A total of 61 patients were treated in 16 dose cohorts (see ) and were evaluable for toxicity. Demographics and baseline characteristics for the safety population are shown in . The majority of patients were male (61%) and median age was 60 years (range, 24–80 years). All patients had a Performance Status of 0 (54%) or 1 (46%). The most common primary diagnoses were colorectal cancer (36%), lung cancer (15%), genitourinary tumors (13%), and sarcoma (13%). Most patients had been heavily pretreated, with 79% having received 3 or more courses of prior treatment before study entry.
Patient Demographics and Baseline Characteristics (N = 61)
Reasons for discontinuation were progressive disease in 39 patients (64%), symptomatic deterioration in 9 (15%), AE in 5 (8%), withdrawal of consent in 3 (5%), death of 1 (2%) due to cardiac arrest unrelated to MLN8054, and other reasons in 4 (7%). The median number of MLN8054 treatment cycles was 2 (range, 1–14). Patients received 98% of all expected doses overall.
Although 60 unique patients were enrolled in the study, 1 patient was enrolled twice and was separately evaluated for safety as a member of both the QD-7D 40 mg cohort and the QID-7D 25 mg cohort, and thus 61 patients were evaluable for safety. A total of 59 patients (97%) were evaluable for DLT; the other 2 patients discontinued treatment during cycle 1, before DLT could be evaluated. One patient in the QD-7D 5 mg cohort discontinued due to hospitalization for renal failure and hypovolemia unrelated to MLN8054 and one patient in the QID/M-21D 60 mg cohort discontinued due to hospitalization for spine fracture unrelated to MLN8054.
summarizes the observed DLTs by cohort. Somnolence, which resolved in all but one patient, was the only DLT for MLN8054 given without methylphenidate or modafinil. The onset of somnolence and its severity generally were correlated with dose and Cmax. Because somnolence was thought to be related to Cmax, the dosing schedule was changed from daily to QID dosing in an effort to lower peak plasma concentrations and allow further dose escalation. However, dose-limiting somnolence was seen at both QD-7D dosing (1 of 6 patients at 30 mg and 2 of 4 patients at 40 mg) and QID-7D dosing (1 of 6 patients at 25 mg and 2 of 4 patients at 55 mg).
The addition of methylphenidate (e.g. 5 mg oral dose) or modafinil repeated as needed with the three daytime MLN8054 doses allowed further dose escalation. Dose-limiting but reversible somnolence was seen in 1 of 6 patients in the QID/M-7D 60 mg cohort and grade 3 cognitive disorder and hallucination were experienced by 1 of 3 patients in the QID/M-7D 80 mg cohort. The QID/M-7D 80 mg cohort was not expanded to further define the MTD using the 7-day schedule because all three patients at this level experienced grade ≥ 2 CNS effects and the investigator consensus was to evaluate longer treatment schedules if possible. With 14-day dosing, DLTs of reversible somnolence or other central nervous system effects (fatigue, confusional state, and cognitive disorder) were seen in 2 of 2 patients at QID/M-14D 70 mg. Because these events were seen during the first week of a planned 2-week treatment, subsequent patients were enrolled to a QID/M-14D 60 mg cohort. None of 3 patients in this cohort had a DLT. Using a QID schedule with 10 mg administered 3 times during the day and 30 mg at night, the total daily dose of 60 mg was generally tolerable over a 7- to 14-day schedule.
Of the 4 patients who were enrolled to a QID/M-21D 60 mg cohort, 2 had a DLT. Both patients had a DLT of somnolence and 1 of the patients also had DLTs of cognitive disorder and confusion. Therefore, no additional cohorts were enrolled to 21-day dosing regimens.
Thus, the estimated MTD of MLN8054 was 60 mg divided QID for 7-14 days, given with methylphenidate or modafinil as needed with the daytime doses to manage somnolence.
All 61 patients (100%) were treated and were evaluable for safety. summarizes the most frequent drug-related adverse events, which included somnolence, fatigue, confusion, nausea and vomiting. Forty-seven patients (77%) experienced drug-related somnolence, with 11 (18%) experiencing grade 3 somnolence. Many of the patients in this study received at least one other medication that could have contributed to somnolence; 37 (61%) received an opioid analgesic, 15 (25%) received a benzodiazepine or other anxiolytic, and 12 (20%) received a hypnotic or sedative agent.
Drug-Related Adverse Events: Any Grade in ≥ 10% of Patients or Grade ≥ 3 in Any Patient (N=61)
Among the 11 patients with dose-limiting somnolence related to MLN8054 across all dose levels, concomitant use of opioid medication was reported in 8 patients. Opioid use was reported frequently in many patients enrolled to this study, however, and the frequency of somnolence was comparable in patients who were or were not receiving concomitant opioids. Moreover, dose-limiting (CTC Grade 3) somnolence was reported in 2 patients without concomitant treatment with opioids or other sedating medications who received the highest MLN8054 dose levels within the first days of dosing, so that further dose escalation was not feasible even in a population not receiving concomitant opioid medications.
Thirty-four patients (56%) had a grade ≥3 AE, including 13 patients (21%) with a drug-related grade 3 AE (); no patient had a drug-related grade 4 or 5 AE. No dose studied was associated with grade ≥ 3 mucositis or myelosuppression, predicted to be mechanistic effects associated with Aurora A kinase inhibition.
Nine patients (15%) died within 21 days of the last dose of MLN8054; none of these deaths were considered drug-related.
Forty-eight patients (79%) had sufficient dosing and MLN8054 concentration-time data to estimate pharmacokinetics. Mean MLN8054 plasma concentration-time profiles for QD-7D doses are shown in . Pharmacokinetic parameters for each cohort are summarized in . MLN8054 was absorbed over a short period, with Tmax
ranging from 1–4 hours. Terminal elimination half-life (t1/2
) was 30–40 hours. AUC0-24
hr and Cmax
were roughly dose-proportional with QD dosing and the peak-to-trough ratio (Cmax
) for all dose levels was approximately 5. Only 1 patient in the QD-7D 30 mg cohort had a trough concentration on day 7 that was >2000 nM, the predicted minimum concentration needed for inhibition of Aurora A kinase based on a tumor xenograft model [20
]. The two patients with the highest Day 1 Cmax
values among PK-evaluable patients enrolled in the QD dosing cohorts both experienced grade 3 somnolence.
MLN8054 plasma concentration-time profiles. (A) Mean values in the QD-7D cohorts; (B) Individual patients in the QID/M-14D 60 mg cohort. Open symbols = mean values; closed symbols = individual data.
Summary of Pharmacokinetic Parameters at Steady State
The protocol was amended to implement QID-7D dosing to reduce Cmax, thereby reducing somnolence, and to increase trough concentrations, thereby increasing the probability of inhibiting Aurora A kinase for a substantial period of time. Using this approach with total daily doses of 25, 35, 45, and 55 mg, the mean Cmax values were 1050, 1966, 1526, and 2484 nM, respectively, and the mean trough concentrations after the second daily dose on day 7 were 720, 1464, 1139, and 1802 nM, respectively. The peak-to-trough ratio was between 1.3 and 1.6 across these 4 cohorts, substantially lower than the ratio for QD dosing regimens. On average, drug concentrations for the highest dose, QID-7D 55 mg, were close to the target of 2000 nM.
Subsequent QID cohorts added oral methylphenidate or modafinil with each of the 3 daytime doses of MLN8054 to mitigate the impact of somnolence. Pharmacokinetic data from the QID/M-7D 70 mg cohort showed promise for maintaining a mean plasma MLN8054 concentration of 2000 nM and a peak-to-trough ratio of 1.65 over the course of treatment.
When the duration of dosing was extended to QID/M-14D, both patients in the 70 mg cohort had a DLT and neither was evaluable for pharmacokinetics. The dose level was reduced to QID/M-14D 60 mg and all 3 patients were evaluable for pharmacokinetics. Mean MLN8054 concentrations in these patients were close to 2000 nM between the second and third doses on day 7, and were >2000 nM between the second and third doses on day 14 ().
Only 1 patient in the QID/M-21D 60 mg cohort was evaluable for pharmacokinetics on days 14 and 21, and MLN8054 concentrations in this patient were <2000 nM between the second and third doses on each of these days. Two of the 3 patients with the highest Day 7 Cmax values among PK-evaluable patients enrolled in the various QID dosing cohorts experienced grade 3 somnolence. One of these patients experienced Grade 3 somnolence despite receiving methylphenidate. Thus, of the 48 patients with sufficient data to estimate pharmacokinetic parameters, 7 patients had trough MLN8054 concentrations that were >2000 nM, including 1 patient in the QD-7D 30 mg cohort, 1 patient in the QID-7D 55 mg cohort, 2 patients in the QID/M-7D 70 mg cohort, 1 patient in the QID/M-7D 80 mg cohort, and 2 patients in the QID/M-14D 60 mg cohort.
Skin biopsies were evaluable pre- and post-treatment in 52 patients. Although some patient skin samples had increased numbers of mitotic cells suggestive of Aurora A kinase inhibition after MLN8054 dosing, these increases generally were slight and did not compellingly indicate Aurora A inhibition in any dose cohort. No relationship was observed between the pharmacodynamic parameters and either the MLN8054 dose or the MLN8054 pharmacokinetic parameters. Despite the fact that 7 patients had trough MLN8054 concentrations >2000 nM, the skin biopsies in these patients did not provide significant evidence of Aurora A kinase inhibition.
No complete or partial responses were seen. Nine patients (15%) had stable disease for at least 4 cycles, including 3 (5%) with stable disease for greater than 6 cycles. These included 1 patient in the QD-7D 5 mg cohort with colorectal cancer (8 cycles; 165 days), 1 patient in the QID/M-7D 55 mg cohort with extraskeletal chondrosarcoma (8 cycles; 129 days), and another patient in the QID/M-7D 55 mg cohort with spindle-cell sarcoma (12 cycles; 266 days).