V O L U M E 2 2 䡠 N U M B E R 5 䡠 M A R C H 1 2 0 0 4
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Beth Israel Deaconess Medi-
`cal 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.
`
`Submitted August 28, 2003; accepted
`December 12, 2003.
`
`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 con-
`flicts of interest are found at the end of
`this article.
`
`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@bidmc
`.harvard.edu
`
`© 2004 by American Society of Clinical
`Oncology
`
`0732-183X/04/2205-909/$20.00
`
`DOI: 10.1200/JCO.2004.08.185
`
`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
`Michael B. Atkins, Manuel Hidalgo, Walter M. Stadler, Theodore F. Logan, Janice P. Dutcher,
`Gary R. Hudes, Young Park, Song-Heng Liou, Bonnie Marshall, Joseph P. Boni, Gary Dukart,
`and Matthew L. Sherman
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`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 hypergly-
`cemia (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.
`
`J Clin Oncol 22:909-918. © 2004 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`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 inter-
`leukin-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 ap-
`proval 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 inpa-
`tient administration and limiting its use to
`highly selected patients treated at a few es-
`tablished treatment centers. Interferon alfa
`(IFN-␣) has produced modest survival ben-
`efits in some phase III trials; however, few
`patients achieve durable benefit [5-17].
`Low-dose IL-2 regimens, even when com-
`bined with IFN-␣, have been generally less
`active than high-dose IL-2 therapy [18].
`There are no established therapies for pa-
`
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`
`Ex. 1092-0001
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`

`
`Atkins et al
`
`tients 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 treat-
`ment 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, re-
`spectively [28]. In states of nutrient sufficiency, Akt phos-
`phorylates tuberin, inactivating the tuberin-hamartin sup-
`pressor 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 fail-
`ure 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 com-
`ponent 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 destruc-
`tion by the proteasome [31]. Loss of VHL function prevents
`the degradation of these factors, leading to their accumula-
`tion and increased expression of HIF-regulated proteins
`such as vascular-endothelial growth factor (VEGF), PDGF,
`TGF␤, and other angiogenic and growth stimulatory mol-
`ecules [32]. mTOR activation increases HIF-1␣ gene ex-
`pression 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 ad-
`vanced 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 eval-
`uations indicated that sirolimus was a major metabolite of
`CCI-779 and exposure to both CCI-779 and sirolimus in-
`creased less than proportionally with increasing dose. Anal-
`ysis 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 treat-
`ment with flat doses of either 25, 75, or 250 mg CCI-779.
`
`PATIENTS AND METHODS
`
`Patients
`Patients with advanced refractory RCC were randomly as-
`signed 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 ad-
`vanced 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 ⱖ 1 cm) and to have docu-
`mented disease progression. They had to be at least 18 years of age;
`have adequate hematologic, renal, and hepatic function (absolute
`neutrophil count [ANC] ⱖ 1,500/␮L, platelet count ⱖ 100,000/
`␮L, hemoglobin ⱖ 8.5 g/dL, serum creatinine ⱕ 1.5 ⫻ the upper
`limit of normal or calculated creatinine clearance ⱖ 60 mL/min,
`bilirubin levels ⱕ 1.5 ⫻ upper limit of normal, AST levels ⱕ 3 ⫻
`upper limit of normal or ⬍ 5 ⫻upper limit of normal in patients
`with liver metastases); and have serum cholesterol ⱕ 350 mg/dL
`and serum triglycerides ⱕ 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 metasta-
`ses 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 squa-
`mous 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 sys-
`temic 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 preg-
`nant, nursing, or of childbearing potential and not using an effec-
`tive contraceptive method also were excluded.
`The study was conducted according to the Declaration of
`Helsinki and its amendments. The study protocol was approved by
`
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`

`
`CCI-779, mTOR Inhibitor, in Advanced RCC
`
`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 di-
`phenhydramine 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 antag-
`onist could also be administered.
`The National Cancer Institute Common Toxicity Criteria,
`version 2.0, was used to grade toxicity. CCI-779 dose modifica-
`tions were made as follows. A decrease in ANC to between 750 and
`1,000/␮L or platelet count to between 50,000 and 80,000/␮L, or
`grade 3 nonhematologic adverse event (AE) resulted in a 25% dose
`reduction. A decrease in ANC to less than 750/␮L or platelet
`count less than 50,000/␮L, 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 assess-
`ments 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 ⱖ 25% decrease but less than 50% decrease in the sum of the
`products of the two greatest perpendicular diameters of all mea-
`surable 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 ⱖ 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 ⱖ
`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 consid-
`erations. 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 prob-
`abilities 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 nonre-
`sponders. Patients were assessable for safety if they received at
`least one dose of CCI-779.
`Time to tumor progression (TTP) was measured as the inter-
`val 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 es-
`timates 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 (pre-
`dose), 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 vali-
`dated high-performance liquid chromatography–mass spec-
`trometry–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 Sim-
`ulations Resource, University of Southern California, Los Angeles,
`CA). This approach was chosen to permit an evaluation of popu-
`lation pharmacokinetics with data from all patients (to be re-
`ported 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 follow-
`ing pharmacokinetic parameters were determined: Cmax, the peak
`observed concentration; tmax, the time to Cmax; t1/2, terminal
`half-life; AUC, area under the concentration-versus-time curve;
`CL, total body clearance; Vdss, steady-state volume of distribution;
`AUCratio, the uncorrected ratio of sirolimus to CCI-779 AUCs;
`and AUCsum, the algebraic sum of CCI-779 and sirolimus AUCs.
`
`RESULTS
`
`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 character-
`istics 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.
`
`Summary of CCI-779 Treatment
`Treatment information is listed in Table 2. The total
`population received a median of 19 doses of CCI-779 and
`was on study for a median of 5.6 months. The median
`number of doses of CCI-779 and the median months of
`
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`

`
`Atkins et al
`
`Table 1. Patient Characteristics
`
`CCI-779 Dose Level
`
`Total
`(n ⫽ 111)
`
`25 mg
`(n ⫽ 36)
`
`75 mg
`(n ⫽ 38)
`
`250 mg
`(n ⫽ 37)
`
`Characteristic
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`Age, years
`Median
`Minimum
`Maximum
`Sex
`Male
`Female
`ECOG PS
`0
`1
`No. of sites of metastasesⴱ
`1
`2
`ⱖ 3
`Site of metastases†
`Lung
`Lymph node
`Bone
`Liver
`Prior therapy
`Immunotherapy or chemotherapy
`Interleukins
`Interferon
`Nephrectomy
`Radiotherapy
`No. of prior immunotherapy or chemotherapy regimens
`0
`1
`2
`ⱖ 3
`
`57
`17
`81
`
`55
`40
`79
`
`58
`17
`78
`
`57
`40
`81
`
`77
`34
`
`39
`72
`
`19
`38
`52
`
`83
`37
`26
`22
`
`101
`94
`50
`89
`39
`
`10
`44
`26
`31
`
`69
`31
`
`35
`65
`
`17
`35
`48
`
`75
`33
`23
`20
`
`91
`85
`45
`80
`35
`
`9
`40
`23
`28
`
`24
`12
`
`12
`24
`
`8
`7
`21
`
`29
`9
`13
`9
`
`32
`30
`18
`27
`14
`
`4
`17
`6
`9
`
`67
`33
`
`33
`67
`
`22
`19
`58
`
`81
`25
`36
`25
`
`89
`83
`50
`75
`39
`
`11
`47
`17
`25
`
`32
`6
`
`9
`29
`
`4
`16
`17
`
`29
`17
`10
`5
`
`36
`34
`16
`31
`12
`
`2
`15
`10
`11
`
`84
`16
`
`24
`76
`
`11
`43
`46
`
`76
`45
`26
`13
`
`95
`90
`42
`82
`32
`
`5
`40
`26
`29
`
`21
`16
`
`18
`19
`
`7
`15
`14
`
`25
`11
`3
`8
`
`33
`30
`16
`31
`13
`
`4
`12
`10
`11
`
`57
`43
`
`49
`51
`
`19
`42
`39
`
`68
`30
`8
`22
`
`89
`81
`43
`84
`35
`
`11
`32
`27
`30
`
`Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status.
`ⴱTwo patients, one in the 75-mg and one in the 250-mg group, did not have these data reported.
`†With or without other sites.
`
`therapy decreased as the dose level increased. These differ-
`ences can be attributed, at least in part, to more frequent
`dose withholding because of toxicity in patients receiving
`the higher dose levels. The median amount of CCI-779
`received per week and cumulatively was 22 and 456 mg
`for the 25-mg dose group, 54 and 977 mg for the 75-mg
`dose group, and 171 and 3,412 mg for the 250-mg dose
`group, respectively.
`Efficacy
`One patient with diffuse lung metastases at the 250-mg
`dose level had a CR. This patient remains disease free well
`into his third year and continues with CCI-779 treatment.
`Two, three, and two patients in the 25-, 75-, and 250-mg
`dose groups, respectively, had PRs (Table 3). Thus, the
`objective response rate (CR ⫹ PR) was 7% for the total
`population (95% CI, 3.2 to 13.7). An additional 29 patients
`(26%) had MRs. For the total patient population, 51% had
`CR, PR, or MR, or SD ⱖ 24 weeks.
`
`Median TTP was 5.8 months for the total patient pop-
`ulation and 6.3, 6.7, and 5.2 months for patients in the 25-,
`75-, and 250-mg dose groups, respectively (Fig 1). Median
`survival was 15.0 months for the total patient population,
`and 13.8, 11.0, and 17.5 months for patients in the 25-, 75-,
`and 250-mg dose groups (Fig 2). The probability of survival
`at 2 years was 29% for the total patient population and 24%,
`26%, and 36% for patients in the 25-, 75-, and 250-mg dose
`groups, respectively.
`Safety
`Of the 111 patients enrolled in this study, 110 received
`CCI-779 and were evaluated for safety. The most common
`CCI-779 –related AEs of all grades were maculopapular rash
`(76%), mucositis (70%), asthenia (50%), and nausea (43%)
`(Table 4). Grade 3 or 4 CCI-779 –related AEs that occurred
`with an overall frequency ⱖ 5% included hyperglycemia
`(17%), hypophosphatemia (13%), anemia (9%), and hy-
`pertriglyceridemia (6%) (Table 5). There were no statisti-
`
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`

`
`CCI-779, mTOR Inhibitor, in Advanced RCC
`
`Table 2. Treatment of RCC Patients With CCI-779
`
`Treatment Parameter
`
`Total (n ⫽ 110)
`
`CCI-779 Dose Level
`25 mg (n ⫽ 36)
`75 mg (n ⫽ 38)
`
`250 mg (n ⫽ 36)
`
`No. of doses administered
`Median
`Minimum
`Maximum
`Median months from first dose to study conclusionⴱ
`95% CI
`% patients with ⱖ 1 dose reduction
`Amount of CCI-779 received per week, mg
`Median
`Minimum
`Maximum
`Amount of CCI-779 received, mg
`Total
`Minimum
`Maximum
`
`Abbreviation: RCC, renal cell carcinoma.
`ⴱKaplan-Meier estimates.
`
`19
`1
`87
`5.6
`4.1 to 6.9
`54
`
`54
`3
`250
`
`1,005
`25
`10,909
`
`23
`1
`87
`6.6
`3.7 to 9.0
`36
`
`22
`3
`26
`
`456
`25
`1,644
`
`18
`2
`74
`5.8
`3.7 to 7.6
`66
`
`54
`13
`75
`
`977
`150
`4,050
`
`15
`2
`72
`4.1
`3.5 to 6.7
`58
`
`171
`59
`250
`
`3,412
`500
`10,909
`
`cally significant differences in the percentages of patients in
`the different dose groups who had either grade 1 to 4 or
`grade 3 to 4 CCI-779 –related AEs.
`Six patients were reported to have had possible nonspe-
`cific pneumonitis, including five at the 75-mg dose level and
`one at the 25-mg dose level. Of these, two were withdrawn
`from additional treatment and four were re-treated, with
`two patients experiencing recurrent pneumonitis.
`Reasons for dose reductions included thrombocytope-
`nia (20% of all patients), mucositis (16%), hypertriglyceri-
`demia (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 discontinua-
`tion. No patients died from CCI-779 –related AEs.
`
`Pharmacokinetics
`The pharmacokinetic parameters of CCI-779 and siroli-
`mus, a major metabolite of CCI-779, in whole blood are re-
`ported for 16 patients after their initial dose of CCI-779. Mean
`values for each dose group are reported (Table 6).
`For CCI-779, Cmax and AUC values increased in a
`less-than-proportional manner with increasing dose. High-
`
`Table 3. Tumor Response Rates of RCC Patients Treated With CCI-779
`
`CCI-779 Dose Level
`
`Total
`(n ⫽ 111)
`
`25 mg
`(n ⫽ 36)
`
`75 mg
`(n ⫽ 38)
`
`250 mg
`(n ⫽ 37)
`
`No.
`
`1
`7
`8
`
`%
`
`0.9
`6.3
`7.2
`
`No.
`
`0
`2
`2
`
`%
`
`0
`5.6
`5.6
`
`No.
`
`0
`3
`3
`
`%
`
`0
`7.9
`7.9
`
`3.2 to 13.7
`
`29
`23
`19
`56
`
`22
`10
`
`26.1
`20.7
`17.1
`50.5
`40.8 to 60.1
`19.8
`9.0
`
`0.7 to 18.7
`
`5
`8
`12
`19
`
`6
`3
`
`13.9
`22.2
`33.3
`52.8
`35.5 to 69.6
`16.7
`8.3
`
`1.7 to 21.4
`
`13
`6
`5
`21
`
`9
`2
`
`34.2
`15.8
`13.2
`55.3
`38.3 to 71.4
`23.7
`5.3
`
`No.
`
`1
`2
`3
`
`11
`9
`2
`16
`
`7
`5
`
`%
`
`2.7ⴱ
`5.4
`8.1
`
`1.7 to 21.9
`29.7
`24.3
`5.4
`43.2
`27.1 to 60.5
`18.9
`13.5
`
`Response
`
`CR
`PR
`CR/PR
`95% CI
`MR†
`SD ⱖ 8 weeks, ⬍ 24 weeks
`SD ⱖ 24 weeks
`CR/PR/MR/SD ⱖ 24 weeks
`95% CI
`PD
`Unknown
`
`Abbreviations: RCC, renal cell carcinoma; CR, complete response; PR, partial response; MR, minor response; SD, stable disease, PD, progressive disease.
`ⴱConfirmation was after the date of data cutoff.
`†No confirmation was required for MR. Unconfirmed PR was considered MR.
`
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`
`Atkins et al
`
`Fig 1. Time to tumor progression for renal cell carcinoma patients in the
`25-, 75-, and 250-mg CCI-779 dose groups. mos, months.
`
`Fig 2. Survival of renal cell carcinoma patients in the 25-, 75-, and 250-mg
`CCI-779 dose groups. mos, months.
`
`est concentrations in whole blood were observed at the end
`of the 30-minute infusion. Vdss was high and increased with
`increasing dose, which is suggestive of extensive tissue dis-
`tribution that increases with increasing dose. CL was mod-
`erate, increased substantially with increasing dose, and ex-
`hibited modest interpatient variability. Mean t1/2 of CCI-
`779 was approximately 13 hours. Sirolimus appeared
`quickly with CCI-779 infusion and exhibited peak concen-
`trations that were typically 10% to 20% that of parent drug
`Cmax values. Owing, in part, to the longer half-life of siroli-
`mus (mean range, 40 to 57 hours), the AUCratio was approx-
`imately 2.8 to 5.3, indicating higher relative exposure to
`metabolite than to CCI-779 over the course of the treatment
`
`cycle. AUCsum also increased with increasing dose in a less-
`than-proportional manner.
`Prognostic Factor Analysis of RCC Patients
`Treated With CCI-779
`Because of the suggestion of biologic activity mani-
`fested by the observed CR, PRs, MRs, and the 15-month
`median survival, an additional analysis on the basis of pre-
`viously 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 ⫻ upper
`
`Table 4. Percentage of Patients With CCI-779-Related Adverse Events, ⱖ 20% Overall Frequency, All Grades, All Cycles
`
`Adverse Event
`
`Maculopapular rash
`Mucositis
`Asthenia
`Nausea
`Acne
`Anorexia
`Pruritis
`Diarrhea
`Vomiting
`Anemia
`Hypertriglyceridemia
`Thrombocytopenia
`Nail disorder
`Taste perversion
`Hyperglycemia
`
`Total
`(n ⫽ 110), %
`
`25 mg
`(n ⫽ 36), %
`
`75 mg
`(n ⫽ 38), %
`
`250 mg
`(n ⫽ 36), %
`
`CCI-779 Dose Level
`
`76
`70
`50
`43
`35
`34
`33
`32
`29
`29
`28
`25
`25
`24
`20
`
`72
`64
`53
`36
`28
`33
`25
`33
`39
`28
`28
`19
`25
`25
`19
`
`68
`74
`47
`37
`37
`29
`26
`21
`18
`26
`21
`24
`24
`21
`21
`
`86
`72
`50
`56
`39
`39
`47
`42
`31
`33
`36
`31
`25
`25
`19
`
`914
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`
`CCI-779, mTOR Inhibitor, in Advanced RCC
`
`Table 5. Percentage of Patients With Grade 3 or 4 CCI-779-Related Adverse Events, ⱖ 5% Overall Frequency, All Cycles
`
`Adverse Event
`
`Hyperglycemia
`Hypophosphatemia
`Anemia
`Hypertriglyceridemia
`
`CCI-779 Dose Level
`
`Total
`(n ⫽ 110), %
`
`25 mg
`(n ⫽ 36), %
`
`75 mg
`(n ⫽ 38), %
`
`250 mg
`(n ⫽ 36), %
`
`17
`13
`9
`6
`
`14
`14
`17
`6
`
`18
`18
`5
`0
`
`19
`6
`6
`14
`
`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 prog-
`nostic 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 prognos-
`tic 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 classi-
`fied into good-, intermediate-, and poor-risk groups in a
`fashion similar to that used by Motzer et al (Table 7).
`Survival of the patients in these risk groups was evalu-
`ated on the basis of dose levels (Table 8). Patients in the
`good- and intermediate-risk groups had about two- to
`three-fold longer median survivals than those in the poor-
`risk group. Within the individual risk groups, the median
`survivals of patients in each dose group were similar.
`
`DISCUSSION
`
`Patients with RCC who have not responded to IL-2 and/or
`IFN-␣– based immunotherapy typically have a bleak prog-
`nosis. Studies have shown that their median time to pro-
`gression is 2 months and median survival is less than 10
`months [41]. Various treatment approaches have been in-
`vestigated in this patient population, including thalidomide
`[42-44], anti–VEGF antibody [41,45], dendritic cell vac-
`cines [46,47], and nonmyeloablative allogeneic transplan-
`tation [48]. Although some of these approaches have pro-
`duced encouraging tumor responses (53% for patients with
`nonmyeloablative allogeneic stem-cell
`transplantation
`[48]) or apparent delays in TTP (median TTP of 4.8 and 2.5
`months for patients treated with the anti–VEGF antibody
`bevacizumab or placebo, respectively [41]; median TTP of 4
`months for patients treated with thalidomide [44]), this
`activity awaits confirmation by additional investigators.
`Hence, there remains no standard second-line therapy for
`patients whose disease does not respond to, or progresses
`after, IL-2 and/or IFN-␣– based therapy. Given that the
`durable responses observed with IL-2 treatment occur in at
`
`Table 6. Pharmacokinetic Parameters of CCI-779 and Sirolimus Metabolite
`
`CCI-779
`
`ⴱ
`
`Cmax
`(ng/mL)
`
`ⴱ
`
`tmax
`(h)
`
`t1/2
`(h)
`
`AUC
`(ng · h/mL)
`
`595
`102
`
`876
`316
`
`2,830
`871
`
`0.51
`0.01
`
`0.50
`0.01
`
`0.50
`0.01
`
`12.8
`1.09
`
`13.5
`1.53
`
`12.5
`2.46
`
`1,580
`270
`
`1,860
`374
`
`2,700
`719
`
`Dose Level
`
`25 mg, n ⱕ 4
`Mean
`SD
`75 mg, n ⱕ 6
`Mean
`SD
`250 mg, n ⫽ 6
`Mean
`SD
`
`CL
`(L/h)
`
`16.1
`2.5
`
`41.6
`8.0
`
`98.0
`25.5
`
`Vdss
`(L)
`
`Cmax
`(ng/mL)
`
`232
`36
`
`565
`181
`
`897
`316
`
`65.9
`35.0
`
`157
`40.7
`
`266
`93.3
`
`tmax
`(h)
`
`1.02
`0.03
`
`1.79
`2.01
`
`1.77
`2.16
`
`Sirolimus
`t1/2
`(h)
`
`AUC
`(ng · h/mL)
`
`3,810
`2,220
`
`11,000
`3,580
`
`13,300
`3,690
`
`48.8
`7.9
`
`57.1
`15.7
`
`40.4
`4.7
`
`AUCratio†
`(Sir:CCI)
`
`AUCsum†
`(ng · h/mL)
`
`2.84
`1.75
`
`5.34
`1.29
`
`5.24
`2.18
`
`5,860
`2,340
`
`11,600
`1,860
`
`16,000
`3,590
`
`NOTE. Data reported to three significant figures as appropriate.
`Abbreviations: Cmax, peak observed concentration; tmax, time to Cmax; t1/2, terminal half-life; AUC, area under the concentration versus time curve; CL, total
`body clearance; Vdss, steady-state volume of distribution; AUCratio, uncorrected ratio of sirolimus to CCI-779 AUCs; AUCsum, algebraic sum of CCI-779 and
`sirolimus AUCs; SD, standard deviation.
`ⴱObserved following week 1 of treatment.
`†AUCs of CCI-779 and sirolimus were not corrected for minor differences in molecular weight.
`
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`Ex. 1092-0007
`
`

`
`Atkins et al
`
`Table 7. Classification of RCC Patients Treated With CCI-779 Into Risk Groups for Survival
`
`Total (n ⫽ 111)
`
`CCI-779 Dose Level
`25 mg (n ⫽ 36)
`75 mg (n ⫽ 38)
`
`No.
`
`8
`48
`49
`6
`
`%
`
`7
`43
`44
`5
`
`No.
`
`2
`14
`20
`0
`
`%
`
`6
`39
`56
`0
`
`No.
`
`2
`14
`19
`3
`
`%
`
`5
`37
`50
`8
`
`250 mg (n ⫽ 37)
`
`No.
`
`4
`20
`10
`3
`
`%
`
`11
`54
`27
`8
`
`Risk Group
`
`Good
`Intermediate
`Poor
`Unknownⴱ
`
`Abbreviation: RCC, renal cell carcinoma.
`ⴱPatients had data missing for one or more of the prognostic factors and could not be assigned to a risk group.
`
`most 10% of patients, establishing an effective second-line
`therapy for patients with metastatic RCC remains a priority.
`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 ⱖ 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 ther-
`apy 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 studie