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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4172-4179 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.2347 Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors
From the Sidney Kimmel Comprehensive Cancer Center; and the Departments of Pathology and Radiology; Division of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD Corresponding author: Manuel Hidalgo, MD, PhD, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans St, Room 1M89. Baltimore, MD 21231; e-mail: mhidalg1{at}jhmi.edu
Purpose Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. Patients and Methods We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). Results Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. Conclusion mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.
Mammalian target of rapamycin (mTOR) is a serine-threonine kinase downstream of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway that mediates multiple biologic functions such as transcriptional and translational control by modulating transducers such as P70 and 4EBP1,1,2 and is a target for anticancer drug development. Rapamycin (sirolimus) is a macrocyclic lactone produced by Streptomyces hygroscopicus with immunosuppressive, antimicrobial, and antitumor properties.3 mTOR signaling also plays a key role in hypoxia-triggered angiogenesis, which is abrogated by rapamycin.4 Rapamycin is used for the prevention of organ rejection after solid organ transplantation.5,6 Phase I studies exploring doses from 0.5 to 6.5 mg/m2 every 12 hours have been conducted in transplant patients.7 Despite a robust rationale, and the benefits of an oral agent, rapamycin has not been evaluated clinically as an anticancer agent. The concept of targeted therapy relies on the assumption that drugs elicit a pharmacodynamic (PD) effect that is necessary for the expected antitumor activity to occur. However this concept has not been uniformly incorporated in phase I dose selection trials. The modified continuous reassessment method (mCRM) is a toxicity-based method that has shown to be feasible in dose-escalating trials, and that has been hypothesized to allow a reduction in patients needed to reach the recommended dose compared with algorithmic dose escalation designs.8 We hypothesized that rapamycin would exert a PD effect in normal tissues, that this effect would correlate with drug exposure, and that real-time PD monitoring would rationally guide dose selection. Thus, we used an mCRM coupled to a PD end point rather than the more classical toxicity-based approach. We selected phospho-P70 as PD end point because prior work in renal cell cancer showed an association between phospho-70 dynamics in normal tissue on mTOR inhibition and outcome.9 This phase I study was conducted to determine the PD optimal and/or maximum-tolerated doses (MTD), acute and chronic toxicity profile, and pharmacokinetics (PK) of rapamycin in adult patients with solid cancers. To this end, we coupled the mCRM to an end point in normal skin tissue, but additionally explored PD end points in peripheral-blood mononuclear cells (PBMCs) and tumor tissue, as well as functional imaging with positron emission tomography (PET).
Patient Eligibility Histologically confirmed malignancy beyond standard curative or palliative measures, age at least 18 years, measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of no greater than 1, life expectancy of at least 12 weeks, willingness to undergo skin and tumor biopsies where appropriate, and adequate bone marrow, hepatic, and renal function (absolute neutrophil count  1,500/µL; platelets 100,000/µL; hemoglobin 9 g/dL; bilirubin < 2 mg/dL; AST, ALT, and alkaline phosphatase < 5x the upper limit of normal [ULN]; triglycerides and total cholesterol < 2.5x the ULN; and creatinine < 2 mg/dL) were required. Patients could have received any prior therapy ending at least 28 days prior without residual toxicity. Patients with brain metastases or clinically significant medical conditions were excluded. Our institutional review board granted approval, and written informed consent was mandatory.
Study Design and Dose Escalation
Treatment
Assessments
PK Sampling, Analytic Assay, and Data Analysis
PD Assessment: PBMCs
Statistical Analysis
Patient Characteristics Between February 2005 and January 2007, 21 patients with advanced solid tumors were accrued. All patients were assessable for toxicity and efficacy. In the first cohort one patient developed rapid progression before completing her first cycle and was replaced. Demographic characteristics of the subjects are summarized in Table 1. A total of 129 cycles of the study drug were delivered (median, two cycles; range, one to 26 cycles).
Dose-Escalation Process The starting dose of rapamycin was 2 mg. The first two dose levels of 2 and 3 mg were evaluated before implementing the mCRM. Of the first six patients, only three reached the defined level of PD efficacy (Fig 1A). These data was used in the mCRM to define the next dose level, which was between 6 and 7 mg (Fig 1B). Because no related grade 2 or greater toxicities were encountered, a 100% dose escalation was allowed; 6 mg was evaluated in three patients who did not meet PD efficacy criteria. The mCRM indicated a next dose level of 13 mg. However, several grade 2 toxicities had occurred, dose escalation was limited to a 50% increase, and 9 mg was selected. At 9 mg the second patient experienced a DLT consisting in grade 3 mucositis, the cohort was expanded, and the fifth patient suffered a second DLT consisting of grade 3 thrombocytopenia, diarrhea, and hyperglycemia. Dose for these two patients was reduced to 6 mg, and therapy continued without recurrence of the toxicities. The previous cohort was expanded to nine total patients, without documenting any DLT. Therefore, the MTD of rapamycin administered orally once daily on an uninterrupted schedule in solid cancer patients is 6 mg.
Toxicity Treatment was generally well tolerated and in concordance with the expected adverse effect profile of rapamycin (Table 2). No grade 4 or 5 toxicities were documented. The most common nonhematologic adverse events observed in greater than 20% of patients were elevated triglycerides, glucose, AST/ALT and cholesterol, rash and mucositis. Hyperlipidemias responded well to statin treatment. A single urinary tract infection was documented. Hematologic toxicity was mild and characterized by anemia, leucopenia, and thrombocytopenia.
Clinical Efficacy In 10 patients, the best response was progressive disease, 10 had stable disease (SD), and one hepatocellular carcinoma patient had a minor response by RECIST that was sufficient to allow a surgical resection by autologous liver transplant that rendered the patient disease free for a year. All seven patients receiving 2 and 3 mg presented with progressive disease at first evaluation, whereas 11 of 14 patients at 6 and 9 mg had SD (P = .001). The ECOG performance status and number of prior lines of treatment were similar between groups (P = .53 and .36, respectively). Five patients with unknown-origin adenocarcinoma, cholangiocarcinoma, and neuroendocrine cancer (n = 3) have been on study for 12, 13, 14+, 22+, and 26+ months, respectively. All five had shown progression to other therapies immediately before study entry, with prior time-to-treatment-failure intervals of 6, 6, 7, 5, and 4 months, respectively.
Functional Imaging Evaluation
PK Evaluation
PD Evaluation No correlation was found between phospho-P70 inhibition in the skin and dose received or observed clinical benefit. At the completion of the trial, we assessed phospho-S6 and phospho-4EBP1. There was no correlation between the latter and dose or outcome parameters, but phospho-S6 dynamics roughly correlated with dose despite a lower inhibition at 9 mg compared with 6 mg (normalized activation 175%, 88%, 34%, and 81% at 2-, 3-, 6-, and 9-mg levels, respectively; analysis of variance P = .003). Had phospho-S6 evaluation been used in lieu of phospho-P70, the escalation result would have been similar, because at higher doses, toxicity-driven decisions would have also prevailed. We assessed phospho-P70 inhibition in the PBMCs evidencing no correlation with skin phospho-P70, dose, or outcome. Four paired tumor biopsies were obtained at the MTD, from patients with unknown primary and neuroendocrine cancers and two sarcomas. The first two received treatment for at least 12 months; the latter two received two and four cycles only. Phospho-S6 only decreased in both patients showing benefit (Fig 3).
PK/PD and Outcome-PD Correlations We correlated PK/PD parameters from our study (Appendix Table A1, online only). No correlation was found between PK and functional imaging or PBMC phospho-P70. No trend was observed between PK and skin phospho-P70 or phospho-4EBP1 dynamics, but there was a strong correlation between PK and phospho-S6 dynamics, indicating increasing inhibition with exposure. No PD parameter showed differences when comparing patients receiving at least12 cycles with the rest.
This study explored whether a PD-based modified continuous reassessment method was a feasible tool to rationally determine the PAD or MTD of rapamycin in solid cancer patients. A comprehensive PK/PD plan was built in parallel to further elucidate the relationship between pharmacologic and biologic end points, and identify biomarkers in normal and finally in tumor tissue. The mCRM-based escalation was feasible, but we encountered several obstacles: The selected PD end point did not correlate with dose, target inhibition in the normal tissue was uninformative regarding efficacy, and toxicity ultimately drove dose-selection decisions. A classic dose-escalation approach would have likely led us to the same dose with approximately the same number of patients. Dose level 3, consisting of 6 mg per day of oral rapamycin continuously was safe with no DLTs in nine patients, as was the MTD. Our PK data challenge the widely accepted notion that rapamycin has poor and erratic absorption; we documented systemic drug exposure increasing proportionally with dose and comparable PK results to those reported in transplant studies. mTOR is now a validated anticancer target. Intravenous weekly temsirolimus (Torisel; Wyeth), a synthetic rapamycin ester, demonstrated superior survival in advanced renal cell carcinoma patients compared with interferon.13 During preclinical testing, temsirolimus demonstrated cytostatic activity rather than tumor shrinkage, prompting the use of end points such as time to progression during clinical development.14,15 We observed minimal efficacy in terms of tumor regression, but SD periods that tripled prior time-to-treatment-failure intervals were documented, especially at the higher dose levels. This, put in context with deeper PD effect in normal skin and higher toxicity than at the lower dose levels, may indicate a dose effect. Five patients remained on study for at least 12 months, which is unusual in a phase I setting. The efficacy in all three neuroendocrine patients is noteworthy considering the negative results of temsirolimus in this disease.16 Higher dose density and deeper pathway shutdown with daily administration may explain these differences. Given mTOR's primary function as a nutrient regulator, the higher incidence of elevations in glucose and lipids compared with temsirolimus also suggest more sustained effect. These alterations may account for the PET efficacy overestimation; alternative tracers should be considered for mTOR inhibitor studies. PD studies are increasingly being incorporated into phase I trials, but basing dose selection in PD effects is uncommon. In this study, we evaluated a novel statistical tool adapted for a PD end point in a normal tissue. Phospho-70 per a radioactivity-based assay in PBMCs from renal cancer patients treated with temsirolimus correlated with outcome.9 This, together with phospho-P70 suggesting predictive value in glioblastoma patients receiving temsirolimus,17 led us to apply this end point to the mCRM using a nonradioactive and seemingly more applicable assay. The chosen threshold was set arbitrarily and is supported by the temsirolimus data in normal tissues, where a 80% decrease in phospho-P70 was documented at steady state.9 Additionally we explored phospho-S6 ribosomal protein and phospho-4EBP1, which has shown prognostic value in ovarian and breast cancer.18,19 Skin phospho-P70 inhibition did not correlate with pharmacologic exposure and toxicity ultimately dictated dosing decisions. In retrospect, skin phospho-S6 dynamics correlated with rapamycin exposure; however, had we used this end point for the mCRM, decisions would have been similar. In tumor biopsies from patients at the MTD, phospho-S6 decreased in patients deriving a clinical benefit, but it needs to be emphasized that this was a subset analysis and its interpretation requires caution. Overall, the data support the use of phospho-S6 as the marker of choice in mTOR PD studies, as reported by other groups.20 Recent data indicate that its baseline expression level could have predictive value.21 We can conclude that normal tissue assessment is a valid strategy to elucidate drug effect, but our results suggest that tumor tissue exploration is more promising because of a wider dynamic range. Rapamycin was well tolerated, had predictable toxicity and PK profiles, and showed evidence of antitumor activity.
The author(s) indicated no potential conflicts of interest.
Conception and design: Antonio Jimeno, Elizabeth Garrett-Mayer, Sharyn D. Baker, Manuel Hidalgo Financial support: Manuel Hidalgo Administrative support: Yasmin Khan, Manuel Hidalgo Provision of study materials or patients: Antonio Jimeno, Michelle A. Rudek, Peter Kulesza, Wen Wee Ma, Anna Howard, Yasmin Khan, Heather Jacene, Wells A. Messersmith, Daniel Laheru, Ross C. Donehower, Manuel Hidalgo Collection and assembly of data: Antonio Jimeno, Michelle A. Rudek, Peter Kulesza, Wen Wee Ma, Jenna Wheelhouse, Ming Zhao, Heather Jacene, Elizabeth Garrett-Mayer, Sharyn D. Baker, Manuel Hidalgo Data analysis and interpretation: Antonio Jimeno, Michelle A. Rudek, Elizabeth Garrett-Mayer, Sharyn D. Baker, Manuel Hidalgo Manuscript writing: Antonio Jimeno, Michelle A. Rudek, Elizabeth Garrett-Mayer, Sharyn D. Baker, Manuel Hidalgo Final approval of manuscript: Antonio Jimeno, Michelle A. Rudek, Sharyn D. Baker, Manuel Hidalgo
Supported by Grant No. R21CA112919. Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
