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Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients With Advanced Refractory Renal Cell Carcinoma

From the Beth Israel Deaconess Medical Center, Boston, MA; University of Texas Health Science Center at San Antonio, San Antonio, TX; University of Chicago, Chicago, IL; Indiana University, Indianapolis, IN; Our Lady of Mercy Cancer Center, NY Medical College, Bronx, NY; Fox Chase Cancer Center, Philadelphia, PA; and Wyeth Research, Cambridge, MA, and Collegeville, PA.

Address reprint requests to Michael Atkins, MD, Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, E Campus, Kirstein 158, Boston, MA 02215; e-mail: matkins{at}bidmc.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC).

PATIENTS AND METHODS: Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics.

RESULTS: CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779–related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar.

CONCLUSION: In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Renal cell carcinoma (RCC) accounts for approximately 3% of all adult malignancies [1] and 2% of all cancer-related deaths [2]. Systemic chemotherapy produces few and only transient tumor responses in patients with metastatic RCC [3]. High-dose interleukin-2 (IL-2) produces tumor responses in 15% to 20% of patients, with nearly half of all responses persisting for greater than 5 years. In phase II trials that led to the approval of high-dose IL-2 in the United States, the median survival was 16.3 months [4]. Unfortunately, this therapy is associated with severe toxicity [5], necessitating inpatient administration and limiting its use to highly selected patients treated at a few established treatment centers. Interferon alfa (IFN-) has produced modest survival benefits in some phase III trials; however, few patients achieve durable benefit [5-17]. Low-dose IL-2 regimens, even when combined with IFN-, have been generally less active than high-dose IL-2 therapy [18]. There are no established therapies for patients who experience relapse after, or are refractory to, IL-2 and/or IFN- therapy, and such patients generally have a poor prognosis.

CCI-779 is a novel mammalian target of rapamycin (mTOR) kinase inhibitor. It was shown to bind with high affinity to the immunophilin FKBP [19], and this complex inhibits mTOR kinase activity as evidenced by inhibition of phosphorylation of the eukaryotic translation initiation factor 4E binding protein-1 and the 40S ribosomal protein p70 S6 kinase, the primary downstream effectors of mTOR [20-22]. These CCI-779–induced changes in proteins downstream of mTOR lead to G₁ phase cell cycle arrest [23].

The upstream activator of mTOR is the serine-threonine kinase, Akt. Akt activity, in turn, is regulated by PI3-kinase and the PTEN tumor suppressor gene [24]. In PTEN heterozygous mice with uterine and adrenal medullary tumors, treatment with CCI-779 produces significant reductions in tumor size [25], which suggest that CCI-779 may be useful in the treatment of human tumors that contain mutations in PTEN.

Although mutations in PTEN have not been detected in RCC, PTEN gene expression is often downmodulated [26,27]. In addition, the mTOR pathway appears to be involved in the development of a hereditary form of RCC seen in patients with tuberous sclerosis. mTOR-mediated downstream signaling appears to be inhibited by a complex composed of tuberin and hamartin, the products of tuberous sclerosis complex (TSC)-2 and TSC-1 genes, respectively [28]. In states of nutrient sufficiency, Akt phosphorylates tuberin, inactivating the tuberin-hamartin suppressor complex and enabling cell growth and proliferation to proceed [29,30]. Mutations in TSC-1 or TSC-2 release mTOR inhibition under all conditions. These mutations have been found in tuberous sclerosis, indicating that failure to inhibit mTOR-mediated downstream signaling is likely to be a critical component of the pathway leading to RCC development in patients with this disease.

In addition, the genetics and pathophysiology of RCC suggest that the inhibition of mTOR might produce other salutary effects. Sporadic RCC is associated with the loss of function of the von Hippel Lindau (VHL) tumor suppressor gene by mutation, deletion, or hypermethylation. As a component of an E3 ubiquitin ligase, the VHL protein normally targets the oxygen-sensitive transcription factors hypoxia-inducible factor 1-alpha (HIF-1) and HIF-2 for destruction by the proteasome [31]. Loss of VHL function prevents the degradation of these factors, leading to their accumulation and increased expression of HIF-regulated proteins such as vascular-endothelial growth factor (VEGF), PDGF, TGFß, and other angiogenic and growth stimulatory molecules [32]. mTOR activation increases HIF-1 gene expression at both the levels of mRNA translation and protein stabilization [33]. Thus, inhibition of mTOR by CCI-779 could also prevent the enhanced angiogenesis associated with sporadic RCC and loss of VHL function [34].

In a phase I study in patients with advanced solid tumors, CCI-779 was administered at doses ranging from 7.5 to 220 mg/m² as a weekly 30-minute infusion [35]. CCI-779 was well tolerated over a wide range of doses, with the most frequently occurring drug-related adverse events being skin toxicity and mucositis. One patient with advanced RCC who received 15 mg/m² CCI-779 and one patient with metastatic breast cancer who received 220 mg/m² had partial tumor responses. Pharmacokinetic evaluations indicated that sirolimus was a major metabolite of CCI-779 and exposure to both CCI-779 and sirolimus increased less than proportionally with increasing dose. Analysis of the exposure obtained with dosages based on body-surface area indicated that dose normalization did not improve variability in patients over that seen with flat doses. Therefore, to further characterize the relationships between dose and both efficacy and toxicity, patients with advanced RCC in our study were randomly assigned to receive treatment with flat doses of either 25, 75, or 250 mg CCI-779.

	PATIENTS AND METHODS

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Patients
Patients with advanced refractory RCC were randomly assigned to receive one of three dose levels of CCI-779 between April and October 2000. Eligible patients had histologically confirmed advanced RCC and either had received previous therapy for advanced disease or were not considered appropriate candidates for first-line IL-2–based therapy.

Patients were required to have bidimensionally measurable disease (both diameters of the tumor 1 cm) and to have documented disease progression. They had to be at least 18 years of age; have adequate hematologic, renal, and hepatic function (absolute neutrophil count [ANC] 1,500/µL, platelet count 100,000/µL, hemoglobin 8.5 g/dL, serum creatinine 1.5 x the upper limit of normal or calculated creatinine clearance 60 mL/min, bilirubin levels 1.5 x upper limit of normal, AST levels 3 x upper limit of normal or < 5 xupper limit of normal in patients with liver metastases); and have serum cholesterol 350 mg/dL and serum triglycerides 300 mg/dL. Patients also had to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and a life expectancy of at least 12 weeks.

Patients were excluded if they had a history of CNS metastases or were receiving hepatic enzyme-inducing anticonvulsants; surgery or local radiotherapy within 3 weeks or chemotherapy, biologic therapy, or investigational drug use within 4 weeks of treatment start; prior malignancy, other than basal cell or squamous cell carcinoma of the skin, within 3 years or a history of systemic treatment for prior malignancy; active infection; known HIV infection; use of immunosuppressive agents including systemic corticosteroids; significant cardiovascular disease including unstable angina or myocardial infarction within 6 months of treatment start or a history of life-threatening arrhythmia; or hypersensitivity to macrolide antibiotics. Women who were pregnant, nursing, or of childbearing potential and not using an effective contraceptive method also were excluded.

The study was conducted according to the Declaration of Helsinki and its amendments. The study protocol was approved by institutional review boards of the participating institutions, and all patients gave written informed consent.

Treatment
Patients were randomly assigned to receive 25, 75, or 250 mg CCI-779 as a weekly 30-minute intravenous infusion. Treatment continued until evidence of disease progression or unacceptable toxicity. During the course of this study, pretreatment with diphenhydramine 25 to 50 mg was given approximately 30 minutes before the start of each CCI-779 infusion to try to prevent acute hypersensitivity reactions. If a patient developed a hypersensitivity reaction despite this pretreatment, a histamine H₂-receptor antagonist could also be administered.

The National Cancer Institute Common Toxicity Criteria, version 2.0, was used to grade toxicity. CCI-779 dose modifications were made as follows. A decrease in ANC to between 750 and 1,000/µL or platelet count to between 50,000 and 80,000/µL, or grade 3 nonhematologic adverse event (AE) resulted in a 25% dose reduction. A decrease in ANC to less than 750/µL or platelet count less than 50,000/µL, or grade 4 nonhematologic AE resulted in a 50% dose reduction. Patients were allowed two dose reductions. If continued toxicity required withholding treatment for more than 2 consecutive weeks, the patient was removed from additional treatment.

Evaluation of Patients
Patients underwent clinical evaluation at baseline and at 4-week intervals during the course of therapy. Tumor size assessments were made at 8-week intervals. Response was defined using standard bidimensional measurements in accordance with WHO guidelines for complete response (CR), partial response (PR), and stable disease (SD). In addition, minor response (MR) was defined as a 25% decrease but less than 50% decrease in the sum of the products of the two greatest perpendicular diameters of all measurable lesions. Two observations not less than 4 weeks apart were required to confirm CR or PR; confirmation of MR was not required. Progressive disease was defined as the appearance of new lesions or an increase 25% (over the minimum measurement) in the sum of the products.

Statistical Considerations
The primary efficacy end point of this study was objective tumor response rate (the percentage of patients with CR or PR). In addition, the percentage of patients with CR, PR, or MR, or SD 24 weeks was determined. The primary efficacy analysis was based on the intent-to-treat population (n = 111). The number of patients chosen for the study was based on mainly clinical considerations. Assuming a 15% dropout rate, approximately 105 eligible patients were to be randomly assigned to have at least 30 assessable patients per treatment arm. If the true objective tumor response rate was 25%, the probabilities that the 95% CIs would not include the spontaneous remission rates of 0.8% [36] to 7% [37] were 0.998 and 0.80, respectively. These probabilities were reduced to 0.95 and 0.29, respectively, if the true response rate was 15%.

All patients were considered assessable for tumor response if they completed the 8-week tumor assessment. Patients who died or experienced disease progression before the first 8-week tumor evaluation were considered assessable but nonresponders. Patients were assessable for safety if they received at least one dose of CCI-779.

Time to tumor progression (TTP) was measured as the interval from the date of first CCI-779 dose until the first date of documented PD. Survival was measured from the date of first CCI-779 dose until the date of death or the last date that a censored patient was known to be alive. Results for survival and time to tumor progression were analyzed according to Kaplan-Meier estimates and compared using the log-rank test. Incidences of AEs among dose groups were compared using the Fisher's exact test. The data cutoff date for reporting tumor response, TTP, and AEs was August 12, 2002. The data cutoff date for reporting survival was June 9, 2003.

Pharmacokinetic Assessment
CCI-779 and sirolimus, a major metabolite, were measured in whole blood samples of patients. Blood samples were drawn for full pharmacokinetic profiling from a subset of patients at 0 (predose), 0.5 (end of infusion), 1, 2, 6, 24, 72, 96, and 168 hours during weeks 1 and 4 of treatment. Concentrations of CCI-779 and sirolimus were measured using a modification of a validated high-performance liquid chromatography–mass spectrometry–mass spectrometry procedure (Taylor Technology Inc, Princeton, NJ) [38].

Data were analyzed using both compartmental (for CCI-779) and noncompartmental (for sirolimus) analysis techniques [39]. Compartmental model fitting for CCI-779 was performed using a two-compartment model with zero-order infusion and solved using the ADAPTII software package, Release 4 (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). This approach was chosen to permit an evaluation of population pharmacokinetics with data from all patients (to be reported in a separate publication). Noncompartmental analysis for sirolimus was performed using the SAS version 8.1 (SAS Institute, Cary, NC) application on the Unix operating system. The following pharmacokinetic parameters were determined: C_max, the peak observed concentration; t_max, the time to C_max; t_1/2, terminal half-life; AUC, area under the concentration-versus-time curve; CL, total body clearance; Vd_ss, steady-state volume of distribution; AUC_ratio, the uncorrected ratio of sirolimus to CCI-779 AUCs; and AUC_sum, the algebraic sum of CCI-779 and sirolimus AUCs.

	RESULTS

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Patient Characteristics
A total of 111 patients were enrolled onto this trial, with 36, 38, and 37 patients randomly assigned to receive 25, 75, and 250 mg CCI-779, respectively. Demographic characteristics are listed in Table 1. The median age of the total patient population was 57 years and was similar for the individual dose groups. Fewer patients in the 250-mg dose group had an ECOG PS of 1 than did patients in the 25-mg and 75-mg dose groups. Patients had extensive disease and were heavily pretreated: 83% of patients had two or more sites of metastases, with lung as the most common site, and 51% had received two or more prior immunotherapy or chemotherapy regimens.

View larger version (19K): [in this window] [in a new window]   Fig 1. Time to tumor progression for renal cell carcinoma patients in the 25-, 75-, and 250-mg CCI-779 dose groups. mos, months.

View larger version (20K): [in this window] [in a new window]   Fig 2. Survival of renal cell carcinoma patients in the 25-, 75-, and 250-mg CCI-779 dose groups. mos, months.

View this table: [in this window] [in a new window]   Table 4. Percentage of Patients With CCI-779-Related Adverse Events, 20% Overall Frequency, All Grades, All Cycles

View this table: [in this window] [in a new window]   Table 5. Percentage of Patients With Grade 3 or 4 CCI-779-Related Adverse Events, 5% Overall Frequency, All Cycles

Reasons for dose reductions included thrombocytopenia (20% of all patients), mucositis (16%), hypertriglyceridemia (5%), and neutropenia (1%). Twenty-one patients (five, seven, and nine in the 25-, 75-, and 250-mg dose groups, respectively) discontinued treatment because of CCI-779–related AEs. Maculopapular rash (five patients) was the most frequent reason for treatment discontinuation. No patients died from CCI-779–related AEs.

Pharmacokinetics
The pharmacokinetic parameters of CCI-779 and sirolimus, a major metabolite of CCI-779, in whole blood are reported for 16 patients after their initial dose of CCI-779. Mean values for each dose group are reported (Table 6).

Prognostic Factor Analysis of RCC Patients Treated With CCI-779
Because of the suggestion of biologic activity manifested by the observed CR, PRs, MRs, and the 15-month median survival, an additional analysis on the basis of previously described prognostic factors was undertaken. Five factors identified by Motzer et al [40] to be indicative of poor prognosis in RCC patients receiving first-line IFN- treatment were Karnofsky performance status less than 80%, lactate hydrogenase levels more than 1.5 x upper limit of normal, corrected serum calcium levels more than 10 mg/dL, serum hemoglobin levels less than lower limit of normal, and time from initial RCC diagnosis to start of IFN- therapy of less than 1 year. They separated patients into a good-risk group that had none of these poor prognostic factors, an intermediate-risk group that had one or two factors, and a poor-risk group that had three or more factors. The patients in this CCI-779 phase II study were retrospectively characterized on the basis of these prognostic factors with two modifications: ECOG PS of 1, rather than Karnofsky performance status less than 80%, and time from initial RCC diagnosis to start of first chemotherapy or immunotherapy, rather than to start of IFN- therapy, of less than 1 year were used. These patients were then classified into good-, intermediate-, and poor-risk groups in a fashion similar to that used by Motzer et al (Table 7).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

In this randomized phase II study, promising results were seen with the novel agent CCI-779. It produced an objective tumor response in 7% of patients. In addition, CR, PR, or MR, or SD 24 weeks was noted in approximately 50% of patients; median TTP was close to 6 months; and median survival was 15.0 months. This level of activity is encouraging considering the heavily pretreated patient population studied (91% had received prior systemic therapy and more than half of the patients had received more than one prior treatment regimen). Tumor response rates were comparable among the dose levels. Median survivals also were comparable among the dose levels in the total patient population and in the good-, intermediate-, and poor-risk groups. Thus, 25 mg CCI-779, the lowest dose level used in this study, seemed to be capable of optimal biologic activity and will be used as the dose of drug for monotherapy in future studies.

The median survivals of the heavily pretreated patients in the different risk groups in this study were compared with the median survivals of first-line RCC patients in the different risk groups treated with IFN- [40]. For patients in the intermediate- and poor-prognosis populations, median survivals of CCI-779–treated patients appeared to be 1.6- to 1.7-fold longer than those of IFN-–treated patients [40]. No such advantage was observed in the good-prognosis patients; however, this may be due to the small number of patients with good prognosis who received CCI-779. Although one must be cautious when comparing patient populations with different treatment histories, these data raise the possibility that mTOR inhibition may be particularly relevant in patients with RCC with poor prognostic features. This observation suggests a relationship between Akt and/or mTOR activation in more aggressive disease and suggests that CCI-779 may provide an alternative to first-line therapy for intermediate- and poor-prognosis patients who typically respond poorly to cytokine-based immunotherapy. In addition, CCI-779 has shown in vitro synergy with IFN- and, in a phase I trial in patients with advanced RCC, the combination of CCI-779 and IFN- was determined to be active at a tolerable dose level [49]. On the basis of these results, a phase III trial comparing IFN- with CCI-779, or the combination, as first-line therapy for patients with metastatic RCC and poor prognostic features has been initiated.

Although toxicity was generally similar across dose levels, the fact that more dose reductions and discontinuations from CCI-779–related AEs were seen at the higher dose levels also suggests that the 25-mg dose level should be the optimum dose for additional investigations. Hyperglycemia was observed in 20% and hypertriglyceridemia in 28% of all patients treated with CCI-779. Given that mTOR is a component of the insulin signaling pathway [50,51], its inhibition could be directly responsible for these laboratory abnormalities. Because of their likely direct relationship to mTOR inhibition, these two simple laboratory parameters might serve as biomarkers of CCI-779 target inhibition and could conceivably correlate with its clinical efficacy.

In conclusion, CCI-779 represents a novel anticancer agent that has promising clinical activity in patients with refractory and poor-risk renal cancer. Additional study of this agent, either alone or in combination, in appropriately selected patients is warranted.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Young Park, Wyeth Research; Joseph P. Boni, Wyeth Research; Gary Dukart, Wyeth Research. Acted as a consultant within the last 2 years: Michael B. Atkins, Wyeth Research; Janice P. Dutcher, Wyeth Research. Performed contract work within the last 2 years: Manuel Hidalgo, Wyeth Research; Song-Heng Liou, Wyeth Research. Received more than $2,000 a year from a company for either of the last 2 years: Yong Park, Wyeth Research; Song-Heng Liou, Wyeth Research; Bonnie Marshall, Wyeth Research; Gary Dukart, Wyeth Research; Matthew L. Sherman, Wyeth Research.

	Acknowledgment

 
We thank all the patients and clinical personnel who participated in these studies and Nicole Hinton for data management, Edward Faith for clinical programming, Steven Kong for biostatistical analysis, and Susan Leinbach for manuscript preparation.

	NOTES

 
Supported by research funding from Wyeth Research, Collegeville, PA.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, and the 39th Annual Meeting, Chicago, IL, May 31-June 1, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 28, 2003; accepted December 12, 2003.

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