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`
`CCI-779 in Metastatic Melanoma
`A Phase II Trial of the California Cancer Consortium
`
`Kim Margolin, M.D.1
`Jeffrey Longmate, Ph.D.2
`Tracey Baratta2
`Tim Synold, Pharm.D.1
`Scott Christensen, M.D.3
`Jeffrey Weber, M.D., Ph.D.4
`Thomas Gajewski, M.D., Ph.D.5
`Ian Quirt, M.D.6
`James H. Doroshow, M.D.1
`
`1 Division of Medical Oncology, City of Hope Com-
`prehensive Cancer Center, Duarte, California.
`
`2 Department of Biostatistics, City of Hope Com-
`prehensive Cancer Center, Duarte, California.
`
`3 University of California Davis Cancer Center, Sac-
`ramento, California.
`
`4 University of Southern California, Norris Compre-
`hensive Cancer Center, Los Angeles, California.
`
`5 University of Chicago, Chicago, Illinois.
`
`6 Ontario Cancer Institute Princess Margaret Hos-
`pital, Toronto, Canada.
`
`Supported by National Cancer Institute Grant N01
`CM-07003-74 (Early Therapeutic Development
`with Phase II Emphasis).
`
`Address for reprints: Kim Margolin, M.D., Divi-
`sion of Medical Oncology, City of Hope Compre-
`hensive Cancer Center, 1500 E. Duarte Rd.,
`Duarte, CA 91010; Fax: (626) 301-8233; E-mail:
`kmargolin@coh.org
`
`Received June 15, 2004; revision received April 7,
`2005; accepted April 7, 2005.
`
`BACKGROUND. CCI-779 is an analog of the immunosuppressive agent, rapamycin,
`that has demonstrated activity against melanoma in preclinical models and shown
`clinical benefit in patients with breast and renal carcinoma. CCI-779 is not immu-
`nosuppressive when administered on an intermittent schedule, and its toxicity is
`modest, consisting of nausea, diarrhea, hypertriglyceridemia, thrombocytopenia,
`asthenia, and follicular dermatitis.
`METHODS. The current trial was designed to detect a median time to disease
`progression of ⬎18 weeks in patients with metastatic melanoma treated with a
`250-mg weekly dose of CCI-779 administered intravenously after diphenhydra-
`mine premedication. Patients with measurable disease, no more than one previous
`chemotherapy regimen for metastatic disease, and normal organ function were
`eligible, and patients with central nervous system involvement, P450-inducing or
`P450-suppressing drugs, or hypertriglyceridemia were excluded.
`RESULTS. Thirty-three patients (21 males) were treated, 21 of whom had been
`treated previously with chemotherapy and/or biologic agents for advanced-stage
`disease. One patient had a partial response lasting 2 months. The median time to
`disease progression and overall survival were 10 weeks and 5 months, respectively.
`Toxicity was mild and predominantly mucocutaneous (stomatitis, diarrhea, and
`rash). Hyperlipidemia was cumulative and was managed with lipid-lowering
`agents.
`CONCLUSIONS. CCI-779 was not sufficiently active in melanoma to warrant further
`testing as a single agent. Cancer 2005;104:1045– 8.
`© 2005 American Cancer Society.
`
`KEYWORDS: CCI-779, rapamycin analog, metastatic melanoma.
`
`CCI-779 mTOR kinase inhibitor is an ester derivative of sirolimus
`
`(rapamycin), which was formulated for intravenous use. Drugs of
`this class inhibit cell cycle progression by binding to FK506-binding
`protein-12 (FKBP12) to form a complex that interacts with the “mam-
`malian target of rapamycin” (mTOR), resulting in inhibition of signal
`transduction pathways required for progression through the cell cy-
`cle.1 Perturbation of these pathways, downstream of protein kinase B
`(PKB/AKT)/phosphoinositol-3-kinase (PI3K) activities, results from
`upstream mutations, that are mutated in human cancers, most com-
`monly loss of the PTEN (phosphatase and tensin homolog deleted on
`chromosome 10) tumor suppressor, which leads to overexpression of
`AKT or PI3K resulting in mTOR overexpression. PTEN mutations are
`found in approximately one-half of melanomas.2 The resulting in-
`crease in the activity of mTOR is believed to “uncouple” it from the
`normal control exerted on its activity by the availability of nutrients
`required for cell proliferation.3
`The CCI-779 –FKBP12 complex inhibits the mTOR kinase activity
`
`© 2005 American Cancer Society
`DOI 10.1002/cncr.21265
`Published online 8 July 2005 in Wiley InterScience (www.interscience.wiley.com).
`
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`of ribosomal subunits responsible for the translation
`of selected mRNAs into proteins required for progres-
`sion from the G1 to the S phase of the cell cycle.
`Although the prototype agent, rapamycin, is used as
`an immunosuppressive due to its inhibition of inter-
`leukin-2 (IL-2)–induced signaling activities in T lym-
`phocytes, related agents such as CCI-779 that inhibit
`malignant cell cycling by this mechanism are not im-
`munosuppressive at doses and schedules associated
`with antitumor activity.4 The preclinical investigation
`of CCI-779 demonstrated that prostate, breast, leuke-
`mia, and melanoma cell lines could be inhibited by
`CCI-779, and animal models confirmed its activity in
`human lymphoma, glioblastoma, melanoma, colon,
`breast, pancreatic, and prostate carcinoma.4 – 6 The in-
`termittent dosing schedule was associated with anti-
`tumor activity but only transient immunosuppression.
`In Phase I clinical trials, the dose-limiting toxici-
`ties included myelosuppression, diarrhea, stomatitis,
`fever, fatigue, and hyperlipidemia. Skin reactions were
`common, ranging from dry desquamation to eczema-
`toid, urticarial, and acneiform rash. Acute infusion
`reactions resembled histamine-release phenomena
`and have been avoided by premedication with anti-
`histamines7,8 (and unpublished data). Based on these
`safety data as well as pharmacokinetic and pharma-
`codynamic results, a fixed dose of 250 mg was pro-
`posed for evaluation on a weekly dosing schedule in
`patients with advanced melanoma. Because the
`mechanism of action may be associated with cyto-
`static rather than cytotoxic effects on tumor cells, the
`primary objective of this Phase II trial was to detect a
`median progression-free interval of ⱖ 18 weeks
`among patients with advanced melanoma who had
`received at most 1 previous therapy regimen for met-
`astatic disease.
`
`MATERIALS AND METHODS
`Patient Eligibility Criteria
`The protocol was conducted by the California Cancer
`Consortium (City of Hope Comprehensive Cancer
`Center, University of Southern California-Kenneth
`Norris Cancer Center, and University of California at
`Davis Cancer Center), the Princess Margaret Hospital,
`and the University of Chicago, and approved by the
`institutional review board at each participating insti-
`tution. Written, voluntary informed consent was ob-
`tained from all patients before initiating any protocol
`procedures. Patient eligibility criteria included the fol-
`lowing: measurable metastatic or locally advanced
`melanoma, age ⱖ 18 years,
`life expectancy ⱖ 4
`months, Eastern Cooperative Oncology Group (ECOG)
`performance status ⱕ 2, leukocyte count ⱖ 3000/␮L,
`absolute neutrophil count ⱖ 1500/␮L, platelet count
`
`ⱖ 100,000/␮L, serum bilirubin and creatinine levels
`within institutional normal limits (or creatinine clear-
`ance ⱖ 60 mL/min), and transaminase level ⬍ 2.5
`times the upper limit of institutional normal. Serum
`cholesterol level was required to be ⬍ 350 m/dL and
`triglyceride level was required to be ⬍ 300 mg/dL,
`which could be achieved with lipid-lowering agents.
`Patients were permitted to have received up to one
`chemotherapy-containing regimen given adjuvantly
`and up to one chemotherapy-containing regimen for
`advanced-stage disease (no previous chemotherapy
`for advanced-stage disease if disease recurrence oc-
`curred within 6 months of adjuvant chemotherapy).
`Patients with any history of central nervous system
`metastasis were excluded, as were patients with hu-
`man immunodeficiency virus infection or ongoing ste-
`roid therapy, patients requiring full anticoagulation
`for previous thromboembolic disease, or patients re-
`quiring any of the excluded concomitant therapies,
`which consisted of a number of agents known to sig-
`nificantly induce or suppress cytochrome P450-3A.
`
`Therapy and Monitoring
`CCI-779 was administered as a fixed weekly intrave-
`nous dose of 250 mg. All patients were premedicated
`with diphenhydramine 25 or 50 mg intravenously, and
`the CCI-779 was then infused over 30 minutes. For any
`patient experiencing an acute hypersensitivity reac-
`tion (urticaria, bronchospasm or dyspnea, hypoten-
`sion), the infusion was stopped, additional H1 and H2
`antihistamines were administered, and infusion was
`resumed at a slower rate after resolution of the reac-
`tion. Patients were generally also premedicated with
`standard antiemetics including modest doses of dexa-
`methasone and 5HT-3 blockers.
`Patients were monitored for toxicity with a weekly
`complete blood count and comprehensive metabolic
`panel and fasting lipid panel. The National Cancer
`Institute-Common Toxicity Criteria version 2.0 was
`used for toxicity grading. For patients whose serum
`triglyceride level was ⬎ 500 mg/dL,
`lipid-lowering
`therapy was instituted and CCI-779 was withheld until
`the level was ⬍ 500 mg/dL. Dose delays and adjust-
`ments for other noninfusion-related toxicities pro-
`vided for approximately 30% dose decrements after
`recovery of toxicity or a ⱕ 2-weeks delay to allow
`resolution of toxicity.
`Tumor assessments were performed every 8
`weeks, using the same modality that had been used for
`initial measurements. For patients experiencing a
`complete or partial response, a confirmatory assess-
`ment was to be done 4 weeks after the first response-
`defining assessment.
`
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`Statistical Analysis
`The primary end point of the study was the percentage
`of patients surviving progression free at 18 weeks.
`Objective response and survival were the secondary
`end points. The assumptions regarding disease pro-
`gression-free survival (PFS) were based on unpub-
`lished data from the Southwest Oncology Group da-
`tabase (J. Moon, personal communication), in which
`the median overall survival period is 7–9 months and
`the median time to disease progression is approxi-
`mately 3 months for patients with advanced-stage
`melanoma enrolled in clinical trials. Thus, for the pur-
`pose of the current study, a meaningful PFS of 4.5
`months, a 50% increase over the natural history of this
`disease, was selected.
`The 1-stage design provided a maximum of 45
`patients and an interim analysis after 22 patients were
`assessable for the primary end point, allowing contin-
`ued accrual during the interval required to assess all
`22 patients. Among the first 22 patients, if ⱖ 16 pa-
`tients developed progressive disease before 18 weeks,
`the probability that the median PFS would be ⬎ 18
`weeks was ⬍ 30%. Because accrual was allowed to
`continue during the required follow-up time for the
`first 22 patients, the final accrual to this protocol was
`33 patients.
`
`RESULTS
`Thirty-three eligible and evaluable patients were en-
`rolled between June 2001 and September 2003. The
`demographic and disease-related data are provided in
`Table 1. Twenty-one patients were male, the median
`age of the patients was 59 years (range, 27– 83 years),
`most patients had an ECOG performance score of 0 or
`1, and 21 patients had received previous chemother-
`apy for advanced-stage disease. Twelve patients had
`sites of metastatic disease that included the liver. The
`median PFS was 10 weeks (range, 3–36 weeks) and the
`median overall survival was 5 months. The median
`time on protocol therapy was 10 weeks (range, 4 –36
`weeks). One patient experienced a partial response
`lasting 2 months. All of the other patients experienced
`disease progression during protocol therapy.
`The toxic side effects of therapy were mild to
`moderate and are listed in Table 2. Treatment-related
`fatigue that abated with discontinuation of therapy
`was common, but never severe. Mucocutaneous tox-
`icity was common, but rarely required a dose adjust-
`ment. The other toxicities requiring treatment dose
`adjustment or delay generally consisted of mucocuta-
`neous symptoms (stomatitis, diarrhea, follicular der-
`matitis) and/or myelosuppression. No patient died of
`treatment toxicity, and there were no episodes of neu-
`tropenic infection.
`
`CCI-779 in Metastatic Melanoma/Margolin et al.
`
`1047
`
`TABLE 1
`Patient Characteristics
`
`Characteristics
`
`Median age (range) (yrs)
`Gender
`Male
`Female
`ECOG performance status
`0
`1
`2
`M classification
`1a
`1b
`1c
`Lactate dehydrogenase level
`Normal
`Elevated
`Previous systemic therapy
`IFN-␣, interleukin-2, or both
`Combination chemotherapy, biotherapy, or both
`Single-agent chemotherapy
`Levamisole
`Tamoxifen
`
`No. of patients
`
`59 (27–83)
`
`21
`12
`
`17
`10
`2
`
`1
`8
`24
`
`20
`13
`
`14
`8
`3
`1
`1
`
`yrs: years; ECOG: Eastern Cooperative Oncology Group; IFN-␣: interferon-alpha.
`
`TABLE 2
`Toxicities of Protocol Therapy
`
`System
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Mucocutaneous
`Rash
`Stomatitis
`Diarrhea
`Hematologic
`Neutropenia
`Thrombocytopenia
`Endocrine/metabolic
`Hypertriglyceridemia
`Hypercholesterolemia
`
`19
`26
`6
`
`5
`21
`
`21
`15
`
`1
`
`2
`
`5
`3
`
`2
`3
`
`4
`10
`
`DISCUSSION
`The results of our clinical trial demonstrated that CCI-
`779 given at the dose and schedule supported by
`Phase I and pharmacodynamic studies did not have
`sufficient antitumor activity in melanoma to warrant
`further evaluation as a single agent. Although the pos-
`sibility of therapeutic synergism requires further in-
`vestigation, the spectrum of toxicities associated with
`this agent overlaps with those of several other drugs in
`routine use, which limits the choices of combinations
`that could be safely considered. Currently, very little
`data exist regarding the clinical or even preclinical
`experience of CCI-779 in combinations. A preliminary
`report in 2003 details the results of a Phase I dose-
`
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`escalation study that combined CCI-779 with interfer-
`on-alpha (IFN-␣) at a low dose, which could be esca-
`lated in the individual patient if no dose-limiting
`toxicity of CCI-779 occurred. In that study,9 even very
`low doses of CCI-779 (the highest dose reported was
`25 mg weekly) in combination with IFN-␣ (starting at
`6 million U subcutaneously 3 times per week) resulted
`in a high frequency of mucositis, nausea, fatigue, and
`hyperlipidemia. Two of the first 20 patients were re-
`ported to have experienced a partial response. The
`authors concluded that the combination was well tol-
`erated and potentially active, with mechanisms of ac-
`tion that included both direct antitumor activity and
`antiangiogenic effects.9 The study design of our trial
`did not allow us to distinguish between the possibility
`that the dose and selected schedule did not provide
`adequate inhibition of mTOR pathways, or to deter-
`mine whether there were other mechanisms in the
`biology of melanoma that allowed this pathway to be
`bypassed as a mechanism of resistance. There remains
`some uncertainty about the optimal dose of this drug
`to be administered on a weekly schedule, which would
`be of importance in designing studies for diseases that
`may be more sensitive to the inhibition of this path-
`way.
`As a single agent in the treatment of patients with
`other diseases, CCI-779 has been more promising and
`is currently undergoing evaluation in Phase III trials.
`In a Phase II trial comprising 109 patients with ad-
`vanced-stage breast carcinoma, approximately one-
`half of the patients previously exposed to anthracy-
`cline and/or taxane experienced an objective response
`or stable disease lasting ⱖ 8 weeks when treated with
`CCI-779 at a dose of 75 or 250 mg weekly.10 In a similar
`study testing 3 different dose levels of CCI-779 (25, 75,
`or 250 mg weekly), a comparable level of activity was
`observed among 110 patients with advanced-stage re-
`nal carcinoma,11 an encouraging result that undoubt-
`edly will be applied to the design of future Phase III
`trials to compare or combine other promising new
`agents with CCI-779 in patients with advanced-stage
`renal carcinoma.Elucidation of the therapeutic mech-
`anisms of antitumor activity for CCI-779 and other
`mTOR inhibitors has led to an increased understand-
`
`ing of the mechanisms of resistance, which include
`mutations in mTOR, FKBP12, or any of the many
`others associated with mTOR-related pathways.12 The
`optimal use of this class of agents in malignancy will
`await the design of regimens that take into account
`the need for nonoverlapping clinical toxicities and
`complementary antitumor mechanisms that minimize
`the emergence of resistant clones.
`
`3.
`
`5.
`
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