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Keywords:

  • kinesin spindle protein inhibitor;
  • ARRY-520;
  • phase 1;
  • maximum tolerated dose;
  • advanced myeloid leukemia;
  • myelodysplastic syndrome;
  • relapsed

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References

BACKGROUND:

ARRY-520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis.

METHODS:

A phase 1 trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 given as a 1-hour infusion in either a single dose or on a day 1, 3, and 5 divided-dose schedule per cycle in patients with advanced or refractory myeloid leukemias. Additional objectives were to characterize pharmacokinetics, assess preliminary clinical activity, and explore biomarkers of KSP inhibition with ARRY-520. A total of 36 patients with acute myelogenous leukemia (n = 34) or myelodysplastic syndromes (n = 2) with a median age of 66 years (range, 21-88 years) were enrolled: 15 in the single-dose schedule (dose levels: 2.5, 3.75, 4.5, and 5.6 mg/m2) and 21 in the divided-dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m2/day).

RESULTS:

The MTD was 4.5 mg/m2 total dose per cycle for both dose schedules. Dose-limiting toxicities included mucositis, exfoliative rash, hand-foot syndrome, and hyperbilirubinemia. Grades 3 or 4 reversible drug-related myelosuppression were observed in 33 of 36 patients. Plasma pharmacokinetic analyses revealed low clearance of ARRY-520 (∼3 L/hour), a volume of distribution of ∼450 L, and a median terminal half-life of >90 hours. Monopolar spindles were observed in blood mononuclear cells, through use of 4′,6-diamidino-2-phenylindole nucleic acid stain and antitubulin antibodies.

CONCLUSIONS:

On the basis of the relative lack of clinical activity, further development of ARRY-520 as an antileukemic agent was halted. (Clinicaltrials.gov identifier NCT00637052). Cancer 2012;3556–3564. © 2011 American Cancer Society.

Treatment of acute myeloid leukemia (AML) has been based for the past 30 years on a combination of an anthracycline and cytosine arabinoside. This approach is effective, and up to 70% of patients achieve remission,1-6 but disease recurrence is common (80%) without consolidation with an allogeneic hematopoietic stem cell transplantation (HSCT)7-9 The majority of relapses occur in the first year after diagnosis,10-14 which is associated with lower chances of achieving and sustaining a second complete remission (CR), a prerequisite for a curative allogeneic transplant.15-19 Therefore, well-tolerated and effective new drugs for the treatment of AML are desperately needed.

Antimitotics are effective anticancer agents, with mechanisms of action that involve inhibition of tubulin polymerization (vinca alkaloids) or stabilization of microtubule polymers (taxanes). However, their lack of specificity results in dose-limiting neurotoxicity from disruption of microtubule dynamics in synaptic vesicles and Golgi apparatus. Mitotic kinesins are a family of motor proteins involved in all phases of mitosis, including chromosome and mitotic spindle dynamics and microtubule depolymerization.20 These proteins convert the energy of adenosine triphosphate hydrolysis to mechanical force resulting in movement of microtubules.21 Kinesin spindle protein (KSP; also known as hsEg5) is one member of the mitotic kinesins involved in the early stages of mitosis responsible for centrosome separation, a prerequisite for formation and maintenance of the bipolar spindle.22 Microinjection of KSP antibodies into cells resulted in monopolar spindles, mitotic arrest, and apoptosis.23, 24 Similar cellular effects and anticancer activity have been observed with several structurally distinct small-molecule KSP inhibitors,20, 25-27 both in vitro and in mouse xenograft models.25, 28-30 Targeting KSP is therefore an attractive novel approach in cancer treatment, given that KSP inhibitors may theoretically permit dose escalation to overcome drug resistance without the concern for neurotoxicity.

ARRY-520 is a potent, highly selective inhibitor of KSP that induces mitotic arrest and tumor cell death at subnanomolar concentrations. ARRY-520 has demonstrated anticancer efficacy in mouse subcutaneous solid-tumor xenograft models (HT-29, HCT-116, A2780, K562, and HCT15).31 Therefore, a phase 1 trial was conducted to identify the optimal dose schedule and determine the maximum tolerated dose (MTD) of ARRY-520 in patients with relapsed and refractory AML and advanced myelodysplastic syndromes (MDS).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References

Study Design

The study was an open-label, multicenter, dose-escalation trial that sought to assess safety and determine the MTD, preliminary efficacy, and pharmacokinetics, and to identify markers of pharmacodynamic activity of ARRY-520. Two dose schedules were sequentially explored: a single-dose schedule where ARRY-520 was given intravenously over 1 hour on day 1 (schedule 1), and a multidose schedule where ARRY-520 was given intravenously over 1 hour daily on days 1, 3, and 5 (schedule 2). The dose of ARRY-520 was escalated after a minimum of 3 evaluable patients were entered at each dose level. Initially, doses of ARRY-520 were increased by 50% until study drug-related grade 2 nonhematological adverse events (AE) occurred; then, the escalation schema was changed to an increase of 30%. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0. Dose escalation to a new dose level occurred in the absence of a dose-limiting toxicity (DLT). A DLT was defined as any grade 2 nonhematological AE occurring in the induction cycle, which was deemed related to ARRY-520. If a DLT was observed in 1 of the 3 evaluable patients, 3 additional patients were recruited at the same dose level. Dose escalation continued unless a DLT was observed in more than 1 of 6 evaluable patients; otherwise, the dose was considered a nontolerated dose, and dose escalation was stopped. When a nontolerated dose was identified, 3 additional evaluable patients were recruited at the lower dose to confirm the MTD. Patients received subsequent cycles in the absence of toxicity or progressive disease. Intraindividual dose escalation was not permitted.

Safety

Safety was assessed on a continuous basis. In addition, patients were monitored with complete blood counts 3 times per week, blood chemistries twice weekly, and coagulation parameters weekly. Bone marrow aspirate and biopsy was done between days 10 and 14 of the first course and repeated at hematological recovery or between days 28 and 31. Electrocardiograms were done prior to start of infusion, within 15 to 30 minutes and 24 hours after the end of infusion. A serious adverse event (SAE) was defined as an AE that was life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect, or death.

Efficacy

Efficacy for patients with AML was assessed by determining the incidence of CR and partial remission during induction therapy and subsequent courses. Response for patients with advanced MDS was evaluated according to the modified International Working Group (IWG) criteria.32

Pharmacokinetics

Blood samples were collected during cycle 1 for determination of plasma concentrations of ARRY-520 on days 1 (1, 2, and 8 hours), 2, 3, 5, and 8 on schedule 1; and on days 1 (1, 2, and 8 hours), 2, 3 (predose, 1 and 4 hours), 5 (predose, 1, 2, and 8 hours), 8, 11, and 15 on schedule 2. Bioanalysis was performed using a validated liquid chromatography tandem mass spectrometry method with a lower limit of detection of 1 ng/mL. Pharmacokinetic (PK) parameters were determined from the individual plasma concentration-time curves of ARRY-520 by noncompartmental analysis.

Pharmacodynamics

Blood samples were collected for pharmacodynamic analyses during cycle 1 and cycle 2 (if applicable). Peripheral blood mononuclear cells (PBMCs) were purified from cycle 1, day 5 samples using Ficoll separation. PBMCs were gently centrifuged for 5 minutes onto poly-lysine–treated cover slips, then fixed in PHEMO buffer (68 mM PIPES, 25 mM HEPES, pH 6.9, 15 mM ethylene glycol tetraacetic acid, 3 mM MgCl2, 10% [vol/vol] dimethyl sulfoxide) for 10 minutes. Cells were washed in phosphate-buffered saline (PBS), then blocked in 10% normal goat serum and incubated with mouse anti-acetylated alpha-tubulin (Sigma #T6793; 1:1000) diluted into 5% normal goat serum for 16 hours at 4°C. Cells were washed in PBS, then incubated with a secondary anti-mouse Alexa 488–conjugated antibody (Invitrogen; 1:500) for 1 hour, and washed in PBS. Cells were then incubated with rat anti-tubulin (Millipore MAB1864) for 1 hour at room temperature, washed in PBS, then incubated with Alexa 565–conjugated anti-rat antibody for 1 hour at room temperature. Cells were washed again in PBS, incubated with 350 nM 4′,6-diamidino-2-phenylindole (DAPI), then mounted onto slides. Confocal z-sections were acquired using a Zeiss LSM510 META microscope.33

Patients

Patients aged ≥17 years with relapsed or refractory AML or high-grade myelodysplastic syndromes (including refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 through 2, and adequate hepatic and renal function were eligible for enrollment in the absence of central nervous system involvement by disease. Patients with newly diagnosed AML who were not eligible for, or refused, standard-of-care treatment were also eligible. All prior antileukemic therapy had to be discontinued ≥2 weeks prior to study entry. Concurrent use of hydroxyurea was allowed during the first 14 days of study to control white blood cell counts. The study was approved by the University of Texas MD Anderson Cancer Center and Emory University ethics committees, and all patients gave written informed consent.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References

Patients

Between March 2008 and April 2010, 36 patients enrolled in this trial: 15 on schedule 1 and 21 on schedule 2. All patients received at least 1 cycle of ARRY-520.

Median age of the 15 patients treated according to schedule 1 was 69 years (range, 44-88 years); 8 were male and 7 were female. ECOG performance status was 0 in 2 patients, 1 in 7 patients, and 2 in 6 patients (Table 1). All patients had AML and were diagnosed an average of 26 months (range, 6-108 months) prior to enrollment. The median number of prior chemotherapy regimens was 4 (range, 1-7). Two patients had relapsed AML after allogeneic HSCT. Median number of cycles of ARRY-520 administered was 1 (range, 1-4).

Table 1. Patient Characteristics
CharacteristicSchedule 1 (n = 15)Schedule 2 (n = 21)Total (n = 36)
  1. Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Median age (range), y69 (44-88)63 (21-83)66 (21-88)
Sex, female/male7/87/1414/22
Race, n (%)   
 Black1 (7)1 (5)2 (6)
 Caucasian14 (93)19 (90)33 (92)
 Other0 (0)1 (5)1 (3)
ECOG performance status   
 02 (13)3 (14)5 (14)
 17 (47)11 (52)18 (50)
 26 (40)7 (33)13 (36)
Diagnosis   
 Myelodysplastic syndromes0 (0)2 (10)2 (6)
 Acute myelogenous leukemia15 (100)19 (90)34 (94)

Median age of the 21 patients who received ARRY-520 according to schedule 2 was 63 years (range, 21-83 years); 14 were male and 7 were female. ECOG performance status was 0 in 3 patients, 1 in 11 patients, and 2 in 7 patients (Table 1). Nineteen patients had AML and 2 patients had MDS. The median number of prior chemotherapy regimens was 3 (range, 1-5). Median time from diagnosis to start of ARRY-520 was 12 months (range, 0-45 months). Three patients had prior allogeneic HSCT. Median number of cycles of ARRY-520 administered was 1 (range, 1-4).

The starting dose for schedule 1 was 2.5 mg/m2 administered on day 1, based on DLTs observed in the phase 1 study with this schedule of administration in patients with solid tumors (Study ARRAY-520-101; Clinicaltrials.gov identifier NCT00462358). The starting dose for schedule 2 was 0.8 mg/m2/day (2.4 mg/m2 total dose).

Safety Profile

All 36 patients were evaluable for safety analysis. All patients experienced at least 1 AE while on study; 27 patients (75%) experienced AEs that were related to the study drug. Table 2 summarizes nonhematological AEs that were observed in more than 10% of patients in both schedules. Twenty-six patients (72%) had an SAE (10 in schedule 1 and 16 in schedule 2). Ten patients (28%) had 1 or more SAEs considered related to the study drug: mucositis (n = 6, 17%), neutropenic fever (n = 3, 8%), exfoliative rash (n = 1, 3%), palmar-plantar erythrodysesthesia (n = 2, 6%), hyperbilirubinemia (n = 1, 3%), bacteremia (n = 1, 3%), pancytopenia (n = 1, 3%), diarrhea (n = 1, 3%), and stomatitis (n = 1, 3%). AEs led to discontinuation in 3 patients (8%). Hematological toxicities were common and included grades 3 or 4 anemia (n = 20), grades 3 or 4 leukopenia (n = 21, present at baseline in n = 6), grade 4 neutropenia (n = 26, present at baseline in n = 21), and grade 4 thrombocytopenia (n = 33).

Table 2. Nonhematological Adverse Events Observed in >10% of Patients
Nonhematological Adverse EventsSchedule 1 (N = 15)Schedule 2 (N = 21)Total (N = 36)
 n(%)n(%)n(%)
Total patients with any adverse event15(100)21(100)36(100)
Diarrhea4(27)11(52)15(42)
Mucosal inflammation6(40)9(43)15(42)
Febrile neutropenia6(40)7(33)13(36)
Nausea1(7)11(52)12(33)
Hypokalaemia4(27)5(24)9(25)
Rash3(20)4(19)7(19)
Constipation0(0)7(33)7(19)
Vomiting2(13)5(24)7(19)
Dyspnea2(13)4(19)6(17)
Cough2(13)3(14)5(14)
Headache2(13)3(14)5(14)
Peripheral edema3(20)2(10)5(14)
Pneumonia1(7)4(19)5(14)
Pyrexia2(13)3(14)5(14)
Anorexia0(0)4(19)4(11)
Asthenia0(0)4(19)4(11)
Cellulitis2(13)2(10)4(11)
Dizziness0(0)4(19)4(11)
Fatigue1(7)3(14)4(11)
Hyperphosphatemia4(27)0(0)4(11)
Hypomagnesemia2(13)2(10)4(11)
Hypotension4(27)0(0)4(11)
Palmar-plantar erythrodysesthesia syndrome2(13)2(10)4(11)
Pleural effusion1(7)3(14)4(11)

When ARRY-520 was administered according to schedule 1, no DLTs were observed at the 2.5, 3.75, or 4.5 mg/m2 doses, but 2 patients experienced grade 3 mucositis at the 5.6 mg/m2 dose; therefore, the 4.5 mg/m2 dose was established as the MTD. In schedule 2, no DLTs were observed at 0.8 mg/m2/day (2.4 mg/m2 total dose per cycle). Grade 3 mucositis was observed in 1 patient at 1.2 mg/m2/day (3.6 mg/m2 total dose per cycle) and in 1 patient at 1.5 mg/m2/day (4.5 mg/m2 total dose per cycle) (Table 2). DLTs were observed in 2 patients at 1.8 mg/m2/day (5.4 mg/m2 total dose per cycle), and included grade 3 mucositis (n = 1), hyperbilirubinemia (n = 1), exfoliative rash (n = 1), and hand-foot syndrome (n = 1). The MTD was therefore also established to be 1.5 mg/m2/day (4.5 mg/m2 total dose) in schedule 2. No grade 3 or 4 QTc prolongation was observed, however; asymptomatic grades 1 and 2 QTc prolongations were noted in 8 (22%) and 1 (3%) patients, respectively. No other clinically significant electrocardiogram changes were observed. Neurotoxicity was not observed at any dose up to the MTD.

Efficacy and Outcomes

Of 34 patients for whom efficacy data were available, 1 (3%) achieved a partial response, 10 (29%) had stable disease, and 23 (68%) experienced disease progression. Thirty-three patients received subsequent therapies after discontinuation of this phase 1 trial, and 6 (17%) died within 30 days following discontinuation of ARRY-520. At last follow-up, 32 patients had died. Causes of death included progressive disease (n = 14), infection (n = 7), and central nervous system bleed (n = 1). Cause of death was not provided for 10 patients.

Pharmacokinetics and Pharmacodynamics

PK data were available from 10 patients in schedule 1 and 18 patients in schedule 2. The geometric mean plasma concentrations of ARRY-520 versus nominal sample collection time for cycle 1 are shown in Fig. 1A (schedule 1) and Fig. 1B (schedule 2). Summaries of PK parameters for cycle 1 in both schedules are shown in Table 3. After single doses of ARRY-520 (schedule 1), geometric mean area under the plasma concentration-time curve (AUCinf) values ranged from 1480 hour · ng/mL (3.75 mg/m2) to 3000 hour · ng/mL (4.5 mg/m2), whereas maximum observed plasma concentrations (Cmax) ranged from 31.1 to 132 ng/mL. The geometric mean clearance across all patients was low, at 3.36 L/hour (range: 2.69-6.77 L/hour). The geometric mean clearance for cycle 2 (all patients, N = 4) was equivalent (3.02 L/hour) to cycle 1, suggesting linear PK with repeat dosing. The coefficient of variation (CV) for mean clearance was 50.7% (cycle 1) and 77.1% (cycle 2), indicating moderately high interpatient variability in exposure. Similar CVs were observed when comparing cycle 1 to cycle 2 AUC values (intrapatient variability). Dose proportionality was difficult to assess given the narrow dose range and variability in exposure. The mean volume of distribution (Vss) was 446 L (55.2% CV), suggesting significant peripheral distribution. Consistent with the large volume and low clearance, the median terminal half-life (t1/2) was 98.6 hours. Similar values were observed for each cohort, indicating that terminal elimination of ARRY-520 was not dose-dependent over the dose range studied. Because of the long t1/2, plasma concentrations of ARRY-520 following a single infusion were maintained above 2 ng/mL for more than 7 days after initiation of infusion for all cohorts. The median of the mean residence time for ARRY-520 was 127 hours (5.3 days). Following intravenous dosing on days 1, 3, and 5 (schedule 2), similar distribution and elimination phases were observed compared to schedule 1 concentration-time profiles for ARRY-520. Exposure tended to increase with each day of dosing. The overall ratio of AUC0-24 values on day 5 compared to day 1 was 2.23 (range across cohorts: 1.54-2.92), indicating a trend toward accumulation with repeated dosing at 48-hour intervals. After the third infusion of ARRY-520 in schedule 2, the median t1/2 (92.5 hours) and median mean residence time (130 hours) were equivalent to values observed following a single infusion in schedule 1. As a result of the repeat dosing, accumulation, and terminal phase, the geometric mean plasma concentrations of ARRY-520 were maintained above 2 ng/mL for more than 14 days for all cohorts.

thumbnail image

Figure 1. Geometric mean plasma concentration of ARRY-520 (with 1 standard deviation) is shown for (A) schedule 1 and (B) schedule 2.

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Table 3. Cycle 1 Pharmacokinetic Parameters for Schedule 1 and Schedule 2a
Schedule 1: Cycle 1 Day 1
 2.5 mg/m23.75 mg/m24.5 mg/m25.6 mg/m2Schedule Total
Parameter(N = 3)(N = 1)(N = 4)(N = 2)(N = 10)
AUCinf (h·ng/mL)1650 (17.2)1480 (NC)3000 (66.1)2520 (NC)NA
CL (L/h)2.69 (6.90)6.77 (NC)2.95 (67.7)4.30 (NC)3.36 (50.7)
Vss (L)405 (87.4)857 (NC)340 (10.8)515 (NC)446 (55.2)
t1/2 (h)97.2 (64.4-291)100 (100-100)100 (29.5-149)92.5 (44.9-140)98.6 (29.5-291)
Cmax (ng/mL)132 (1410)31.1 (NC)53.4 (39.9)49.6 (NC)NA
Tmax (h)2.00 (1.00-2.03)1.00 (1.00-1.00)1.01 (1.00-1.08)0.959 (0.917-1.00)1.00 (0.917-2.03)
MRT (h)92.7 (53.2-314)127 (127-127)142 (42.7-202)131 (63.7-198)127 (42.7-314)
Schedule 2: Cycle 1
 0.8 mg/m21.2 mg/m21.5 mg/m21.8 mg/m23.6 mg/m2Schedule Total
Parameter(N = 3)(N = 6)(N = 6)(N = 2)(N = 1)(N = 18)
  • Abbreviations: AUC0-24, geometric mean area under the plasma concentration-time curve; CL, geometric mean clearance; Cmax, maximum observed plasma concentration; MRT, mean residence time; NA, not applicable; NC, not calculated; t1/2, terminal half-life; Vss, mean volume of distribution; Tmax, time to peak concentration.

  • a

    Parameters are reported as geometric mean (geometric % coefficient of variation) with exceptions of MRT, t1/2, and Tmax, which are median (min-max), and Vss, which is mean (% coefficient of variation).

Day 1
AUC0-24 (h·ng/mL)116 (161)133 (58.1)264 (142)208 (NC)345 (NC)NA
CL (L/h)6.55 (87.2)7.82 (110)5.90 (92.5)7.81 (NC)11.2 (NC)7.12 (81.5)
Vss (L)295 (82.7)363 (50.7)251 (81.5)306 (NC)278 (NC)306 (57.6)
t1/2 (h)29.8 (4.44-30.6)25.6 (22.2-61.1)26.1 (16.6-32.4)27.1 (25.8-28.4)18.7 (18.7-18.7)26.1 (4.44-61.1)
Cmax (ng/mL)19.5 (550)18.8 (22.9)57.9 (590)24.4 (NC)73.9 (NC)NA
Tmax (h)1.00 (0.983-1.00)1.09 (1.00-2.25)1.00 (1.00-2.00)1.00 (1.00-1.00)1.00 (1.00-1.00)1.00 (0.983-2.25)
Day 3
Cmax (ng/mL)6.68 (108)29.8 (116)79.8 (393)47.1 (NC)70.3 (NC)35.6 (245)
Tmax (h)1.08 (1.00-1.18)1.00 (1.00-1.25)1.00 (1.00-1.08)0.959 (0.917-1.00)1.08 (1.08-1.08)1.00 (0.917-1.25)
Day 5
AUC0-24 (h·ng/mL)179 (75.7)320 (96.9)667 (134)608 (NC)733 (NC)NA
CL (L/h)2.03 (62.5)0.947 (51.4)1.11 (70.9)1.10 (NC)1.33 (NC)1.19 (60.1)
Vss (L)193 (82.5)239 (95.8)169 (70.3)127 (NC)202 (NC)191 (78.0)
t1/2 (h)92.5 (33.3-93.3)94.9 (75.3-572)82.2 (32.2-350)80.0 (77.4-82.6)108 (108-108)92.5 (32.2-572)
Cmax (ng/mL)25.3 (567)24.3 (80.8)134 (465)53.6 (NC)199 (NC)NA
Tmax (h)1.08 (1.00-1.08)1.00 (1.00-2.08)1.02 (0.983-2.00)1.00 (1.00-1.00)1.08 (1.08-1.08)1.00 (0.983-2.08)
MRT (h)130 (24.8-132)134 (108-819)119 (37.6-421)114 (108-119)152 (152-152)130 (24.8-819)

A common defect observed with KSP inhibition is monopolar spindle formation; therefore, microtubule spindle morphology was imaged in PBMCs from cycle 1, day 5 in patients dosed at 1.2 mg/m2/day. Aberrant spindles along with misaligned DNA were observed in some PBMCs of these patients (Fig. 2), through use of confocal imaging of tubulin and DAPI (DNA). Thus, these results are consistent with the on-target activity of ARRY-520.

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Figure 2. Aberrant spindles are observed in peripheral blood mononuclear cells after ARRY-520 treatment. Confocal imaging is shown for peripheral blood mononuclear cells from patients with (A) 4′,6-diamidino-2-phenylindole (DAPI), (B) tubulin, and (C) merge of tubulin and DAPI staining.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References

This phase 1 trial sought to identify an optimal dose schedule and the MTD of ARRY-520 in patients with relapsed and/or refractory AML or advanced MDS. This study demonstrated that the single-dose schedule of ARRY-520 (schedule 1) and the multidose schedule (schedule 2) where ARRY-520 was given on days 1, 3, and 5 were comparable. The MTD was defined at the same total dose per cycle for both schedules (4.5 mg/m2 total dose). The DLTs included oral mucositis at 5.6 mg/m2 with the single-dose schedule and at 1.2 mg/m2/day with the multidose schedule (3.6 mg/m2 total dose per cycle), with additional AEs of hand-foot syndrome and hyperbilirubinemia observed at 1.8 mg/m2/day (4.5 mg/m2 total dose).

Overall, ARRY-520 demonstrated an acceptable safety profile in both schedules at dose levels up to the MTD (4.5 mg/m2), with no difference in the toxicity observed between the 2 schedules. Drug-related SAEs occurred in 28% of patients and led to study discontinuation in 8%. Neurotoxicity was not observed at any dose up to the MTD.

The PK parameters demonstrated moderately high interpatient variability and overall dose-dependent increases in exposure. The half-life of ARRY-520 (>90 hours) was consistent with the low clearance and relatively large volume of distribution when administered once per cycle and displayed a similar terminal phase with more frequent dosing. These values suggest the potential for prolonged exposure of ARRY-520 at the site of action. Based on imaging of PBMCs (Fig. 2), ARRY-520 appears to be targeting the microtubule spindle, because abnormal spindles were observed in patients after 3 doses of ARRY-520. This is consistent with mitotic defects observed both in vitro and in vivo following KSP inhibition.25, 34

ARRY-520 has shown activity in xenograft models of multiple myeloma,35 which led to a phase 1/2 trial in relapsed and refractory multiple myeloma. The trial is currently in phase 2 after the MTD was reached with ARRY-520 administered on days 1 and 2 and repeated every 2 weeks. This trial has shown promising preliminary responses, and led to the development of a phase 1b study of ARRY-520 administered on days 1, 2, 15, and 16 every 4 weeks in combination with bortezomib and dexamethasone. Of interest, other KSP inhibitors are currently being investigated in clinical trials. These include AZD4877, MK0371, and SB-715992/ispinesib. Preliminary results of a phase 2 trial have shown that ispinesib has clinical activity in patients who have resistant ovarian cancer.36

In the current study, although ARRY-520 demonstrated an acceptable safety profile in heavily pretreated patients with relapsed and/or refractory AML or MDS, we did not observe CRs in this patient population. The detection of monopolar spindles was suggestive of targeted KSP inhibition, and it is possible that mucositis was a limiting factor for further dose escalation to identify an effective dose. Alternatively, it may be unrealistic to expect responses using a single agent in this highly resistant patient population. Combination of ARRY-520 with a synergistic drug is perhaps a more optimal approach to better evaluate the efficacy of this drug. Based on the relative lack of clinical activity, no further development of this agent as an antileukemic therapy is planned.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References

We thank Laura Bender for her contribution to the imaging techniques.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURE

Selena Rush, Kevin Litwiler, Sharon Karan, Heidi Simmons, and Mieke Ptaszynski are employed by Array BioPharma Inc. Hagop Kantarjian received commercial research funding from Array BioPharma, and Gautam Borthakur has been a consultant and advisory board member for Array BioPharma.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. FUNDING SOURCES
  8. References
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