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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 361-367 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.0345 Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies
From the Cancer Therapy and Research Center, Institute for Drug Development; The University of Texas Health Science Center, San Antonio, TX; Cognigen Corp, Buffalo, NY; and ARIAD Pharmaceuticals Inc, Cambridge MA Corresponding author: Anthony W. Tolcher, MD, FRCPC, South Texas Accelerated Research Therapeutics, 4319 Medical Drive, Suite 205, San Antonio, TX 78229; e-mail: atolcher{at}start.stoh.com
Purpose This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. Patients and Methods Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QDx5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. Results Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. Conclusion The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QDx5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that functions as a central regulator of multiple signaling pathways that control cell growth, division, metabolism, and angiogenesis.1-4 mTOR is activated in response to environmental and nutritional conditions and plays a critical role in the transduction of proliferative signals mediated through the phosphoinositide-3 kinase (PI3K)/Akt pathway by activating two key downstream proteins, the p70 S6 kinase (S6K) and the eukaryotic initiation factor 4E binding protein 1 (4E-BP1).5 Both of these downstream proteins are involved in ribosomal biosynthesis and translation of specific mRNAs required for cell-cycle regulation.3,4,6 Deregulation of the PI3K/Akt pathway has been linked to oncogenesis in many human cancers.7 Mechanisms underlying aberrant PI3K/AKT pathway activation include mutation and silencing of the PTEN tumor suppressor gene, activating mutations in the PI3K catalytic subunit, and Akt amplification.8,9 These data, together with the observation that mTOR inhibition results in disruption of cell-cycle progression and cell growth, point to mTOR as an antitumor target.2,5,10 Rapamycin, the first compound demonstrating mTOR inhibition, is a macrolide that forms a complex with FK506 binding protein 12 (FKBP12).3 The FKBP12-rapamycin complex binds to and inhibits mTOR and subsequent S6K and 4E-BP1 phosphorylation.2 Deforolimus (also known as AP23573) is a nonprodrug analog of rapamycin that has been shown to inhibit mTOR activity, as evidenced by reduced phosphorylation of 4E-BP1 and S6.11,12 Deforolimus also inhibits the proliferation of multiple tumor cell lines in vitro and in vivo, including tumors of breast, colon, lung, prostate, glial, and pancreatic origin.13,14 On the basis of encouraging preclinical data, this first human phase I study was designed to determine the maximum-tolerated dose (MTD), safety profile, pharmacokinetic (PK) parameters, pharmacodynamic activity, and preliminary antitumor activity of intravenous (IV) deforolimus.
Patient Selection Patients with solid malignancies who experienced treatment failure with standard therapy or for whom adequate therapy was not available were eligible. Additional eligibility criteria were as follows: age at least 18 years; an Eastern Cooperative Oncology Group performance status of 2 or less; adequate hematopoietic, hepatic, and renal functions; no anticancer medical or radiation therapy within 4 weeks (6 weeks for nitrosourea and mitomycin) of starting deforolimus; no prior therapy with rapamycin or rapamycin analogs. Patients were excluded for significant serum chemistry abnormalities (eg, serum cholesterol > 350 mg/dL or triglycerides > 400 mg/dL), primary CNS malignancies or metastases, hypersensitivity to macrolide antibiotics or polysorbate 80, significant cardiovascular disease/medical problem(s), and pregnancy. All patients provided informed consent according to federal and institutional guidelines. The trial was conducted in accordance with current Good Clinical Practice.
Trial Design, Dose Escalation, and Modification An accelerated titration design and flat-fixed dosing were used.15 Deforolimus starting dose was 3 mg/d, chosen on the basis of preclinical toxicology data. In the absence of a grade 2 or worse treatment-related adverse event (AE), the dose was doubled (100%) in the subsequent cohort. If a grade 2 or worse treatment-related AE was observed, the dose increased by 50%. If a dose-limiting toxicity (DLT) occurred in cycle 1, subsequent doses increased by 25%. Each dose-level cohort comprised one patient fully assessable for cycle 1 AE. Cohorts were expanded to a minimum of three patients after a treatment-related grade 2 or 3 event occurred in cycle 1. If a DLT occurred during cycle 1, the cohort was expanded to at least six patients. Dose reduction by one dose level was permitted for patients who developed DLT. If two or more patients per cohort had a cycle 1 DLT, dose escalation was terminated. The MTD was one dose level below the dose at which at least 33% of patients in a cohort of six or more patients experienced a cycle 1 DLT. The MTD cohort was expanded to at least 12 patients to further evaluate tolerability.
DLTs were treatment related (1) grade 3 nonhematologic toxicity lasting more than 3 days despite supportive care, with the exception of self-limiting or medically controllable toxicities (fever without neutropenia, nausea, vomiting, fatigue, hypersensitivity reactions); (2) grade 4 nonhematologic toxicity; (3) grade 4 neutropenia (absolute neutrophil count < 500/µL) lasting more than 5 days and/or grade 3 or 4 neutropenia with fever (
Patient Evaluation Radiographic studies for disease assessment were conducted at baseline and every 2 cycles (8 weeks). Tumor response was assessed by the Response Evaluation Criteria for Solid Tumors (RECIST) guidelines.17 Minor responses (MR) were defined as regression of target tumor lesions by 10% to 30% with no new lesions and no nontarget lesion progression.
PK Analyses A linear three-compartment PK model characterized the deforolimus whole-blood concentration-time profile. Model characteristics included separate compartments for whole blood and highly and less perfused tissues. Deforolimus whole-blood concentrations were representative of concentrations in the central compartment. PK data were individually modeled. Maximum concentration (Cmax), half-life, area under the curve (AUC0-24), clearance, and volume of distribution were summarized from the individual patient parameters. Analyses for compartmental modeling were performed using WINNonlin Pro, Version 4.1 (Pharsight Corp, Mountain View, CA).
Pharmacodynamic Analyses
General Thirty-three patients with advanced or refractory malignancies were enrolled, and 32 received at least one deforolimus dose. Patient characteristics are summarized in Table 1. The median number of cycles was four, and 11 (34%) patients completed six or more cycles. Median time receiving treatment for the overall population was 117 days (range, 1 to 943 days; Fig A1, online only). Two patients discontinued treatment during cycle 1, one for disease progression and another for non–treatment-related pain.
Six dose levels (3 to 28 mg/d) were evaluated for DLT (n = 32). Three cycle 1 DLTs were recorded. All were grade 3 mouth sores and limited to the two highest dose levels. Two patients with DLT in the 28-mg/d cohort were hospitalized for pain management and IV fluids. Deforolimus treatment resumed at 18.75 mg/d; however, both patients subsequently experienced recurrent grade 2 mouth sores. By definition, the 28-mg/d cohort with two of six patients with DLT exceeded the MTD and the 18.75 mg/d cohort expanded to 13 patients. One patient in this expanded cohort experienced a DLT, leading to a 1-week treatment delay and subsequent dose reduction to 12.5 mg/d in cycle 1. Thus, the MTD was established as 18.75 mg/d. Four patients treated with deforolimus 18.75 mg/d required dose reduction after cycle 1, two for grade 2 mucosal or skin toxicities, one for grade 3 mouth sores, and one for grade 3 increased AST. As a result, a lower dose level of 15 mg/d (n = 6) was explored. At this dose level, no DLTs were observed, and only one patient required dose reduction during cycle 1 for grade 2 thrombocytopenia.
Safety
Mouth sores were similar to aphthous ulcers and were more frequent and severe at doses exceeding 12.5 mg/d (Table 2). One patient each in the 3- and 12.5-mg/d cohorts experienced mild or moderate mouth sores, but was not observed in the 6.25-mg/d cohort. In contrast, the majority of patients treated at doses of at least 15 mg/d had grade 1 to 3 treatment-related mouth sores (Table 2). Most patients who developed mouth sores were treated symptomatically, and recovery was usually complete. Generally, mouth sores decreased in frequency and severity with subsequent cycles of treatment. At least one patient per cohort, 25 patients (78%) total, experienced reversible treatment-related dermatologic events, consisting primarily of rash (66%). When described, rashes were typically "erythematous maculopapular." Three patients (16%) had acneiform dermatitis. Only one patient (3%; 12.5 mg/d cohort) developed a grade 3 event, which was a reversible erythematous maculopapular lesion occurring after cycle 1. Topical corticosteroids or systemic antibiotics effectively controlled rash. Other treatment-related dermatologic manifestations included pruritus (13%), nail disorders (9%), folliculitis (9%), and skin discoloration (9%). Treatment-related grade 1 or 2 hypertriglyceridemia and/or hypercholesterolemia were recorded in 13 (41%) and nine (28%) patients, respectively, over the entire dose range. Patients were treated with atorvastatin, simvastatin, or gemfibrozil with good recovery and subsequent control while continuing deforolimus treatment. Interstitial and alveolar pulmonary infiltrates were detected in five patients (one patient each at 3, 15, and 28 mg/d and two patients at 18.75 mg/d). Three patients were asymptomatic. Treatment discontinuation alone or with a brief course of corticosteroids led to resolution of pulmonary infiltrates in four patients, and re-treatment was possible in three patients. The fifth patient ultimately developed acute respiratory distress and died despite medical treatment. Because lung biopsies from this patient revealed intra-alveolar hemorrhage and a malignant cell infiltrate from Ewing sarcoma, a single cause of pneumonitis was difficult to establish. Hematologic treatment-related events were generally mild or moderate (Table 2) and reversible. Grade 1 to 2 treatment-related anemia occurred in 17 patients (53%) at doses of 12.5 mg/d and higher. One patient experienced treatment-related grade 3 neutropenia at 18.75 mg/d, and another patient in this cohort developed brief, uncomplicated treatment-related grade 4 thrombocytopenia. Treatment-related grade 4 neutropenia was not observed.
Pharmacokinetics
Pharmacodynamics The pharmacodynamic activity of deforolimus was assessed by measuring levels of p-4E-BP1 in PBMCs by Western blot. Within 4 hours after the first infusion, p-4E-BP1 levels in PBMCs decreased dramatically in all patients (typically > 90%). Representative data from three patients, including patients in the lowest and highest dose groups, are shown in Figure 1B. Summary data from all patients are shown in Table A1 (online only).
Tumor Response
Twenty-nine patients were evaluated for tumor response by RECIST guideline, and 22 (76%) patients had stable disease (SD) or partial responses (PR). Interestingly, all patients with sarcoma and renal cell carcinoma (RCC) experienced PR, MR, or SD for more than 3 months. Four patients had confirmed PR. A 67-year-old chemotherapy-naïve woman with a mixed müllerian tumor (carcinosarcoma) treated with deforolimus 3 mg/d experienced progressive reduction of pulmonary metastases and disappearance of liver metastases, and achieved PR after 10 cycles. At the time of the data cutoff, her PR had been sustained for 22 months. She continues receiving treatment (> 42 months), with a sustained PR more than 31 months. A 57-year-old male patient in the 18.75-mg/d cohort, with advanced non–small-cell lung cancer refractory to three previous chemotherapy regimens and erlotinib, had a PR for 2 months followed by development of brain metastasis, with overall SD of 6 months (Fig 3A). After four cycles, a 20-year-old male patient with recurrent Ewing sarcoma in the 15-mg/d cohort, who had progressed through nine previous regimens, had significant reduction of pleural metastases and PR lasting two months (Fig 3B). The fourth PR was achieved by a 65-year-old male patient in the 6.25-mg/d cohort who had metastatic RCC refractory to prior therapy with interferon and erlotinib. The PR occurred after 4 months of deforolimus treatment and was sustained for 5 months.
Eighteen patients had SD, nine of whom maintained SD for more than four cycles. The median time receiving treatment among these patients was 307 days (range, 68 to 574 days). Of these patients, three had MR, including a 45-year-old male in the 18.75-mg/d cohort with refractory anaplastic large-cell lymphoma that had progressed through six previous chemotherapy regimens. This patient demonstrated a significant reduction in tumor burden (27.9%), including a dramatic reduction of a nontarget lesion, an axillary lymph node, which decreased from 10 to 3 cm (70% reduction) within 1 week of initiating deforolimus treatment and showed a further reduction to 2 cm by the beginning of cycle 2.
The results of this trial show that deforolimus administered once daily for 5 days every 2 weeks to patients with advanced solid malignancies is safe and well tolerated. Tumor regression or lack of tumor progression was observed at all doses. Only three patients experienced DLT, all of which were grade 3 mouth sores and restricted to the highest dose-level cohorts. Because 33% of patients (two of six) in the 28-mg/d cohort experienced DLTs, 18.75 mg/d was established as the MTD. Treatment-related AEs were generally mild or moderate in severity and were manageable. The most frequently encountered treatment-related events were mouth sores (78%) and rash (66%) and occurred most often in patients receiving more than 12.5 mg/d of deforolimus. In general, mouth sores resolved with symptomatic treatment, but more severe episodes required deforolimus dose interruption. Dermatologic events were predominantly a nonconfluent, acne-like rash on the face. Rash was usually mild or moderate in severity and readily manageable. Severe related myelosuppression was observed rarely, suggesting that deforolimus could be combined with other antitumor agents. There were no events suggestive of clinically relevant immunosuppression. Five patients developed pneumonitis, an AE also reported with administration of the mTOR inhibitors sirolimus (rapamycin), temsirolimus, and everolimus.18-21 All episodes occurred after at least 4 months of deforolimus treatment, with no apparent relationship to dose. Deforolimus is a nonprodrug with reproducible and predictable pharmacokinetics. Cmax and AUC0-24 increased dose proportionally at lower doses, but exposure was nonlinear at higher doses. Model-predicted interpatient variability was low, suggesting that deforolimus pharmacokinetics are reproducible within a cohort. Potent inhibition of mTOR signaling was demonstrated in all patients who received deforolimus, as evidenced by a significant reduction (typically > 90%) of p-4E-BP1 levels in PBMCs within 4 hours after dosing. In most patients, a substantial reduction in p-4E-BP1 levels persisted during the 10-day period between deforolimus infusions.12 Deforolimus also inhibits mTOR signaling in patient tissue; in 22 of 28 patients analyzed, mTOR signaling in biopsied skin specimens was reduced by at least 50% after deforolimus treatment.11 A complete description of these pharmacodynamic analyses will be reported separately. Antitumor activity was observed with all deforolimus doses. During the trial, 67% of patients (18 of 27) achieved tumor shrinkage compared with baseline measurements. The majority (22 of 29; 76%) of assessable patients exhibited either tumor regression or stabilization according to RECIST guidelines. PRs were observed in patients with mixed müllerian tumor, advanced non–small-cell lung cancer, RCC, and Ewing sarcoma. The patient with Ewing sarcoma, who had a PR lasting more than 2 months, ultimately succumbed with multifactorial acute respiratory distress including pulmonary disease progression and possibly related pneumonitis; lung biopsies from that patient showed intra-alveolar hemorrhage as well as malignant cell infiltrate from Ewing sarcoma indicating the probably multifactorial nature of the event. A substantial reduction in tumor burden was observed in one patient with anaplastic large-cell lymphoma. The observed lack of progression of various tumors, sustained for extended time intervals, is noteworthy because many of these patients had been refractory to multiple standard and/or investigational antitumor agents. Furthermore, all patients with sarcoma and RCC experienced PR, MR, or SD for more than 3 months. This encouraging antitumor activity supports additional disease-specific clinical evaluation of deforolimus. In summary, deforolimus was safe and well tolerated, and exhibited antitumor activity at all doses tested. There was little change in PK parameters at doses exceeding 12.5 mg/d, and the frequency and severity of the main AE, mouth sores, increased at doses greater than 12.5 mg/d. Therefore, on the basis of the safety and PK profiles, 12.5 mg once daily for 5 consecutive days every 2 weeks was chosen as the recommended phase II dose for further evaluation of intravenously administered deforolimus. Because of the promising antitumor activity observed across a broad range of tumor types and a safety profile of generally mild/moderate and manageable AEs, deforolimus is being developed in follow-on disease-focused clinical trials and in combination with established chemotherapy agents.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Heather Knowles, ARIAD Pharmaceuticals (C); Victor M. Rivera, ARIAD Pharmaceuticals (C); Camille L. Bedrosian, ARIAD Pharmaceuticals (C) Consultant or Advisory Role: Eric K. Rowinsky, ARIAD Pharmaceuticals; Jeff Kreisberg, ARIAD Pharmaceuticals (C); Gerald J. Fetterly, ARIAD Pharmaceuticals (C); Anthony W. Tolcher, ARIAD Pharmaceuticals (C) Stock Ownership: Victor M. Rivera, ARIAD Pharmaceuticals; Camille L. Bedrosian, ARIAD Pharmaceuticals Honoraria: Anthony W. Tolcher, ARIAD Pharmaceuticals Research Funding: Anthony W. Tolcher, ARIAD Pharmaceuticals Expert Testimony: None Other Remuneration: None
Conception and design: Eric K. Rowinsky, Victor M. Rivera, Camille L. Bedrosian, Anthony W. Tolcher Provision of study materials or patients: Monica M. Mita, Alain C. Mita, Quincy S. Chu, Eric K. Rowinsky, Michelle Goldston, Lesley Mathews, Alejandro D. Ricart, Theresa Mays, Camille L. Bedrosian, Anthony W. Tolcher Collection and assembly of data: Monica M. Mita, Michelle Goldston, Heather Knowles, Victor M. Rivera, Jeff Kreisberg, Anthony W. Tolcher Data analysis and interpretation: Monica M. Mita, Eric K. Rowinsky, Gerald J. Fetterly, Heather Knowles, Victor M. Rivera, Jeff Kreisberg, Camille L. Bedrosian, Anthony W. Tolcher Manuscript writing: Monica M. Mita, Gerald J. Fetterly, Victor M. Rivera, Anthony W. Tolcher Final approval of manuscript: Monica M. Mita, Alain C. Mita, Eric K. Rowinsky, Gerald J. Fetterly, Amita Patnaik, Lesley Mathews, Jeff Kreisberg, Camille L. Bedrosian, Anthony W. Tolcher
We thank the patients and personnel who participated in the trial. We also thank John Loewy, PhD; Katherine Kacena, PhD; and Susan Tierney for critical review of the manuscript; and Dianne Barry, PhD, for writing assistance.
Supported by ARIAD Pharmaceuticals Inc, Cambridge, MA. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA, and at the 16th European Organisation for Research and Treatment of Cancer/National Cancer Institute/American Association for Cancer Research International Conference on Molecular Targets and Cancer Therapeutics, September 28–October 1, 2004, Geneva, Switzerland. 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
38.5°C); (4) platelet count less than 25,000/µL; (5) inability to complete one dosing cycle because of any drug-related toxicity; and (6) unresolved toxicities delaying re-treatment for more than 2 weeks. 
