TY - JOUR
T1 - Oral idasanutlin in patients with polycythemia vera
AU - Mascarenhas, John
AU - Lu, Min
AU - Kosiorek, Heidi
AU - Virtgaym, Elizabeth
AU - Xia, Lijuan
AU - Sandy, Lonette
AU - Mesa, Ruben
AU - Petersen, Bruce
AU - Farnoud, Noushin
AU - Najfeld, Vesna
AU - Rampal, Raajit
AU - Dueck, Amylou
AU - Hoffman, Ronald
N1 - Funding Information:
This study was an investigator-initiated phase 1 clinical trial performed at a single site in compliance with an Investigational New Drug application, which was approved by the US Food and Drug Administration. All participating patients provided informed consent before they participated, in accordance with the principles of the Declaration of Helsinki. This study was approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai. This study was supported by the National Cancer Institute and the Leukemia Lymphoma Society, and idasanutlin was supplied by Roche/ Genentech. High-risk PV/ET patients who met World Health Organization diagnostic criteria with JAK2 V617+ hematopoiesis and were refractory or intolerant to prior therapy with hydroxyurea, IFN-a, or anagrelide were eligible for study entry. Part A of this protocol was a phase 1 open-label study of single-agent oral idasanutlin administered at a starting dose of 100 mg daily for 5 days for the first cycle, which was 56 days in duration.16,17 Subsequent cycles were 28 days in duration. Patients were enrolled in a standard 3 + 3 phase 1 design, with 2 dose levels ultimately tested. The maximum tolerated dose was defined as 1 dose level below that dose with unacceptable toxicity, with a total of 6 patients treated at the maximum tolerated dose.
Funding Information:
This research was supported by grants from the National Institutes of Health, National Cancer Institute (MPN Research Consortium grant 5P01CA108671-09), and the Leukemia and Lymphoma Society (LLS Translational Research Program R6506-17).
Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/8/8
Y1 - 2019/8/8
N2 - A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD341 cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-a2a (IFN-a2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-a2a. Thirteen patients with JAK2 V617F1 PV/ET were enrolled, and 12 (PV, n 5 11; ET, n 5 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.
AB - A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD341 cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-a2a (IFN-a2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-a2a. Thirteen patients with JAK2 V617F1 PV/ET were enrolled, and 12 (PV, n 5 11; ET, n 5 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.
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U2 - 10.1182/blood.2018893545
DO - 10.1182/blood.2018893545
M3 - Article
C2 - 31167802
AN - SCOPUS:85070741891
SN - 0006-4971
VL - 134
SP - 525
EP - 533
JO - Blood
JF - Blood
IS - 6
ER -