Study design and patients
This report covers three open-label, phase I, dose-escalation studies investigating volasertib monotherapy and combination therapy with azacitidine in adult patients with MDS, AML, and/or CMML: studies 1230.33 (Study 1), 1230.35 (Study 2), and 1230.43 (Study 3).
Inclusion criteria differed across the three studies in terms of treatment history. Study 1 (NCT01957644) investigated the combination of volasertib and azacitidine in patients with previously untreated intermediate-2 or higher-risk MDS or CMML, who were not candidates for HSCT. Study 2 (NCT02201329) investigated the combination in Japanese patients with intermediate-2 or higher-risk MDS or CMML, who were also not candidates for HSCT; patients could have previously received treatment with azacitidine or be untreated. Study 3 (NCT02721875) investigated volasertib monotherapy or volasertib plus azacitidine in patients with higher-risk MDS, CMML, or AML after failure of treatment with hypomethylating agents. Other inclusion criteria included: age ≥ 18 years (Studies 1 and 3) or between 20 and 80 (Study 2), Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1 (Study 2), or ≤ 2 (Studies 1 and 3).
Patients were excluded from all three studies if they had received prior treatment with volasertib or had a concomitant malignancy requiring active therapy. Patients in Study 1 were excluded if they had received prior or concomitant therapy for higher-risk MDS or prior treatment with any PLK1 inhibitor. In Study 2, patients were excluded if they had received systemic therapy for MDS within 14 days before treatment. Patients were excluded in Study 3 if they had received any prior systemic therapy for MDS, CMML, or AML within 14 days of treatment, and if they had received any prior PLK inhibitor or hypomethylating treatment.
In all three studies, escalating doses of intravenous volasertib were administered to determine the maximum tolerated doses (MTD); all cycles were 28 days. In Part 1 of Study 1, patients received volasertib infusions on days 1 and 15, starting at a flat dose of 250 mg and escalating in 50 mg steps to 350 mg (Fig. 1). In Part 2 of Study 1, patients received body surface area (BSA)-adapted doses of volasertib and different schedules (Schedule A [planned], volasertib 170 mg/m2 on day 1; Schedule B, volasertib 170 mg/m2 on day 7; Schedule C, volasertib 110 mg/m2 on days 1 and 7). After the MTD was determined, it was planned to enroll up to 40 patients in an expansion cohort to characterize safety further.
In Study 2, a schedule of infusions on days 1 and 15 was planned, starting at a flat dose of 200 mg in Cohort 1 and escalating in 50 mg steps to 300 mg (250 mg in Cohort 2 and 300 mg in Cohort 3). In Study 3, a schedule of infusions on days 1 and 8 was planned, starting at a dose of 110 mg/m2 (other doses and another schedule were also planned).
Patients in Studies 1 and 2 also received subcutaneous azacitidine 75 mg/m2 on days 1–7 of the 28-day cycle. Study 3 planned to evaluate two different treatment schedules: volasertib monotherapy (Schedule A) and subcutaneous or intravenous azacitidine in combination with volasertib (Schedule B). The dose escalation cohorts for each Schedule were planned to be enrolled alternately.
All trials were carried out in accordance with the principles of the Declaration of Helsinki, with the International Conference on Harmonization Harmonised Tripartite Guideline for Good Clinical Practice (GCP), and with applicable regulatory requirements. All patients provided written informed consent.
Endpoints
The primary objective of each study was to determine the MTD of volasertib in combination with azacitidine (or as monotherapy in Study 3), which was defined as the dose level in which less than 2 of 6 patients (Study 1), not more than 1 of 6 patients (Study 2), or not more than 33% of patients (Study 3) experienced a dose-limiting toxicity (DLT).
DLTs were defined as any of the following considered to be drug-related: 1) grade ≥ 3 (Common Terminology Criteria for Adverse Events [CTCAE] Version 3.0 or 4.03) non-hematological toxicity (exceptions were untreated nausea, vomiting, or diarrhea; clinically non-significant laboratory abnormalities, or laboratory abnormalities that resolved spontaneously; febrile neutropenia or grade 3 infection if the patient recovered with appropriate treatment within 7 days [all studies]); 2) inability to deliver the full dose of volasertib according to the assigned dose level within cycle 1; 3) treatment delay of ≥ 4 weeks due to drug-related adverse events (DRAEs).
Further safety endpoints included the incidence and intensity of adverse events (AEs) graded according to CTCAE Version 3.0 or Version 4.03. Efficacy was a secondary endpoint in these studies and was assessed by determining objective response to treatment according to International Working Group 2006 criteria [15]. In Studies 1 and 3, the objective response rate was calculated (proportion of patients with complete remission [CR] or partial remission [PR]).
Statistical analyses
All analyses were summarized descriptively; no formal hypothesis testing was planned.
Protocol amendments
Study 1
Following reports of an increased rate of fatal infection in the phase III 1230.14 trial of volasertib in patients with AML, Study 1 was modified: volasertib dosing adaptation to the patient’s individual BSA instead of a volasertib flat starting dose of 250 mg and the introduction of volasertib dosing schedules A (day 1), B (day 7), and C (days 1 and 7) instead of a single dosing schedule (days 1 and 15).
Study 2
In consideration of the DLT occurrence status in Study 1, planned doses in Cohorts 2 and 3 were changed from 300 mg to 250 mg for Cohort 2 and from 350 mg to 300 mg for Cohort 3, with the change of number of patients per cohort from 3-6 to 6, and Cohort Intermediate was deleted.
Study 3
The amendments to the protocol for Study 3 were as follows: the analysis of efficacy was to be performed only for the secondary endpoint because only 1 patient was treated in this study.