Bethesda, Maryland, and presenter of the study, said.

The current cohort study included data from 3308 patients with hematologic malignancies treated as part of 161 phase 1 trials supported by the Cancer Therapy Evaluation Program (CTEP) at the NCI and initiated from 2000 to 2019. Most of the phase 1 trials evaluated targeted therapy as part of a combination regimen (68.5%), with the remaining studied as monotherapy (31.5%).

The median age of patients in the cohort was 61 years, and 61% of patients were male. The most common hematologic malignancy was acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), followed by lymphoma, acute lymphoblastic leukemia (ALL), and myeloma.

During the entire time period, the ORR was 25.1% and the complete response (CR) rate was 14.7%. Both ORR and CR increased significantly over time. ORR increased from 18.3% between 2000 and 2005, to 24.7% between 2006 and 2012, to 50.6% between 2013 and 2019 (P <.001). CR also increased from 10.4% to 16.5% and 26% between the 3 time periods (P <.001).

In a multivariate analysis, topoisomerase inhibitors, antimetabolites, monoclonal antibodies, alkylating agents, cyclin-dependent kinase (CDK) inhibitors, immunomodulatory drugs, and Bruton tyrosine kinase (BTK) inhibitors were associated with higher response rate. The median overall survival (OS) was 277 days among all patients, but was shortest among patients with ALL at 86 days compared with 255 and 289 days among patins with AML/MDS and lymphoma, respectively.

There were 60 (of 468) deaths attributed to treatment during the trials, with a rate of grade 5 toxicities of 1.81%. Grade 5 toxicity was more frequent among patients with leukemic disease, with the highest rate among patients with AML/MDS (2.49%), followed by ALL (2.17%), lymphoma (0.71%), and myeloma (0.35%). Overall, the rate of grade 5 toxicities has remained stable since 2000.

Treatment with anti–programmed cell death 1 (PD-1) antibodies was associated with a higher grade 5 toxicity rate at 7.14% compared with 1.65% among patients who did not receive PD-1 blockade medications (odds ratio [OR], 4.93; 95% CI, 1.54-15.8) and were primarily in trials that also included an anti– cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor. In contrast, there were no grade 5 events reported with poly (ADP)-ribose polymerase (PARP) inhibitors.

Grade 5 toxicities were also associated with several baseline characteristics, including older age and higher performance status. “We saw a significant improvement in response rates over time, likely due to better treatments with targeted agents,” Dr Chihara concluded.

Read more of MPR’s coverage of the ASH 2020 meeting by visiting the conference page.


Chihara D, Huang EP, Finnigan SR, et al. Phase I studies in hematologic malignancy: 20-year experience from Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute/National Institutes of Health. Presented at: 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; December 5-9, 2020. Abstract 373.

This article originally appeared on Cancer Therapy Advisor