Abstract
Background
The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway is aberrantly activated in several cancers. Notch signaling maintains cell proliferation, growth, and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway.
Methods
This phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumors. No intrapatient dose escalation was permitted.
Results
28 patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among 8 evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (1 each grade 3 stomatitis, grade 3 diarrhea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week + 1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhea, decreased appetite, hyperglycemia, thrombocytopenia, asthenia, and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response (CR) and one with partial response (PR). In addition, one patient experienced stable disease ≥6 months.
Conclusions
Combined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development.
Keywords: Ridaforolimus, mTOR inhibitor, MK-0752, Notch inhibitor, head and neck cancer, Phase I
Introduction
The phosphatidylinositol-3-kinase (PI3K) signaling pathway is dysregulated in many human malignancies [1–3]. The PI3K pathway links growth factor ligand-receptor interactions on the cell surface to downstream effectors such as the mammalian target of rapamycin (mTOR), which regulates cell cycle progression and cellular growth processes, and is involved in tumor progression for many cancers [4–6]. The mTOR inhibitor ridaforolimus has demonstrated preclinical antitumor activity in vitro and in vivo [7–10]. Its clinical safety and efficacy is being explored in patients with advanced malignancies as both a single agent and in combination with other targeted agents or chemotherapy [11–21]. To date, ridaforolimus has been generally well tolerated and has demonstrated antitumor activity in several cancers [3, 8]. The most frequently reported adverse effects associated with ridaforolimus have been mucositis, nausea, pruritus, anemia, thrombocytopenia, hypokalemia, and hyponatremia [8]
MK-0752 inhibits γ-secretase, an aspartic protease that activates the Notch receptor by cleaving the Notch ligand/receptor complex [22]. MK-0752 has shown single-agent clinical activity in patients with high-grade gliomas in a dose-escalation trial of weekly MK-0752 doses up to 4200 mg; the dose-limiting toxicities (DLTs) were fatigue and diarrhea [23]. The maximum tolerated dose (MTD) of MK-0752 was 3200 mg given once weekly (QW), and the biologically effective dose was 1800 mg QW [23]. MK-0752 was also well-tolerated in a dose-escalation trial in pediatric patients, and although no objective responses were observed, 2 patients (1 with ependymoma and 1 with glioblastoma multiforme) experienced prolonged stable disease (≥3 months) [24].
We hypothesized that combining ridaforolimus with MK-0752 could lead to complementary blockade of the PI3K pathway (Fig. 1). The combined activity of a Notch inhibitor and an mTOR inhibitor is expected to produce improved efficacy by targeting the tumor directly as well as blocking the recruitment of new blood vessels on which tumors depend. Notch signaling maintains cell proliferation, growth, and metabolism in part by driving PI3K pathway signaling. As mTOR is downstream in this pathway, mTOR inhibitors can constrain some of the oncogenic signaling initiated by Notch. The mTOR inhibitor could also restore inhibition of PI3K signaling in cells that are resistant to γ-secretase inhibition as a result of mutations in the phosphatase and tensin homolog (PTEN) gene, through which γ-secretase inhibition acts, in part, to inhibit growth and proliferation. Preclinical data have demonstrated that targeting both Notch and mTOR can result in antitumor activity in cell lines and prolonged survival in a mouse leukemia model [25]. In pancreatic cancer cells coadministration of a Notch inhibitor with rapamycin inhibited cell proliferation to a greater degree than either agent alone [26]. The present study investigated the safety and tolerability of the ridaforolimus plus MK-0752 combination in patients with advanced solid tumors, characterizing the DLTs and identifying the MTD.
Fig. 1.
Rationale for mTOR inhibitor + NOTCH inhibitor combination. The PI3K/AKT/mTOR signaling pathway is aberrantly activated in a variety of cancers. Notch signaling has been shown to maintain cell proliferation, growth, and metabolism in part by driving PI3K pathway signaling. The combination of mTOR inhibitor ridaforolimus and Notch inhibitor MK-0752 may lead to complementary blockade of the PI3K pathway.
Abbreviations: AKT, protein kinase-B; DLL4, Delta-like ligand 4; HES1, Hairy/enhancer of split 1; HIF, hypoxia-inducible factor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; rida, ridaforolimus; RTK, receptor tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.
Methods
Study Design
This was an international, multicenter, open-label, nonrandomized, phase 1 study to determine the DLTs and MTD for the combination of oral ridaforolimus with oral MK-0752 (ClinicalTrial.gov identifier, NCT01295632). This study also evaluated the combination of ridaforolimus + MK-2206 (a protein kinase-B [AKT] inhibitor); results will be disseminated in a separate manuscript.
The study protocol was approved by the Institutional Review Board or Independent Ethics Committee at each participating site and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and all local and federal regulatory guidelines. Patients provided written informed consent.
Patients
Adult (≥18 years old) male or female patients were eligible for the study if they had histologically confirmed metastatic or locally advanced solid tumors that had failed to respond to standard therapy, that had progressed despite standard therapy, or for which standard therapy does not exist. Patients could only enroll in 1 dose group, and were not permitted to have any medical conditions that could affect compliance with the protocol, limit interpretation of study results, or pose an unacceptable medical risk. The number of prior treatments permitted was not limited. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and adequate organ function. Patients had to have at least 1 measurable recurrent or metastatic lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) [27], with the exception of patients with prostate cancer which did not require measurable disease if PSA level >10 ng/mL.
Exclusion criteria included treatment with chemotherapy or radiotherapy within 4 weeks prior to study day 1, biological therapy (excluding antibodies) within 2 weeks prior to study day 1, or lack of recovery to ≤ grade 1 or baseline from adverse events due to agents administered more than 4 weeks earlier. Patients with known symptomatic or progressing central nervous system (CNS) metastases or with prior exposure to related agents, were also excluded.
Treatments
Ridaforolimus was administered as monotherapy for 5 days prior to beginning combination dosing. During combination treatment, ridaforolimus was administered orally for 5 consecutive days followed by 2 consecutive days off each week, and MK-0752 (fixed dose 1800 mg) was administered orally once per week on cycle day 1, in repeating 28-day treatment cycles. The starting dose of ridaforolimus was 20 mg (DL1), with planned sequential dose increases to 30 mg (DL2) and 40 mg (DL3) using a 3+3 patients dose-escalation scheme. The fixed dose of MK-0752 was chosen based on the phase 1 trial that found 1800 mg/wk to be a biologically effective dose [23]. Additional dose increases up to 3200 mg/wk did not result in additional drug exposure, so a fixed dose for MK-0752 was selected rather than dose escalation. DLTs observed in cycle 1 were used to determine escalation (or de-escalation).
End Points and Assessments
The DLT rate (primary end point) was assessed in the DLT-evaluable population, which included all patients who had a cycle 0 or cycle 1 DLT or who completed both cycle 0 and cycle 1 without a DLT. The MTD was defined as the dose level for which <1/3 or <2/6 patients developed a DLT.
Adverse events were graded and recorded throughout the study according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). Assessments included vital signs, electrocardiogram (at screening and 2 hours after dose on day 2, cycle 1), ECOG performance status, comprehensive ophthalmologic examination, laboratory measures, and medical history.
A secondary end point was response rate, defined as the proportion of patients whose best response was partial response (PR) or complete response (CR). Response was evaluated according to RECIST v1.1, using either computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, then every 2 cycles (±5 days) during treatment, and at the time of treatment discontinuation. Image analysis was undertaken both locally by the investigator and centrally by an independent imaging laboratory.
Statistics
No formal statistical hypothesis was tested for the primary objective of defining DLT and MTD. Adverse events were summarized using descriptive statistics per NCI CTCAE v 4.0. The safety analysis population consisted of all patients who received at least 1 dose of study treatment. The primary efficacy population consisted of all patients who received at least 1 dose of study treatment and who had baseline data for those analyses that required baseline data.
The study utilized a 3+3 dose-escalation scheme; a maximum of 6 patients could be enrolled per dose level during dose escalation. A cohort of 3 patients was enrolled at the initial dose level. If 0/3 patients developed a DLT, escalation to the next dose level would occur. If 1/3 patients developed a DLT, another 3 patients would be enrolled at that dose level. Providing that 0 of these 3 new patients developed a DLT (giving a total of 1/6 patients with a DLT at this dose level), escalation to the next dose level would occur. However, if ≥1 of the 3 new patients developed a DLT (giving a total of ≥2/6 patients [≥33%] with a DLT at that dose level), the dose escalation stage of the trial would be terminated and the dose(s) directly below the current dose would be considered the MTD. If ≥2/3 patients developed DLTs, the dose level will not be considered further and the dose(s) directly below the current dose would be explored.
Results
Disposition
Thirty patients were allocated and assigned to treatment, of whom 28 patients received at least 1 dose of ridaforolimus plus MK-0752. There were 7 trial centers in 4 countries (4 in the United States; 1 in France; 1 in Norway, and 1 in Spain).
The majority of patients discontinued the study because of progressive disease (19 of 30 allocated patients; 63.3%). Eight patients (26.7%) withdrew consent (6 of these 8 patients had a serious adverse event [SAE] and/or DLT), 1 patient (3.3%) discontinued because of an adverse event, and 1 patient discontinued per physician decision. The other patient, who has continued in the extension phase for >9 months after database lock, remains on therapy with no evidence of disease and is tolerating therapy well.
Baseline Demographics and Disease Characteristics
Most of the patients were white, and the median age was 63 years old (Table 1). The most common type of tumor was head and neck cancer, in 50% of the patients overall, followed by colorectal cancer in 17% of patients. Most patients had received prior chemotherapy (96.7%) or surgery (96.7%), and many had received biologic agents (53.3%) or radiation therapy (66.7%).
Table 1.
Baseline demographics and disease characteristics.
| n (%)a | Ridaforolimus 20 mg QD × 5 d/wk + MK-0752 1800 mg weekly n = 21 |
Ridaforolimus 30 mg QD × 5 d/wk + MK-0752 1800 mg weekly n = 9 |
Total N = 30 |
|---|---|---|---|
| Age, y | |||
| <65 | 13 (61.9) | 6 (66.7) | 19 (63.3) |
| Mean (SD) | 62.0 ± 11.3 | 59.4 ± 8.7 | 61.2 ± 10.5 |
| Median (range) | 63 (38–80) | 59 (42–70) | 63 (38–80) |
| Gender | |||
| Male | 12 (57.1) | 5 (55.6) | 17 (56.7) |
| Female | 9 (42.9) | 4 (44.4) | 13 (43.3) |
| Race | |||
| White | 18 (85.7) | 9 (100.0) | 27 (90.0) |
| Asian | 1 (4.8) | 0 | 1 (3.3) |
| Black or African American | 1 (4.8) | 0 | 1 (3.3) |
| Unknown | 1 (4.8) | 0 | 1 (3.3) |
| Ethnicity | |||
| Hispanic or Latino | 1 (4.8) | 1 (11.1) | 2 (6.7) |
| Tumor Type | |||
| Breast | 1 (4.8) | 1 (11.1) | 2 (6.7) |
| Colorectal | 3 (14.3) | 2 (22.2) | 5 (16.7) |
| Glioblastoma multiforme | 1 (4.8) | 1 (11.1) | 2 (6.7) |
| Head and neck | 12 (57.1) | 3 (33.3) | 15 (50.0) |
| Ovarian | 1 (4.8) | 1 (11.1) | 2 (6.7) |
| Other | 3 (14.3) | 1 (11.1) | 4 (13.3) |
| Prior treatment | |||
| Chemotherapy | 20 (95.2) | 9 (100.0) | 29 (96.7) |
| Biologic | 10 (47.6) | 6 (66.7) | 16 (53.3) |
| Radiationb | 15 (71.4) | 5(55.6) | 20 (66.7) |
| Surgery | 21 (100.0) | 8 (88.9) | 29 (96.7) |
| Number of prior systemic regimens | |||
| Median (range) | 2 (0–6) | 3 (1–5) | 2 (0–6) |
Abbreviations: QD, once daily; SD, standard deviation.
Unless otherwise specified, figures represent n (%).
Includes chemoradiation treatment.
Dose-Limiting Toxicity and Maximum Tolerated Dose
Ridaforolimus doses were escalated from 20 mg/d (n = 19; DL1) to 30 mg/d (n = 9; DL2). Patients received a median of 3 (range, 1 to 21) cycles of ridaforolimus and 2 (range, 1 to 20) cycles of MK-0752 at DL1, and 3 (range, 2 to 11) cycles of ridaforolimus and 2 (range, 1 to 10) cycles of MK-0752 at DL2.
In DL1 there were 14 patients evaluable for DLTs; 1 DLT (grade 2 stomatitis, second episode) was reported. At DL2, 3 DLTs were reported among 8 evaluable patients (1 each of grade 3 stomatitis, grade 3 diarrhea, and grade 3 asthenia). Based on these results, the MTD was determined to be ridaforolimus 20 mg by mouth (PO) daily 5 days/week plus MK-0752 1800 mg PO QW (DL1).
Safety
Twenty-four of the 28 treated patients (85.7%) experienced 1 or more drug-related adverse events. At the MTD (DL1) approximately 42.1% of patients experienced a grade 3 adverse event versus 55.6% at DL2; no grade 4 adverse events were reported (Table 2). Fifteen of the 28 treated patients (53.6%) experienced ≥1 serious adverse event. At DL2, two of the 9 patients experienced a drug-related serious adverse event: grade 3 diarrhea (1 patient) and grade 3 asthenia (1 patient). None of the 19 patients treated at DL1 experienced a drug-related serious adverse event (Table 2). There were 2 deaths on study, neither of which was considered drug-related: malignant neoplasm progression during cycle 1 at DL2 (1 patient), and neoplasm progression during the safety follow-up period at DL1 (1 patient).
Table 2.
AE summary.
| n (%) | Ridaforolimus 20 mg QD × 5 d/wk + MK-0752 1800 mg weekly n = 19 |
Ridaforolimus 30 mg QD × 5 d/wk + MK-0752 1800 mg weekly n = 9 |
Total N = 28 |
|---|---|---|---|
| ≥1 AE | 18 (94.7) | 9 (100.0) | 27 (96.4) |
| Drug-related AE | 15 (78.9) | 9 (100.0) | 24 (85.7) |
| Grade 3 AE | 8 (42.1) | 5 (55.6) | 13 (46.4) |
| SAE | 11 (57.9) | 4 (44.4) | 15 (53.6) |
| Drug-related SAE | 0 | 2 (22.2) | 2 (7.1) |
| Deaths | 1 (5.3) | 1 (11.1) | 2 (7.1) |
| Discontinued because of AE | 1 (5.3) | 0 | 1 (3.6) |
| Discontinued because of drug-related AE | 0 | 0 | 0 |
| Discontinued because of SAE | 1 (5.3) | 0 | 1 (3.6) |
| Discontinued because of drug-related SAE | 0 | 0 | 0 |
Abbreviations: AE, adverse event; QD, once daily; SAE, serious adverse event.
The most commonly reported drug-related adverse events included stomatitis, diarrhea, decreased appetite, hyperglycemia, thrombocytopenia, asthenia, and rash; most were mild to moderate in severity (Table 3). With the exception of diarrhea and decreased appetite, the incidence of these specific drug-related adverse events was 2 to 3 times greater in patients treated at DL2. At the MTD, the most common drug-related adverse events were diarrhea (32%), stomatitis (32%), and decreased appetite (32%). Adverse events of grade 3 severity that occurred at the MTD included anemia (3 patients) and stomatitis (2 patients), and 1 patient each experienced diarrhea, fatigue, alanine aminotransferase elevation, aspartate aminotransferase elevation, hypokalemia, and hypophosphatemia. These were not considered DLTs as they occurred beyond cycle 1.
Table 3.
Summary of drug-related adverse events occurring in ≥15% of patients (for all grades of severity) in either treatment group.
| n (%) | Ridaforolimus 20 mg QD × 5 days/week + MK-0752 1800 mg weekly n = 19 |
Ridaforolimus 30 mg QD × 5 days/week + MK-0752 1800 mg weekly n = 9 |
Total N = 28 |
|||
|---|---|---|---|---|---|---|
| All | Grade 3 or 4 | All | Grade 3 or 4 | All | Grade 3 or 4 | |
| Stomatitis | 6 (31.6) | 2 (10.5)a | 7 (77.8) | 1 (11.1)a | 13 (46.4) | 3 (10.7)* |
| Diarrhea | 6 (31.6) | 1 (5.3)a | 4 (44.4) | 1 (11.1)a | 10 (35.7) | 2 (7.1)a |
| Decreased appetite | 6 (31.6) | 0 | 3 (33.3) | 0 | 9 (32.1) | 0 |
| Hyperglycemia | 2 (10.5) | 0 | 4 (44.4) | 0 | 6 (21.4) | 0 |
| Thrombocytopenia | 2 (10.5) | 0 | 3 (33.3) | 1 (11.1)a | 5 (17.9) | 1 (3.6)a |
| Asthenia | 1 (5.3) | 0 | 4 (44.4) | 1 (11.1)a | 5 (17.9) | 1 (3.6)a |
| Rash | 2 (10.5) | 0 | 3 (33.3) | 0 | 5 (17.9) | 0 |
| Hemoglobin decreased | 3 (15.8) | 1 (5.3)a | 1 (11.1) | 0 | 4 (14.3) | 1 (3.6)a |
| Hypophosphatemia | 3 (15.8) | 1 (5.3)a | 1 (11.1) | 1 (11.1)a | 4 (14.3) | 2 (7.1)a |
| Vomiting | 1 (5.3) | 0 | 2 (22.2) | 1 (11.1)a | 3 (10.7) | 1 (3.6)a |
| Hypomagnesemia | 3 (15.8) | 0 | 0 | 0 | 3 (10.7) | 0 |
| Hypertriglyceride mia | 1 (5.3) | 0 | 2 (22.2) | 0 | 3 (10.7) | 0 |
| Weight decreased | 1 (5.3) | 0 | 2 (22.2) | 0 | 3 (10.7) | 0 |
Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase; QD, once daily.
All grade 3.
Tumor Response
Eighteen patients were evaluable for tumor response per RECIST 1.1 (they had measurable target lesions and at least 1 postbaseline scan), of which 10 had HNSCC. The maximum percentage change from baseline in target lesions for all response-evaluable patients is presented in Fig. 2A, and Fig. 2B shows maximum percentage change from baseline in target lesions for patients with HNSCC only. One patient with HNSCC, who did not have measurable lesions per RECIST 1.1 but was evaluable for disease response, had a CR and remained on therapy for >20+ months (Fig. 3). Another patient with HNSCC had a confirmed PR (Fig. 4). Stable disease ≥6 months was seen in a third patient with HNSCC.
Fig. 2.
Maximum change from baseline in the size of target lesions in patients evaluable for response (at least 1 postbaseline scan available) as assessed per RECIST v1.1 by investigator review. A. All patients (n = 18). B. Patients with HNSCC (n =10).
Abbreviations: HNSCC, head and neck squamous cell carcinoma; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.
Fig. 3.
Imaging results for a patient with recurrent HNSCC obtained at baseline (5/2/2012), cycle 4, day 27 (9/10/12) and cycle 20, day 35 (1/7/14). The patient developed a contrast allergy, and CT of the neck done at baseline was later changed to PET-CT. The patient exhibits no evidence of disease and continues on therapy.
Abbreviations: CT, computed tomography; HNSCC, head and neck squamous cell carcinoma; PET, positron emission tomography.
Fig. 4.
Imaging results for a patient with recurrent HNSCC obtained at baseline (3/2/11) and cycle 8, day 26 (10/28/11). The best response per RECIST v1.1 by local assessment was a decrease in target lesions of 46%.
Abbreviations: HNSCC, head and neck squamous cell carcinoma; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.
Discussion
This phase 1 study, novel in that it assessed the combination of 2 investigational targeted therapies, demonstrated the feasibility of combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 for treating advanced solid malignancies, and identified the MTD for the combination. Indications of clinical activity were observed in patients with HNSCC, but there were issues with tolerability even at the MTD, with 42% of patients experiencing grade 3 drug-related adverse events.
There is some overlap in the toxicity profiles of ridaforolimus and MK-0752, but not extensively. The most common adverse events associated with single-agent MK-0752 therapy were nausea, vomiting, diarrhea, fatigue, and rash [23, 24]. For ridaforolimus monotherapy, the most commonly reported adverse events were stomatitis/mucositis, rash, anemia, infection, and fatigue [12–16]. In combination, these agents resulted in a relatively high incidence of stomatitis, diarrhea, and decreased appetite (all around 32%) at the MTD. Interestingly, rash is a common adverse event for both agents as monotherapies, but was not a significant issue with combination therapy. Prophylactic strategies to reduce the occurrence of common adverse events could improve the tolerability of the regimen. In particular, stomatitis/mucositis is a class toxicity associated with mTOR inhibitor therapy [28–30], with high incidence rates in clinical trials of other mTOR inhibitors in malignancies [31, 32]. Prevention or early treatment is crucial to avoid any dose interruptions or reductions that could compromise the efficacy of the therapy [30, 33, 34].
A previous study combining the mTOR inhibitor temsirolimus with the Notch inhibitor RO4929097 in patients with advanced solid tumors reported no objective responses, although 73% of patients experienced stable disease [35]. In the present study, combination ridaforolimus and MK-0752 produced clinical activity in 3 patients with HNSCC (1 CR, 1 PR, and 1 prolonged stable disease). Development of HNSCC is frequently associated with inactivating mutations in Notch or PTEN, and activating mutations in elements of the PI3K-AKT-mTOR pathway [36, 37]. In a mouse model of HNSCC, reduced PTEN expression and/or inactivation was associated with HNSCC progression [38]. In patients with HNSCC, tumor samples have shown evidence of transcriptional alterations in the Notch signaling pathway, suggesting that the Notch pathway may be driving tumor progression in a subset of HNSCC tumors [39]. Given these genetic associations with Notch and the PI3K-AKT-mTOR pathway and the clinical activity seen in this phase 1 trial, HNSCC would appear to be a good candidate for exploring further with this therapeutic combination.
In conclusion, the combination of ridaforolimus and MK-0752 demonstrated some clinical activity in HNSCC, but there were issues with tolerability leading to study discontinuation. Use of prophylactic strategies to prevent some of the common adverse events, careful patient education, and aggressive early intervention for patients who develop these adverse events may improve the balance between efficacy and safety of this combination.
Highlights.
Novel combination of 2 investigational agents, ridaforolimus and MK-0752
Inhibiting mTOR and Notch could lead to complementary blockade of the PI3K pathway
The MTD was ridaforolimus 20 mg PO daily 5 days/week plus MK-0752 1800 mg PO QW
There were 2 responses (1 CR, 1 PR), both in patients with SCC of the head and neck
Acknowledgments
Medical writing and editorial assistance was provided by Alison Comer of ApotheCom Ltd, with funding provided by Merck & Co., Inc.
Role of the Funding Source
This study was funded by Merck & Co., Inc. Employees of Merck & Co. were involved in the study concept and design, the collection, analysis and interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of Interest Statement
S.A. Piha-Paul, A. Hollebecque, G. Argilés, O. Dajani, and S. Gupta have nothing to disclose. P.N. Munster received research support from Merck & Co., Inc. J.D. Cheng, R. Wang, A. Swift, and A. Tosolini are employees of Merck & Co., Inc.
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