V O L U M E 2 2 䡠 N U M B E R 1 2 䡠 J U N E 1 5 2 0 0 4
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Safety and Pharmacokinetics of Escalated Doses of
`Weekly Intravenous Infusion of CCI-779, a Novel
`mTOR Inhibitor, in Patients With Cancer
`Eric Raymond, Jérôme Alexandre, Sandrine Faivre, Karina Vera, Eric Materman, Joseph Boni,
`Cathie Leister, Joan Korth-Bradley, Axel Hanauske, and Jean-Pierre Armand
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of
`the mammalian target of rapamycin, in patients with advanced cancer.
`
`Patients and Methods
`Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic
`study of CCI-779 given as a weekly 30 minutes intravenous (IV) infusion.
`
`Results
`Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m2. No immunosuppressive
`effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m2. At 220
`mg/m2, dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two
`of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were
`acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment
`discontinuation. Maximum concentration and area under the concentration-time curve increase sub-
`proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus
`was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was
`nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m2). Variability predicted with flat doses appears
`comparable with data based on body-surface area–normalized treatment. Partial responses were
`observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma.
`
`Conclusion
`CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at
`doses up to 220 mg/m2, the highest dose tested. Based on our results, weekly doses of 25, 75, and 250
`mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II
`trials in patients with breast and renal cancer.
`
`J Clin Oncol 22:2336-2347. © 2004 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`rapamycin
`The mammalian target of
`(mTOR), a member of the phosphatidyl
`inositol 3' kinase family, is a multifunctional
`serine-threonine kinase that acts as central
`regulator of cell growth, proliferation, and
`apoptosis.1-4 mTOR is activated in response
`to growth stimuli such as nutrients and/or
`growth factors including insulin,
`insulin
`growth factor, platelet-derived growth fac-
`tor, and the stem-cell factor.1,2,5 Stimulation
`of mTOR results in a series of events involv-
`
`ing phosphorylation of translational regula-
`tion factors such as eukaryotic initiation fac-
`tor 4E-binding protein and p70s6 kinase.6,7
`Rapamycin (sirolimus), an immuno-
`suppressant macrolide produced by Strepto-
`myces hygroscopicus, binds FKBP-12 (FK506
`binding protein), creating a molecular com-
`plex that specifically inhibits mTOR func-
`tions.8 Inhibition of mTOR by rapamycin
`leads to downregulation of G1 cyclin/cdk
`complexes and p27 accumulation that
`blocks progression in late G1/S phase of cell
`cycle.9,10 In addition to immunosuppres-
`
`From the Department of Medicine,
`Gustave Roussy Institute, Villejuif,
`France; Onkologische Tagesklinik, Mu-
`nich, Germany; and Wyeth, Collegeville,
`PA.
`
`Submitted August 15, 2003; accepted
`March 31, 2004.
`
`Supported by Wyeth Research, Colle-
`geville, PA.
`
`Eric Raymond and Jérôme Alexandre
`contributed equally to this work and
`shall be considered as joint first
`authors.
`
`Authors’ disclosures of potential con-
`flicts of interest are found at the end of
`this article.
`
`Address reprint requests to Eric
`Raymond, MD, PhD, Department of
`Medical Oncology, Saint-Louis Hospital,
`1 Avenue Claude Vellefaux, 75475
`Paris Cedex 10, France; e-mail:
`eric.raymond@sls.ap-hop-paris.fr.
`
`© 2004 by American Society of Clinical
`Oncology
`
`0732-183X/04/2212-2336/$20.00
`
`DOI: 10.1200/JCO.2004.08.116
`
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`

`

`Phase I of CCI-779 Weekly IV Infusion
`
`sion, sirolimus is thought to retard proliferation of endo-
`thelial and vascular smooth muscle cells required for tumor
`angiogenesis.11 Recently, studies showed that sirolimus also
`inhibited the oncogenic transformation of human cells in-
`duced by either PI3K or AKT in mice with loss of the normal
`PTEN allele (PTEN⫾).12-14 Sirolimus can also induce apo-
`ptosis and sensitize cancer cells to apoptosis induction by
`DNA-damaging agents such as cisplatin.15 In humans,
`sirolimus was usually well tolerated at daily doses ranging
`0.5 to 60 mg/d; hypercholesterolemia, hypertriglyceride-
`mia, lymphopenia, thrombocytopenia, mucositis, arthral-
`gia, and infection are the main toxicities.16
`CCI-779 (Fig 1), a water-soluble ester of sirolimus,9-17
`was identified by the Developmental Therapeutic Branch of
`the National Cancer Institute as a noncytotoxic agent that
`delayed tumor proliferation.18 At several nontoxic doses,
`CCI-779 demonstrated antitumor activity in a variety of
`human cancer models, such as gliomas; rhabdomyosar-
`coma; primitive neuroectodermal tumor, such as medullo-
`blastoma; and prostate and breast cancer.19-23 Treatment
`of mice with CCI-779 normalizes p70s6 kinase activity
`and reduces neoplastic proliferation. As with sirolimus,
`PTEN-deficient human tumors are more sensitive to CCI-
`779-mediated growth inhibition than PTEN-expressing
`cells.12,14,24 Interestingly, preclinical studies indicate that
`intermittent administration of CCI-779 reduces its immu-
`nosuppressive properties while retaining its antitumor ac-
`tivity (CCI-779 investigator brochure).
`Based on the promising antitumor activity and safety
`data showing limited immunosuppression with intermit-
`tent exposure to CCI-779 in animals, this phase I dose-
`escalation study was undertaken to determine the safety,
`basic pharmacokinetic characteristics, and preliminary an-
`titumor effects of weekly intravenous (IV) infusion of CCI-
`779 in patients with advanced malignancies.
`
`PATIENTS AND METHODS
`
`Patient Selection
`Patients entered onto this study met the following criteria:
`histologically confirmed diagnosis of solid tumor refractory to
`standard therapy or for whom no standard therapy existed; age ⱖ
`18 years; life expectancy ⱖ 3 months; Eastern Cooperative Oncol-
`ogy Group (ECOG) performance status ⱕ 2; no chemotherapy,
`hormonal therapy, immunotherapy or radiotherapy within 4
`weeks before treatment with CCI-779 (6 weeks for previous treat-
`ment with nitrosoureas, mitomycin, or extensive radiotherapy)
`and no immunosuppressive agents within 3 weeks before study
`entry (except corticosteroids used as antiemetics); adequate he-
`patic function defined as serum bilirubin less than 25 ␮mol/L
`(⬍ 1.5 mg/dL), transaminases ⱕ 3.0 times the upper limit of
`normal (or ⱕ 5 in the case of liver metastases); adequate bone
`marrow function defined as absolute neutrophil count ⬎ 1,500/
`␮L, platelets ⬎ 100,000/␮L, and hemoglobin ⬎ 8.0 g/dL; adequate
`renal function with serum creatinine less than 2.0 mg/dL) and/or
`creatinine clearance (Cockroft formula) ⱖ 60 mL/min; baseline
`cholesterol ⬍ 350 mg/dL, triglycerides ⬍ 300 mg/dL, no history
`of alcoholism, drug addiction, or psychotic disorders; no med-
`ical condition which, in the opinion of the investigator, was
`incompatible with the protocol; no uncontrolled systemic in-
`fection; and signed informed consent according to institutional
`and national guidelines.
`Patients were excluded if they were pregnant or breast feed-
`ing, had symptomatic brain metastases or leptomeningeal tumor
`involvement, active infection or serious intercurrent illness,
`known hypersensitivity to macrolide antibiotics, or were receiving
`any of the following: concomitant antitumor therapy, anticonvul-
`sant therapy, or cardiac antiarrhythmic drugs. Patients were not
`required to have evaluable or measurable disease.
`Based on known toxicities of rapamycin, patients entered
`onto this trial were also required to have baseline serum choles-
`terol ⬍ 350 mg/dL, triglycerides ⬍ 300 mg/dL, no immunosup-
`pressive agents within 3 weeks before study entry (except cortico-
`steroids used as antiemetics), and no known concomitant genetic
`or acquired immunosuppressive diseases (such as AIDS).
`
`Fig 1. Chemical formula of sirolimus
`(A) and CCI-779 (B).
`
`www.jco.org
`
`2337
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`
`

`

`Raymond et al
`
`Pretreatment and Follow-Up Examinations
`Complete medical history, physical examination, ECOG per-
`formance status, and biochemical profile including cholesterol,
`triglycerides, full blood count and urinalysis were performed at
`baseline and repeated weekly (twice weekly for blood count). A
`12-lead electrocardiogram and a chest x-ray were obtained within
`14 days before administration of CCI-779 and repeated every 4
`weeks. Toxicity was evaluated by weekly clinical and laboratory
`examination and graded using the National Cancer Institute
`Common Toxicity Criteria, version 2.0.19 Additional laboratory
`tests and/or an increase in the frequency of observations were
`permitted to document acute drug-related toxicity until recovery.
`Total serum testosterone, follicle stimulating hormone, and
`luteinizing hormone were determined in males at baseline and
`every 4 weeks. A serum pregnancy test was performed in females of
`childbearing potential. Lymphocyte subsets CD45, CD14, CD3,
`CD4, CD8, and CD56 and mitogen proliferation assays were done
`in the prestudy period, before the first three infusions, and then
`every 2 months.Tumors were measured by computed tomography
`scans 4 weeks before starting CCI-779 and then every 8 weeks.
`
`Drug Administration
`CCI-779 (Wyeth Pharmaceuticals, Collegeville, PA) was sup-
`plied in concentrated form in sterile, 1mL or 5mL glass ampules
`(containing 25 mg CCI-779/mL 100% ethanol). Before each CCI-
`779 administration, the patient’s body-surface area (BSA) was
`recalculated from height and weight. Study drug was administered
`once weekly as a 30-minute IV infusion after pretreatment with IV
`antihistamine with close monitoring during and for at least 2
`hours after the end of CCI-779 infusion.
`
`Dose-Escalation Procedure
`Based on animal toxicology data and prior clinical experience
`with sirolimus, the starting dose was 7.5 mg/m2. This study was
`designed with no prefixed dose levels. A modified continual reas-
`sessment method was used to generate a new estimate of the
`maximum-tolerated dose (MTD) using a Bayesian approach after
`each patient had completed three infusions.25,26 The MTD was
`defined as the dose level at which ⱖ 33% of the patients would
`experience dose-limiting toxicity (DLT). DLT was defined as ⱖ
`grade 3 nonhematological toxicity (excluding alopecia, untreated
`nausea and vomiting, and/or serum triglycerides if ⬍ 1,500 mg/dL
`and recovered within 1 week), grade 4 thrombocytopenia, grade 4
`neutropenia lasting ⬎ 5 days, grade 4 febrile neutropenia requir-
`ing hospitalization, or treatment delay of ⬎ 2 weeks as a result of
`unresolved toxicity.
`Additional rules were applied to determine the proportion by
`which the dose was escalated or reduced. If grade ⱕ 1 toxicity
`occurred, then the dose could be escalated by ⱕ 100% (maximum
`of two times the previous dose); if grade 2 toxicity occurred, then
`the dose could be escalated by ⱕ 50%; if grade 3 thrombocytope-
`nia or grade 3 to 4 nonfebrile neutropenia lasting ⱕ 5 days oc-
`curred (no hospitalization and no treatment delay ⬎ 2 weeks),
`then the dose could be escalated by up to 33%. If DLT occurred,
`then the dose was decreased by up to 33%.
`Infusions could be delayed for less than 2 weeks for the
`patient to recover from toxicities. No intrapatient dose escalation
`was allowed. Dose reduction of 0% to 33% was allowed in re-
`sponse to unacceptable toxicity if the patient exhibited evidence of
`clinical benefit from CCI-779. If unacceptable toxicity occurred
`after this dose reduction, the patient was no longer allowed to take
`
`CCI-779 at any dose level. These reduced doses were not included
`in the MTD calculations.
`
`Bioanalytic Method
`Blood samples (3 mL each) for determination of CCI-779
`and sirolimus in sodium EDTA-anticoagulated whole blood were
`collected before treatment and at 0.25, 0.5 (end of infusion), 1, 2, 4,
`6, 24, 48, 72, 96, and 168 hours (before the next weekly treatment)
`following the start of infusion during the first and fourth doses. In
`addition, 10 mL of blood for plasma was obtained at 0.5 (end of
`infusion), 72 and 168 hours during the first dose, and if possible,
`during the fourth dose of CCI-779.
`CCI-779 and sirolimus concentrations in whole blood were
`validated from 0.25 to 100 ng/mL (CCI-779) and from 0.1 to 100
`ng/mL (sirolimus) using separate, slightly differing methods (Tay-
`lor Technology Inc, Princeton, NJ). Briefly, to 0.1 mL of methanol
`was added an aliquot of d7-CCI-779 or 32-desmethoxyrapamycin
`internal standard. The spiked mixtures were added to 1 mL of
`whole blood treated with sodium EDTA. Analytes were extracted
`into 1-chlorobutane, evaporated, reconstituted with a 70:30 meth-
`anol:water solution, and chromatographed using either a C18
`column (for CCI-779) or C4 column (for sirolimus) with a gradi-
`ent of methanol and water containing ammonium acetate and
`acetic acid as the mobile phase solvents. The analytes were detected
`and quantified by tandem mass spectrometry using atmospheric
`pressure chemical ionization.
`CCI-779 concentrations in plasma were validated from 0.25
`to 100 ng/mL. To 0.1 mL of methanol was added an aliquot of
`d7-CCI-779 internal standard. The spiked mixture was then added
`to 1 mL of plasma. Analytes were extracted into tert-butyl methyl
`ether and analyzed as described previously. These methods exhibit
`adequate inter- and intrasubject variability (ⱕ 12.7%) and bias
`(ⱕ 15%). CCI-779 and sirolimus concentrations in whole blood
`were stable following several freeze-thaw cycles, brief incubations
`at room temperature, and long-term storage at ⫺80°C.
`Pharmacokinetic Analyses
`The concentration-versus-time data for CCI-779 and siroli-
`mus in whole blood were analyzed using a noncompartmental
`analysis technique.27 Pharmacokinetic analysis is based on con-
`centrations measured in whole blood due to the limited stability of
`CCI-779 and sirolimus in plasma. Calculated were peak concen-
`tration (Cmax), half-life (t1/2), area under the concentration-time
`curve (AUCt), clearance (Cl), and steady-state volume of distribu-
`tion (Vdss). An accumulation ratio (AR) was determined by taking
`the ratio of AUCt on week 4 to AUCt on week 1. In addition, the
`ratio of sirolimus to CCI-779 AUC (AUCSIR/AUCCCI) and the
`sum of CCI-779 plus sirolimus AUCs (AUCsum) were calculated
`(unadjusted for modest differences in molecular weight). To pre-
`liminarily assess the proportionality of exposure with dose, an
`exponential regression model was used to describe the relation-
`ship between CCI-779 Cmax, AUC, and AUCsum versus dose.28
`
`RESULTS
`
`General
`A total of 24 patients were enrolled onto the study and
`received at least one cycle (four weekly doses) of CCI-779 at
`doses of 7.5 to 220 mg/m2. A total of 273 infusions were
`administered. Patient characteristics at study entry are sum-
`marized in Table 1. Dose escalation was based on acute
`
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`JOURNAL OF CLINICAL ONCOLOGY
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
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`

`

`Phase I of CCI-779 Weekly IV Infusion
`
`Table 1. Patient Characteristics (N ⫽ 24)
`
`No. of Patients
`
`Sex
`Male
`Female
`Age, years
`Median
`Range
`ECOG performance status
`0
`1
`2
`Primary tumor type
`Renal
`Colorectal
`Soft tissue sarcoma
`Mesothelioma
`NSCLC
`Adrenocortical carcinoma
`Breast
`Head and neck, squamous cell
`Melanoma
`Neuroendocrine carcinoma
`Pancreatic
`Prostate
`Prior therapy
`Chemotherapy alone
`Surgery
`Chemotherapy and radiotherapy
`No. of prior chemotherapy regimens
`1
`2
`3
`ⱖ 4
`
`14
`10
`
`54
`30-63
`
`10
`10
`4
`
`6
`4
`3
`2
`2
`1
`1
`1
`1
`1
`1
`1
`
`24
`19
`12
`
`5
`8
`3
`8
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; NSCLC,
`non–small-cell lung cancer.
`
`toxicity evaluated during the first four infusions of CCI-
`779. As shown on Table 2, no grade 3 to 4 toxicity was
`observed up to the dose of 22.5 mg/m2. At a dose of 34
`mg/m2, one patient developed a grade 3 neutropenia,
`
`thrombocytopenia, and hypophosphatemia. Bone marrow
`aspiration found no megacaryocyte. This patient had previ-
`ously received extensive radiation therapy that could have
`participated to CCI-779 hematologic toxicity. This event
`led us to enter two additional patients at the dose level of 34
`mg/m2 without further evidence of severe toxicity. There-
`fore, the dose escalation was resumed. At a dose of 45
`mg/m2, one patient had grade 3 thrombocytopenia, asthe-
`nia, and diarrhea. Three additional patients were entered at
`this dose level without additional DLT. Dose escalation
`continued without additional DLT up to 220 mg/m2. At the
`220 mg/m2 dose-level, a 51-year-old woman with meta-
`static breast cancer and no history of psychiatric disorders
`developed grade 2 euphoria and insomnia after 2 weeks of
`treatment. At week 4, the patient was hospitalized for grade
`3 depression and received antidepressive treatment with
`paraxetine and cyanemazine (no evidence of brain and
`leptomeningeal metastasis); grade 3 stomatitis; and grade 3
`transaminases elevation. The toxicity was reversible within
`2 weeks of treatment discontinuation. The patient was sub-
`sequently restarted at a dose of 165 mg/m2 without further
`evidence of psychiatric disorder. At the 220 mg/m2 dose
`level, two additional patients without prior neuropsychiat-
`ric disorder developed reversible grade 1 to 2 depression
`preceded by grade 1 to 2 euphoria. Among subsequent
`patients entered at this dose level, one developed DLTs that
`consisted of grade 3 asthenia and grade 3 stomatitis. There-
`fore, although the formal definition of MTD was not met, it
`was decided to stop the dose escalation.
`Safety and Tolerability After Repeated Cycles
`Tables 3 and 4 summarize drug-related toxicities ob-
`served with a total frequency of ⱖ 20% during this study.
`No immunosuppressive effects were detected during treat-
`ment with CCI-779. For example, in eight patients treated
`at the highest tested doses, the median changes (⫾ standard
`deviation [SD]) from the pretreatment value for lympho-
`cytes (all CD45⫹) including CD14⫹, CD3⫹, CD58⫹/
`CD3⫺, CD56⫹/CD3⫹, CD4⫹/CD3⫹, and CD8⫹/CD3⫹
`
`Dose (mg/m2)
`
`No. of Patients
`
`Grade 3-4 Toxicity
`
`Type of Toxicity and Grade
`
`Table 2. Grade 3-4 and Dose-Limiting Toxicities During First Month of Treatment With CCI-779
`
`7.5
`15.0
`22.5
`34.0
`45.0
`
`60.0
`80.0
`110.0
`165.0
`220.0
`
`www.jco.org
`
`1
`2
`1
`3
`4
`
`1
`1
`1
`1
`9
`
`—
`—
`—
`1
`1
`
`—
`—
`—
`—
`2
`
`—
`—
`—
`—
`One patient with grade 3 neutropenia, thrombocytopenia, and hypophosphatemia;
`one patient with grade 3 thrombocytopenia, asthenia, and diarrhea
`—
`—
`—
`—
`One patient with grade 3 manic-depressive syndrome with grade 3 stomatitis, and
`grade 3 ALT elevation; one patient with grade 3 asthenia and stomatitis
`
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`

`Raymond et al
`
`Table 3. Drug-Related Toxicities With Total Frequencies ⱖ 20% After
`Repeated Dosing of CCI-779ⴱ
`
`Intermediate Doses
`(7.5-165.0 mg/m2)
`(n ⫽ 15)
`
`Highest Dose
`(220 mg/m2)
`(n ⫽ 9)
`
`No. of
`Patients %
`
`Dermatologic
`Grade 1-2
`Grade 3-4
`Mucositis
`Grade 1-2
`Grade 3-4
`Asthenia
`Grade 1-2
`Grade 3-4
`Nausea
`Grade 1-2
`Grade 3-4
`Thrombocytopenia
`Grade 1-2
`Grade 3-4
`Anorexia
`Grade 1-2
`Grade 3-4
`Diarrhea
`Grade 1-2
`Grade 3-4
`Vomiting
`Grade 1-2
`Grade 3-4
`Hypercholesterolemia
`Grade 1-2
`Grade 3-4
`Hypertriglyceridemia
`Grade 1-2
`Grade 3-4
`Peripheral edema
`Grade 1-2
`Grade 3-4
`Weight loss
`Grade 1-2
`Grade 3-4
`Taste perversion
`Grade 1-2
`Grade 3-4
`
`12
`1
`
`10
`—
`
`7
`1
`
`5
`—
`
`4
`2
`
`3
`—
`
`3
`1
`
`2
`—
`
`—
`3
`
`2
`2
`
`3
`—
`
`3
`—
`
`3
`—
`
`5
`—
`
`7
`1
`
`2
`1
`
`5
`—
`
`1
`—
`
`2
`—
`
`1
`—
`
`3
`—
`
`—
`2
`
`—
`1
`
`2
`—
`
`2
`—
`
`2
`—
`
`17
`1
`
`17
`1
`
`9
`2
`
`10
`—
`
`5
`2
`
`5
`—
`
`4
`1
`
`5
`—
`
`—
`5
`
`2
`3
`
`5
`—
`
`5
`—
`
`5
`—
`
`71
`4
`
`71
`4
`
`38
`8
`
`42
`—
`
`21
`8
`
`21
`—
`
`17
`4
`
`21
`—
`
`—
`21
`
`8
`13
`
`21
`—
`
`21
`—
`
`21
`—
`
`ⴱNo grade 3 or 4 drug-related adverse event was reported at the doses
`of 22.5, 60, 110, and 165 mg/m2.
`
`were 6.5% (SD, 6.4%), ⫺3.1% (SD, 7.8%), ⫺1.4% (SD,
`6.5%), 0.07% (SD, 0.6%), 0.2% (SD, 5.5%), and ⫺0.2%
`(SD, 1.7%), respectively. Likewise, large interpatient vari-
`ability in mitogene proliferation assay was observed with a
`4.5% (SD, 37%) increase in median values of concanavaline
`A after 1 month of treatment (P ⬎ .5). Thrombocytopenia
`was grade 1 to 2 in five patients and grade 3 to 4 in two
`patients. Asthenia was grade 1 to 2 in nine patients and
`grade 3 in two patients.
`The most frequent drug-related adverse events were
`dermatologic toxicities and mucositis/stomatitis (18 of 24
`patients; Table 3). Stomatitis consisted mainly of 1 to 3
`
`round grade 1 to 2 aphtous lesions in the mouth and
`tongue. Stomatitis was severe (grade 3) in only one of nine
`patients treated at the highest dose and was reversible de-
`spite treatment continuation. Antiseptic mouthwashes
`were inconsistently effective in preventing stomatitis.
`Specific dermatologic toxicities are presented in Table
`4. Skin toxicity consisted of grade 1 to 2 herpes simplex
`lesions (five patients; Fig 2A), acne-like rash (nine patients;
`Fig 2B), maculopapular rash (12 patients; Fig 2C), dry skin
`(nine patients), pruritus (seven patients), and nail disorders
`(11 patients; Fig 2D).
`Herpes lesions were documented using viral cultures
`and both topic and systemic treatments with acyclovir were
`given to patients with herpetic lesions. Maculopapular
`rashes, generally consisting of 5 to 10 cm reactions on face
`and neck, mainly occurred during the first few weeks of
`treatment and were spontaneously reversible. Grade 1 to 2
`acne-like rash on erythematous base occurred on the face
`and the upper part of the trunk. Histopathologic examina-
`tion revealed a nonspecific accumulation of neutrophils in
`dermis and epidermis. This skin reaction was reversible
`with and without topical steroid cream.
`Grade 3 elevations of total cholesterol and triglycerides
`were observed in five and three patients, respectively, across
`the range of doses explored. Three patients had grade 1 to 2
`and one patient had grade 3 ALT elevations. Among 11 males
`who had normal baseline testosterone levels, nine showed
`reduction of these levels with increased follicle-stimulating
`hormone and/or luteinizing hormone levels during CCI-779
`treatment. At doses of 15 and 45 mg/m2, two patients reported
`reduced sexual activity (considered grade 2).
`
`Pharmacokinetic Results
`Typical pharmacokinetic profiles of CCI-779 and its main
`metabolite sirolimus are displayed in Figure 3. Mean pharma-
`cokinetic parameters are presented in Tables 5 and 6.
`Following treatment, CCI-779 decreased in a polyex-
`ponential manner. AUC increased proportionally with
`doses up to 150 mg. Doses higher than 300 mg CCI-779
`yielded high AUCs and low clearance in some patients.
`Thus, the interpatient variability made difficult to assess the
`linearity of AUC with doses greater than 300 mg (Fig 4).
`CCI-779 did not exhibit preferential partitioning into
`RBCs, and yielded mean end-of-infusion blood/plasma
`ratio values of 0.64-1.15 (Coefficient of variation [CV]:
`17% to 68%). Mean steady-state volume of distribution
`was large with mean values of 127 to 384 L (CV, 7% to
`44%). Interestingly, Vdss appeared to exhibit an inverted
`U-shaped profile throughout the dose range, suggestive of
`saturable drug distribution at very high doses. Clearance of
`CCI-779 from whole blood increased with increasing dose
`with mean values ranging 19 to 51 L/h (CV, 14% to 32%).
`Two-way analysis of variance showed that doses signifi-
`cantly affected the Clearance of CCI-779 (P ⬍ .001). Mean
`
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`

`Phase I of CCI-779 Weekly IV Infusion
`
`Table 4. CCI-779–Related Dermatologic Toxicities With Total Frequency ⱖ 20% After Repeated Dosing
`
`Intermediate Dosesⴱ
`(7.5-165.0 mg/m2)
`
`No. of Patients
`(n ⫽ 15)
`
`Maculopapular rash
`Nail disorder
`Dry skin
`Acne
`Pruritus
`Eczema
`Herpes simplex virus infection
`Alopecia
`
`9
`7
`5
`7
`4
`4
`4
`2
`
`Highest Dose
`(220 mg/m2)
`
`No. of Patients
`(n ⫽ 9)
`
`3
`4
`4
`2
`3
`1
`1
`3
`
`%
`
`60
`47
`33
`47
`27
`27
`27
`13
`
`%
`
`33
`44
`44
`22
`33
`11
`11
`33
`
`Total Patients
`(N ⫽ 24)
`
`12
`11
`9
`9
`7
`5
`5
`5
`
`%
`
`50
`46
`38
`38
`29
`21†
`21
`21
`
`ⴱNo drug-related dermatologic toxicity was reported at 165 mg/m2 CCI-779.
`†The only grade 3-4 dermatologic toxicity was eczema at 110 mg/m2 CCI-779.
`
`terminal half-life for CCI-779 appeared to decrease with in-
`creasing dose from 22 hours following the 34 mg/m2 dose to 13
`hours following the 220 mg/m2 dose (CV, 7% to 29%). No
`significant change was observed in the pharmacokinetic pro-
`file of CCI-779 with multiple dosing (mean AR values ⬍ 1).
`Sirolimus appears as early as 15 minutes after CCI-779
`infusion with a peak at 0.5 to 2.0 hours, followed by a
`monoexponential decrease (Fig 3). Exposure to sirolimus
`was typically higher than that of CCI-779, with a mean AUC
`ratio (sirolimus/CCI-779) of ⬃ 2.5 to 3.5 (CV, 0.2% to
`69%), and AR less than 1 (Table 6). Dose-related increases
`in AUCsum were significantly less than proportional. Mean
`terminal half-life for sirolimus ranged 61 to 69 hours (CV,
`7% to 60%). At doses higher than 34 mg/m2, residual con-
`
`centrations of sirolimus were detectable before the next
`infusion for subsequent cycles. However, this did not re-
`sulted in higher AUC of sirolimus after repeated cycles.
`To gain information regarding the need for dosing
`based on BSA, a simulation was performed in which ob-
`served values for AUCsum based on the 34, 45, and 220
`mg/m2 doses were adjusted to reflect fixed IV doses of
`CCI-779 of 60, 85, and 375 mg, respectively. Simulated
`AUCsum values were approximated based on actual AUCsum
`and actual dose (mg) each patient received during cycle 1
`(Fig 5). The mean AUCsum for the 220 mg/m2 group was
`determined to be 27,058 ng䡠hr/mL (CV, 50.4%) whereas
`AUCsum for the 375 mg group (the average of flat doses
`received in the 220-mg/m2 cohort) was 27,015 ng䡠hr/mL
`
`Fig 2. Dermatologic effects of CCI-
`779. Representative forms of oral her-
`pes simplex infection (A), acne-like rash
`of the chest (B), maculopapular rash of
`the neck (C), and nail dystrophia (D).
`
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`

`Raymond et al
`
`Fig 3. Mean plasma concentrations (with standard deviations) of CCI-779 (solid spots) and sirolimus (rings) following intravenous doses of 34, 45, and
`220 mg/m2.
`
`(CV, 48.2%). The data indicated that the degrees of variabil-
`ity between BSA-normalized and flat dosing were compa-
`rable and that no improvement in variability was expected
`from normalizing the dose. Therefore, flat dosing on a
`milligram basis could also be considered appropriate for
`this once-weekly regimen and does not afford improve-
`ment in exposure variability.
`Tumor Responses
`Confirmed partial responses were observed in two pa-
`tients. One patient with renal cell carcinoma received 15
`mg/m2 CCI-779 after documented tumor progression
`of
`lung and pleural metastasis under treatment with
`interferon-␣ and interleukin 2. The partial response was
`observed after 8 weeks of treatment and lasted for 6.5
`months under therapy (Fig 6). A second patient with breast
`cancer and measurable disease in liver and cervical lymph
`nodes (previously treated with anthracycline, docetaxel,
`and vinorelbine) received 220 mg/m2 CCI-779 and had,
`after 4 weeks, a partial response lasting 5.4 months. Minor
`responses corresponding to 34% and 39% tumor reduc-
`tions and lasting for 3 and 4.9 months were reported in two
`additional patients with renal cell carcinoma treated at the
`dose of 15 mg/m2 and 45 mg/m2, respectively.
`
`DISCUSSION
`
`In this study, we show that IV weekly infusion of CCI-779 at
`a broad range of doses can be administered to patients with
`advanced malignancies without clinically relevant immu-
`nosuppressive effects. No opportunistic infection and no
`significant modification of lymphocyte counts and func-
`tions were detected after repeated injections. However, oc-
`currence of labial herpes simplex infection was frequently
`observed and subsequently complicated by a severe staph-
`ylococci infection in one patient. Thus vigorous treatment
`of herpes simplex infection in patients treated with CCI-779
`seems advisable.
`The main dose-limiting toxicity of CCI-779 was re-
`versible thrombocytopenia. Thrombocytopenia could be
`schedule-dependent as it was less frequent in our study
`compared with that in the study where CCI-779 was
`administered once daily for 5 days every 2 weeks and in
`which thrombocytopenia prevented dose-escalation above
`19.1 mg/m2/d.29
`the dose of 220 mg/m2 CCI-779
`Unexpectedly,
`induced striking euphoria followed by melancholy,
`mimicking biopolar disorder. This toxicity occurred in
`
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`

`

`Phase I of CCI-779 Weekly IV Infusion
`
`Table 5. Representative Mean Pharmacokinetic Parameters of CCI-779
`in Whole Blood Following Once-Weekly IV Administration
`
`Table 6. Representative Mean Pharmacokinetic Parameters of Sirolimus
`in Whole Blood Following Once-Weekly IV Administration of CCI-779
`
`Parameter
`
`Cmax, ng/mL
`Mean
`SD
`t1/2, hours
`Mean
`SD
`AUC, ng/mL
`Mean
`SD
`MRT, hours
`Mean
`SD
`Clearance, L/hour
`Mean
`SD
`Vdss, L
`Mean
`SD
`ARⴱ
`Mean
`SD
`Blood-plasma ratio, 0.5 hours
`Mean
`SD
`
`Dose Group (mg/m2)
`34 (n ⫽ 3)
`45 (n ⫽ 4)
`220 (n ⫽ 9)
`
`2,200
`798
`
`1,368
`249
`
`11,417
`3,554
`
`22.3
`6.1
`
`17.3
`1.2
`
`13.0
`3.8
`
`3,221
`809
`
`3,414
`1,441
`
`8,001
`2,712
`
`12.8
`1.0
`
`19.1
`2.69
`
`14.7
`2.3
`
`27.0
`7.36
`
`242.0
`15.6
`
`385.0
`60.4
`
`0.66
`0.08
`
`0.64
`0.11
`
`0.84
`0.23
`
`0.83
`0.12
`
`2.4
`0.6
`
`51.4
`16.6
`
`127.0
`56.1
`
`—
`—
`
`1.15
`0.79
`
`NOTE. Statistical analysis performed on all data 7.5 to 220 mg/m2; Cmax
`and AUC normalized to 1 mg dose prior to analysis.
`Abbreviations: IV, intravenous; Cmax, maximum concentration; SD,
`standard deviation; t1/2, half-life; AUC, area under the concentration
`curve; MRT, mean residence time; Vdss, steady-state volume of
`distribution; AR, accumulation ratio.
`ⴱAR is ratio of AUCt on week 4 to AUCt on week 1.
`
`patients without previous medical history of any psychi-
`atric disorders and required hospitalization for IV anti-
`depressive treatment in one patient. The relationship of
`this neutrotoxicity to CCI-779 is supported by reversibil-
`ity on treatment discontinuation. The physiopathology
`of this event is not understood; recent evidence has sug-
`gested that sirolimus could interfere with the neuro-
`transmitter metabolism.30,31
`The most frequent adverse events that limited the tol-
`erability of CCI-779 were skin toxicity and stomatitis. Skin
`toxicity was observed at all doses from 7.5 to 220 mg/m2.
`Maculopapular rash observed on the face and neck and
`acne-like rash observed on the face and upper chest were the
`predominant forms of dermatologic injury. These types of
`rash have also been reported with several epidermal growth
`factor receptor targeted agents such as the tyrosine kinase
`inhibitors gefitinib (ZD1839) and erlotinib (OSI-774)
`and monoclonal antibody cetuximab (IMC-225).32-34 Since
`mTOR appears to mediate intracellular signaling from EGFR
`in normal skin, a similar toxicity for an mTOR inhibitor might
`be expected. Pathologic examinations revealed nonspecific ac-
`
`Parameter
`
`Cmax, ng/mL
`Mean
`SD
`tmax, hours
`Mean
`SD
`t1/2, hours
`Mean
`SD
`AUC, ng.h/mL
`Mean
`SD
`Cl/fm, L/hour
`Mean
`SD
`Vdss/fm, L
`Mean
`SD
`ARⴱ
`Mean
`SD
`AUC ratio, sirolimus/CCI-779
`Mean
`SD
`AUCsum, ng/mL
`Mean
`SD
`
`Dose Group (mg/m2)
`34 (n ⫽ 3)
`45 (n ⫽ 4)
`220 (n ⫽ 9)
`
`125
`65
`
`126
`25
`
`798
`475
`
`0.83
`0.29
`
`69.2
`5.00
`
`2.26
`2.52
`
`60.8
`4.3
`
`0.74
`0.27
`
`60.5
`36.3
`
`8,753
`2,205
`
`11,740
`4,267
`
`19,057
`13,039
`
`7.01
`1.00
`
`622
`182
`
`0.85
`0.25
`
`2.72
`0.00†
`
`7.77
`2.13
`
`27.2
`13.2
`
`697
`124
`
`0.91
`0.19
`
`3.52
`0.69
`
`1,732
`860
`
`—
`—
`
`2.51
`1.73
`
`11,973
`3,014
`
`15,154
`5,523
`
`27,058
`13,625
`
`NOTE. Statistical analysis performed all dat