Idasanutlin Clinically Active and Tolerable in PV, Phase I Trial Finds

The MDM2 antagonist idasanutlin was found to be clinically active and well tolerated in patients with previously treated polycythemia vera. Additionally, on-target <em>TP53 </em>pathway activation was observed in treatment-refractory patients with PV who were treated with idasanutlin, according to the results of a phase I clinical trial.<br /> &nbsp;

John O. Mascarenhas, MD

The MDM2 antagonist idasanutlin (RG7388) was found to be clinically active and well tolerated in patients with previously treated polycythemia vera (PV). Additionally, on-targetTP53pathway activation was observed in treatment-refractory patients with PV who were treated with idasanutlin, according to the results of a phase I clinical trial.

The overall response rate after 6 cycles of idasanutlin monotherapy was 58% (7 out of 12 patients) and 50% (2 of 4) with the addition of interferon-alfa-2a (IFN-α-2a). The median duration of response was 16.8 months (range, 3.5-26.7).

“In order to exploit the therapeutic window between normal and MPN [myeloproliferative neoplasm] hematopoietic stem/progenitor cells, we hypothesized that lower doses of a therapeutically active nutlin could be used to selectively deplete the malignant hematopoietic stem/progenitor cells rather than their normal counterparts, thereby, avoiding the cumulative potential gastrointestinal and hematological toxicity seen in other oncology trials,” the authors, led by John O. Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York City, wrote in their report published inBlood. “[We found that] clinical responses were attained in the majority of the patients receiving idasanutlin monotherapy with rapid and dramatic symptom responses achieved.”

Investigators enrolled patients with high-risk PV (n = 11) and essential thrombocythemia (ET, n = 1) who met World Health Organization (WHO) diagnostic criteria withJAK2V617F—positive hematopoiesis. Patients who were refractory or intolerant to prior treatment with hydroxyurea (Hydrea), IFN-α, or anagrelide were eligible.

Enrolled patients participated in an open-label, dose-escalation study of oral idasanutlin monotherapy. The starting dose was 100 mg daily for 5 days during an initial 56-day cycle. Later cycles were 28 days long. The maximum tolerated dose (MTD), defined as one dose level below the dose with unacceptable toxicity with a total of 6 patients treated at the MTD, was 150 mg daily.

This study had 2 primary objectives: to assess the toxicity, safety, and tolerability of single-agent idasanutlin in patients with PV or ET, and to identify an idasanutlin dose to be evaluated in a single-agent phase Il trial. The secondary objective was to estimate the response rate of PV/ET patients treated with escalating doses of single-agent idasanutlin (100 mg/150 mg).

The protocol also allowed patients who did not respond to idasanutlin but tolerated it to continue, after 6 cycles of monotherapy, with a regimen that combined idasanutlin with a low dose of pegylated IFN-α-2a (Pegasys, 45 mg).

Following the initial 56-day cycle, patients who did not develop dose-limiting toxicities (DLT) continued to receive the study drug in 28-day cycles. Once in the extension phase, patients could continue receiving idasanutlin treatment until disease progression, unacceptable toxicity, or physician/patient decision to withdraw from the study.

The investigators amended the trial to stop dose escalation at the 150-mg dose level based on emerging data from trials of idasanutlin. “Additionally, a signal of clinical activity already noted at 100 mg daily with a concern for added gastrointestinal toxicity prompted an amendment to cap the dose level at 150 mg and expand the trial to include a total of 6 patients treated at each dose level,” they wrote.

Investigators enrolled 6 patients at each dose level (100 and 150 mg). The median patient age was 63.5 years. All 12 patients had aJAK2V617F—positive MPN. Three of the 12 patients had a history of venous thrombosis and all but one (JAK2V617F+) patient had a diagnosis of PV. Ten patients were considered either intolerant of or resistant to prior hydroxyurea treatment and 5 had received prior IFN-α, but none had received prior ruxolitinib (Jakafi).

All patients received next-generation high-throughput sequencing with a targeted deep sequencing assay to assess their MPN driver mutational status and the presence of wild-type andTP53inactivating mutations. Quantitative assessment ofJAK2V617Fallele burden was monitored at baseline, every 3 to 4 months, and when study treatment was terminated.

Only one patient had an inactivating mutation ofTP53. The medianJAK2V617Fvariant allele frequency prior to therapy was 40.6%. Additional mutations in myeloid malignancy—associated genes were noted in several of the patients, including most commonlyTET2(4/12) andDNMT3A(3/12). Eleven of the patients had a normal karyotype, but a baseline deletion 5q abnormality was noted in one patient.

The median duration of study was 54.2 weeks (range, 23.1-131.1), while the median number of therapy cycles was 10.5 (range, 5-20). Four patients received combination therapy in the extension phase (median, 3 cycles; range, 2-15). As of publication, 7 patients had ended treatment. Two patients remained on trial after 24 and 36 months.

The authors found that idasanutlin therapy was associated with significant clinical activity. The objective response rate (ORR) was 58% (n = 7) in the dose-escalation portion and 50% (2 of 4 patients) in the extension phase for a combined ORR of 75% (95% CI, 42.8%-94.5%). The authors found the median duration of response to be 16.8 months (95% CI, 12.5—not estimated; range, 3.5-26.7). Nine patients responded to idasanutlin therapy, including those in the combination cohort.

Additionally, the median number of therapeutic phlebotomies during the 12 months prior to enrollment was 2.5 (range 0-11) and 1.5 (range 0-5) during the 12 months after enrollment. The 6 patients who received treatment for 12 months or more had a median of 0.5 therapeutic phlebotomies, while the median in patients treated for less than a year was 2.0.

The investigators observed no DLTs. They reported that 5 patients (41.7%) developed a grade 3 non-hematological adverse event (AE), with nearly all occurring at the 100 mg dose. No grade 4 AEs were noted. The most common AEs involved the gastrointestinal tract and were limited to days 3 to 6 of individual cycles. Grade 1/2 nausea was observed in 10 patients (83%) and was controlled with an antiemetic regimen in the majority of these patients.

The single patient with ET developed a grade 2 deep venous thrombosis after 1 week on combination therapy and left the trial. Thrombocytosis persisted in this patient despite resolution of baseline microvascular symptoms.

Mascarenhas et al noted that gastrointestinal toxicity remains a limiting factor for some patients. “It is important to note that low grade gastrointestinal toxicity occurring during the 5 days of idasanutlin dosing each month can contribute to reduced quality of life and work productivity, thereby leading to treatment discontinuation despite excellent hematologic responses,” they wrote. “This was the main reason patients withdrew consent in this study despite not experiencing grade 3/4 non-hematologic toxicity. This phenomenon is important to consider as this class of agents is further developed in a setting for a hematologic malignancy that has a median survival of nearly 2 decades and [where] treatments are administered for extended periods.”

Currently, a global phase II trial of idasanutlin therapy for patients with hydroxyurea-resistant or -intolerant PV is underway.


Mascarenhas J, Lu M, Kosiorek H, et al. Oral idasanutlin in patients with polycythemia vera [published online June 5, 2019].Blood.doi: 10.1182/blood.2018893545.