Background
The intracellular RAS/RAF/MEK/ERK pathway converges on MEK1/2, of which the only known substrates are ERK1/2. Constitutive activation of the pathway is implicated in cell proliferation and is central to driving cancer growth and progression [
1,
2]. The integral role of MEK1/2 in this signaling cascade highlights its potential as a therapeutic target. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and highly selective, allosteric MEK1/2 inhibitor [
3] with a short half-life [
4,
5]. Clinical activity of selumetinib monotherapy in some patients with advanced solid tumors has been reported in phase I [
4,
6] and phase II studies [
7‐
10], and the recommended dose for selumetinib monotherapy is 75 mg twice daily (BID). The potential benefit of combining MEK inhibitors with chemotherapy has been demonstrated in preclinical studies of tumor xenograft models, in which selumetinib in combination with cytotoxic agents, such as docetaxel or the dacarbazine derivative temozolomide, showed enhanced tumor growth inhibition compared with selumetinib monotherapy, or chemotherapy alone [
1,
11]. Selumetinib plus docetaxel in previously treated patients with
KRAS-mutant advanced non-small cell lung cancer (NSCLC) [
12], and selumetinib plus dacarbazine in patients with
BRAF-mutant metastatic melanoma [
13], have more recently been assessed in phase II trials. Additional phase II and phase III trials of selumetinib plus docetaxel in advanced NSCLC were also initiated (ClinicalTrials.gov identifiers: NCT01750281; NCT01933932). Here we present the phase I study on which development of these combinations was based.
The objectives of this four-arm dose-escalation study were to assess the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of selumetinib in combination with selected anticancer therapies (docetaxel, dacarbazine, erlotinib, or temsirolimus) in patients with advanced solid tumors. An exploratory assessment of tumor response was also conducted. A single-institution assessment of patients with metastatic melanoma enrolled in this study has previously been reported [
14]. In consideration of the notable differences in safety and tolerability profiles when combining selumetinib with different classes of cancer therapeutics, we present here data from 60 patients who received selumetinib in combination with cytotoxic agents (docetaxel or dacarbazine). Results for those patients who received selumetinib in combination with other molecularly targeted therapies (erlotinib or temsirolimus) are presented by Infante et al. in a companion manuscript (in preparation).
Methods
This phase I, open-label, multicenter, dose-escalation study (NCT00600496) was conducted at four centers in the USA between December 2007 and August 2010 (data cut-off occurring 6 months after the last patient began treatment).
Patient selection
Patients with advanced solid tumors who would be candidates for docetaxel or dacarbazine treatment as a standard of care, or those who might have derived benefit from combination therapies with these agents, were eligible for the study. Other eligibility criteria included: age ≥18 years; measurable and/or non-measurable disease lacking curative options; World Health Organization (WHO) performance status 0 or 1; and calculated serum creatinine clearance >50 mL/min.
Patients meeting any of the following criteria were excluded from the study: prior treatment with a MEK inhibitor; received an investigational drug within 30 days of entering the study, and/or had not recovered to < grade 1 toxicity; received radiotherapy or standard chemotherapy within 21 days of study entry; use of strong cytochrome (CYP)1A2 or 3A4 inducers and/or inhibitors; brain metastases or spinal cord compression unless treated and stable (>1 month) and off steroids; having factors that increased the risk of QT prolongation or arrhythmic events or QTc interval of >450 ms for males or >470 ms for females; or inadequate bone marrow, hepatic, cardiac, or renal function.
All patients provided written informed consent and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol was approved by the institutional review board at each study site (Additional file
1: Table S1).
Study design and dosing
For each treatment arm, the study was conducted in two parts: part A (dose escalation) enrolled cohorts of three to six evaluable patients and assessed the safety, tolerability, PK, and MTD of selumetinib in combination with either docetaxel or dacarbazine; part B (dose expansion) further evaluated the safety, tolerability, and PK in a minimum of 12 additional patients at the MTDs for combination treatments determined in part A. The study safety review committee (SRC), comprising representatives from the study sponsor and at least one investigator, assessed the available safety and PK data. Dose-limiting toxicities (DLTs) in the study were defined as those related to treatment and occurring within the first 28 days of therapy. Hematologic DLTs were defined as afebrile grade 4 neutropenia for >5 days, grade 4 neutropenia associated with fever, or grade 4 thrombocytopenia. Non-hematological DLTs were defined as any ≥ grade 3 adverse event (AE) for >7 days that could not be controlled to grade ≤2 with appropriate treatment.
Patients received intravenous docetaxel 75 mg/m2 or dacarbazine 1000 mg/m2 over 60 mins on day 1 of each 21-day cycle. Selumetinib was initiated BID, orally, beginning on day 3 of cycle 1. Patients could remain on combination treatment or selumetinib monotherapy after discontinuation of chemotherapy, providing they were continuing to derive clinical benefit, until disease progression or intolerable AEs occurred. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor (ppG-CSF), including pegylated G-CSF, according to standard guidelines.
Dose exploration commenced at the starting dose level of selumetinib 50 mg BID. Patients were enrolled into part A in initial cohorts of three to six patients and subsequent dose levels were determined by the SRC, which reviewed the emerging tolerability and safety profile on an ongoing basis, and upon completion of each dose level cohort. In addition, the predicted exposure to selumetinib at each dose level evaluated was not to exceed the exposures previously observed at the monotherapy MTD of 75 mg BID [
4]. Patients were considered evaluable if they had received at least 28 days of therapy from cycle 1/day 1, received approximately 80% of the planned doses of selumetinib, had experienced a DLT, or at the discretion of the SRC. The combination MTD in this study was defined as the highest selumetinib dose achieved at which no more than one of six evaluable patients experienced a DLT. In part B (dose expansion) of the study, an additional 12 evaluable patients received treatment at the combination MTDs.
Assessments
Tolerability
Safety assessments included: all AEs graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0; vital signs (including blood pressure, pulse rate, weight, and body temperature); electrocardiogram; Multi-Gated Acquisition (MUGA) scan; clinical chemistry; brain natriuretic peptide; troponin I; hematology; urinalysis; and ophthalmologic examinations. Incidence of DLTs was also recorded.
Pharmacokinetics assessments
Pharmacokinetic parameters of selumetinib, N-desmethyl selumetinib, docetaxel, and dacarbazine were determined following administration of each drug alone and in combination. Blood sampling was performed pre-dose and after chemotherapy infusion as follows: cycle 1/day 1 (selumetinib) and cycle 2/day 1 (combination) for measurement of docetaxel or dacarbazine levels; and cycle 1/day 3 (selumetinib) and cycle 2/day 1 (combination).
Maximum plasma concentration (Cmax) and time to reach the Cmax (Tmax) were determined on day 1, 3, and 22 of cycle 1 for docetaxel or dacarbazine, and day 3 and 22 of cycle 1 for selumetinib. Area under the plasma concentration-time curve from 0 to 12 h post dose (AUC(0–12)) was calculated using the linear trapezoidal rule. When more than one maximum occurred, the reported value was assigned to the first occurrence.
Tumor response
Objective tumor response was assessed according to Response Evaluation Criteria In Solid Tumours (RECIST) (version 1.0) with baseline tumor assessments up to 4 weeks before the planned first dose of selumetinib. Subsequent tumor assessments were conducted prior to the third cycle, every alternate cycle thereafter, and on withdrawal of treatment.
EGFR and KRAS mutation analyses
Mutation status was an exploratory endpoint and an optional part of the protocol. DNA was extracted from formalin-fixed paraffin-embedded tissue samples using the Cobas™ DNA Sample Preparation kit (Roche Molecular Systems Inc., Pleasanton, CA, USA). Plasma DNA was extracted using a non-commercial plasma preparation kit supplied by Roche. DNA was assayed using the Cobas™ KRAS Mutation Test and Cobas™ EGFR Mutation Test (Roche) according to the manufacturer’s protocols. The EGFR mutation assay covered the following mutations: exon 18 G719X (G719A, G719C, and G719S); exon 19 deletions and complex mutations; exon 20 S768I, T790M, and insertions; and exon 21 L858R. The KRAS mutation assay covered mutations in codons 12, 13 (exon 2), and 61 (exon 3). Data were generated and analysed using the Cobas z480.
Statistical analysis
Three populations were defined for analysis: safety population, evaluable for dose escalation (part A), and evaluable for PK analysis. The safety population included all patients who received one or more doses of selumetinib and chemotherapy. Patients were considered evaluable for dose escalation if they had received approximately 80% of the planned doses of selumetinib in cycle 1, provided PK data, and had all safety evaluations performed or experienced a DLT, or at the discretion of the SRC. Patients who could not complete 80% of planned doses or had to drop out due to toxicity were considered DLT evaluable. The evaluable for PK analysis population included all patients with concentration-time data available.
No formal statistical hypothesis testing was performed on the data; all data reported are based on summary statistics: frequency counts and percentages for categorical data and mean, median, range, standard deviation, geometric mean, and % co-efficient of variation for continuous data as appropriate.
Discussion
At the time of study initiation, data from preclinical studies suggested that selumetinib in combination with a variety of DNA-damaging agents and molecularly targeted therapies may enhance anti-tumor efficacy compared with single agent administration [
1,
11]. Combinations with docetaxel and dacarbazine have since shown clinical activity in phase II trials [
12,
13].
This phase I study was the basis for establishing the safety, tolerability, MTD, and PK of selumetinib BID in combination with standard doses of two commonly used cytotoxic chemotherapeutic drugs in patients with advanced solid tumors. Data from patients who received selumetinib in combination with erlotinib or temsirolimus are presented in the companion paper (Infante et al., in preparation).
Selumetinib was tolerable in combination with docetaxel or dacarbazine. As with the monotherapy recommended phase II dose [
4], we determined that the MTD of selumetinib was 75 mg BID when administered with standard doses of docetaxel 75 mg/m
2 without ppG-CSF or with dacarbazine 1000 mg/m
2. Consistent with our expectations, combination treatment reported here did not affect exposure to docetaxel, dacarbazine, or to selumetinib and its metabolite N-desmethyl selumetinib [
6,
15,
16].
The tolerability of selumetinib in combination with docetaxel or dacarbazine was broadly consistent with the safety profiles of the individual regimen components [
9,
17‐
19]. AEs that occurred most frequently with either combination were diarrhea, peripheral/periorbital edema, fatigue, nausea, and vomiting. Only a limited number of patients had ophthalmologic or LVEF assessments on study, so no definitive conclusions could be made relating to these domains.
The tolerability profiles in this phase I study have been seen in subsequent placebo-controlled, phase II trials of selumetinib plus dacarbazine in patients with treatment-naïve
BRAF-mutant metastatic melanoma and selumetinib plus docetaxel in pretreated patients with
KRAS-mutant advanced NSCLC [
12,
13]. In both trials, the most frequently reported AEs for selumetinib combination arms were nausea, acneiform dermatitis, diarrhea, vomiting, and peripheral edema.
We determined a recommended phase II dose of selumetinib 75 mg BID plus docetaxel without ppG-CSF. However, in two phase II studies of selumetinib plus docetaxel without ppG-CSF for patients with treatment-naïve advanced melanoma and pretreated
KRAS-mutant advanced NSCLC, increased incidences of grade ≥3 febrile neutropenia were reported compared with placebo (21% vs. 12% and 18% vs. 0%, respectively) [
12,
20]. The reason for this discrepancy likely derives from the inaccuracy of many recommended phase II dose determinations based on studies of a relatively small number of carefully selected patients treated at phase I research centres. Two subsequent multicenter trials of selumetinib plus docetaxel for patients with advanced NSCLC included mandatory administration of ppG-CSF in the protocol: SELECT-1, evaluating the combination as second-line treatment in
KRAS-mutant advanced NSCLC (ClinicalTrials.gov identifier: NCT01933932); and SELECT-2, evaluating the hypothesis that clinical activity of the combination is not limited to patients with advanced NSCLC that harbours
KRAS mutations (ClinicalTrials.gov identifier: NCT01750281).
Although this study was not designed to assess clinical efficacy, objective tumor responses were reported in some patients. Among evaluable patients receiving selumetinib plus docetaxel, 6/27 (22%) had a confirmed partial response and an additional 14/27 (52%) had stable disease ≥6 weeks. At week 12, 11 (31%) patients had stable disease and five (14%) patients had an objective response. Interestingly, KRAS or EGFR mutations were not detected in any of the patients who responded, supporting the hypothesis under investigation in the SELECT-2 trial. Confirmed partial responses occurred in 4/23 (17%) evaluable patients receiving selumetinib plus dacarbazine and 15/23 (65%) had stable disease ≥6 weeks. At week 12, seven (28%) patients had stable disease, and two (8%) patients had an objective response.
Acknowledgments
Medical writing services were provided by Jon Moran, PhD, and Tom Hudson, PhD, of iMed Comms, an Ashfield company, part of UDG Healthcare, and were funded by AstraZeneca. The authors thank the patients and their families who participated in this study, study staff at the respective sites, physicians who referred their patients for this study, and Roz Brant, of AstraZeneca, Macclesfield, UK, for tumor mutation analysis.