Investigational New Drugs 23: 357–361, 2005.
`C(cid:1) 2005 Springer Science + Business Media, Inc. Manufactured in The Netherlands.
`
`357
`
`Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme
`
`Susan M. Chang1, Patrick Wen2, Timothy Cloughesy3, Harry Greenberg4, David Schiff5, Charles
`Conrad6, Karen Fink7, H.Ian Robins 8, Lisa De Angelis9, Jeffrey Raizer9, Kenneth Hess6, Ken
`Aldape6, Kathleen R. Lamborn1, John Kuhn10, Janet Dancey11, Michael D. Prados1 for the North
`American Brain Tumor Consortium and the National Cancer Institute
`1University of California, San Francisco; 2Dana Farber Cancer Institute; 3University of California, Los Angeles;
`4University of Michigan; 5University of Virginia; 6MD Anderson Cancer Center; 7University of Texas, Southwestern;
`8Unversity of Wisconsin; 9Memorial Sloan Kettering Cancer Center; 10University of Texas, San Antonio; 11Cancer
`Therapy Evaluation Program, National Cancer Institute
`
`Key words: chemotherapy, CCI-779, rapamycin, glioblastoma multiforme, recurrent, efficacy
`
`Summary
`
`Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian
`target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle
`progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of
`CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug. Experimental Design: CCI-779 was
`administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs).
`Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable
`side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary
`endpoint was 6-month progression-free survival. Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The
`expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological
`toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there
`were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks. Conclusions:
`CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent
`GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because
`of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.
`
`Introduction
`
`Novel therapeutic strategies are needed for the treat-
`ment of patients with recurrent glioblastoma multiforme
`(GBM), for whom the median survival is currently 4
`to 6 months. Recent advances in the understanding of
`aberrant molecular and cytogenetic pathways involved in
`GBM pathogenesis and progression have led to the ra-
`tional targeting of some of these pathways. A significant
`percentage of GBM have altered PTEN gene suppres-
`sion activity [1], which results in the increased activity
`of the phosphotidylinositol 3-kinase (PI3K)/Akt pathway.
`The PI3K/Akt pathway activates the mammalian target of
`rapamycin (mTOR), increasing translation of a number
`of key proteins required for cell-cycle progression. The
`presence of PTEN gene alterations and the subsequent
`
`activation of these downstream pathways have been as-
`sociated with poor prognosis in anaplastic astrocytoma,
`anaplastic oligodendroglioma, and GBM [2–4]. Restora-
`tion of PTEN function or targeting of the components of
`the PI3K/Akt/mTOR pathways can result in cell-cycle ar-
`rest, apoptosis, or reduced tumorigenicity and are rational
`targets for clinical evaluation.
`CCI-779 is a dihydroxymethyl propionic acid ester
`of the immunosuppressive agent sirolimus (rapamycin,
`(cid:1)R) that targets the mTOR pathway. CCI-779
`Rapamune
`binds to FKBP-12 to form a complex that interacts with
`mTOR, which results in cell-cycle arrest by means of inhi-
`bition of RNA translation [5–7]. CCI-779 is lipid soluble
`and inhibits the growth of a number of human tumor lines
`in nude mouse models, including GBM [8]. Based on
`these promising pre-clinical studies, there was an interest
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`in evaluating this novel agent in patients with recurrent
`GBM.
`There is increasing evidence that brain tumor patients
`receiving P450 enzyme-inducing anti-epileptic drugs
`(EIAEDs) have markedly altered pharmacokinetics, re-
`sulting in accelerated drug metabolism. CCI-779 and ra-
`pamycin are substrates for the cytochrome P450 isoen-
`zyme 3A4. A North American Brain Tumor Consortium
`phase I study established the maximum tolerated dose of
`CCI-779 in patients with malignant glioma who are taking
`EIAEDs at 250 mg [9].
`We report on the results of a phase II study of CCI-779
`in patients with recurrent GBM. The primary objectives
`of this study were to determine the efficacy (defined by
`6-month progression-free survival) of patients with recur-
`rent GBM treated with CCI-779 and to further assess its
`toxicity.
`
`Methods
`
`Patient eligibility
`
`Patients at least 18 years of age were eligible for partic-
`ipation if they had histopathologically confirmed GBM
`with recurrence documented by neuroimaging. Patients
`were also eligible if they had a prior low-grade glioma
`and a subsequent histological confirmation of GBM. Pa-
`tients must have relapsed after prior treatment with radi-
`ation therapy, with an interval of at least 4 weeks from
`treatment with radiation therapy, and could not have un-
`dergone treatment for more than 2 prior relapses. Patients
`were required to have a Karnofsky Performance Scale
`(KPS) score of at least 60, an estimated survival of >8
`weeks, hematologic, renal, and hepatic status within the
`normal ranges, levels of cholesterol <350 mg/dl, and lev-
`els of triglyceride <400 mg/dl. No exclusions were made
`based on gender, race, minority status, or economic sta-
`tus. Female patients were not pregnant or nursing, and
`all patients (both men and women) agreed to practice
`birth control during and for 3 months after completing the
`study. Patients or their surrogates signed an institutionally
`approved Committee on Human Research consent form.
`Patients did not have any serious intercurrent illness or
`disease that obscured or altered drug metabolism.
`
`Study design
`
`Patients were treated with CCI-779 as a 30-minute intra-
`venous (IV) infusion weekly with no rest period required.
`For the purpose of evaluation, a cycle was defined as ev-
`ery 4 weeks. Because of the documented side effect of
`lipid elevation, allowance for the use of lipid-lowering
`agents was incorporated into the phase II study. After ev-
`ery 2 cycles of treatment, patients underwent re-staging
`
`with neuro-imaging and clinical evaluation including neu-
`rological examination and assessment of corticosteroid
`use. Determination of tumor status was made using stan-
`dard criteria [10]. Therapy with CCI-779 was continued
`as long as the tumor was stable or smaller in size and
`the patient was clinically stable or improved on stable or
`decreasing corticosteroid doses. Treatment continued in-
`definitely as long as there were no unacceptable toxicities,
`patient refusal to continue participation, or tumor progres-
`sion. For all patients, the initial phase II dose was 250 mg
`IV weekly. Toxicities were graded according to the NCI
`Common Toxicity Criteria (CTC Version 2.0) scale.
`
`Statistical considerations
`
`Enrollment of 32 patients would give a 92% probabil-
`ity of successfully detecting a 35% 6-month progression
`free-survival (PFS) rate and a 90% probability of re-
`jecting the drug if the 6-month progression-free survival
`(PFS) rate was 15% or less. The study would be consid-
`ered worth pursuing if at least 8/32 patients had 6-month
`progression-free survival.
`
`Results
`
`Forty-three patients were enrolled (65% male). All pa-
`tients enrolled had primary GBM. The median age was
`48 years (range 26–71 years) and the median KPS was 90.
`Patients’ characteristics are shown in Table 1. For patients
`not on EIAEDS, the initial dose was 250 mg weekly; how-
`ever, this was reduced to 170 mg weekly in many patients
`because of intolerable side effects (stomatitis). Thirteen
`patients were treated at 250 mg and 16 patients at 170 mg.
`The 14 patients on EIAEDs were treated at 250 mg. The
`major toxicities observed were elevation in lipid profiles,
`lymphopenia, and stomatitis (Table 2). Twenty-one pa-
`tients were started on lipid-lowering agents during the
`study; none were on lipid-lowering agents at the time of
`enrollment. There were no grade IV hematological toxi-
`cities and no toxic deaths.
`Two patients were lost to follow-up and were censored
`for the endpoint of progression-free survival. Of the 41
`evaluable patients, only 1 patient was progression free at
`6 months. There were 2 partial responses and 20 patients
`who had stabilization of disease; however, the median
`time to progression was short, at 9 weeks. The Kaplan
`Meier estimate for time to progression is shown in Fig-
`ure 1.
`
`Discussion
`
`Mutations of the PTEN gene result in constitutive ac-
`tivation of the PI3K pathway, resulting in increased
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`Table 1. Patients’ characteristics
`
`Patients taking
`Patients taking
`NEIAEDs (N = 29) EIAEDs (N = 14)
`
`51 (29–71)
`
`46 (26–71)
`
`13 (44.8%)
`16 (55.2%)
`
`10 (34.5%)
`19 (65.5%)
`
`2 (6.9%)
`27 (93.1%)
`
`2 (6.9%)
`22 (75.9%)
`2 (6.9%)
`3 (10.3%)
`
`4 (28.6%)
`10 (71.4%)
`
`5 (35.7%)
`9 (64.3%)
`
`0 (0%)
`14 (100%)
`
`0 (0%)
`9 (64.3%)
`5 (35.7%)
`0 (0%)
`
`Median Age in
`years (range)
`Karnofsky
`Performance Status
`90–100
`≤80
`
`Sex
`
`Race
`
`Female
`Male
`
`Black
`White
`Prior Chemotherapy
`Regimens
`0
`1
`2
`3
`
`Table 2. Grade III and IV toxicities observed (n = 43 pa-
`tients) using the National Cancer Institute common toxicity grad-
`ing system
`
`Toxicity
`
`Grade III (%)
`
`Grade IV (%)
`
`Lymphopenia
`Anemia
`Stomatitis
`Elevated cholesterol
`Elevated triglyceride
`
`14
`5
`2
`9
`5
`
`–
`–
`2
`7
`5
`
`proliferation, dysregulation of the cell cycle, and resis-
`tance to chemotherapy-induced apoptosis. This is rele-
`vant in glioma therapy, as PTEN mutations are present in
`approximately 40% to 60% of all GBM, and alterations
`
`359
`
`in PTEN are of prognostic significance [1]. One of the
`downstream pathways of PTEN involves mTOR, which
`is inhibited by CCI-779. Based on preclinical data on CCI-
`779, which showed potential antiglioma activity, we eval-
`uated this agent in patients with recurrent GBM. Because
`CCI-779 and rapamycin are metabolized by the p450 hep-
`atic enzyme system, and concurrent use of EIAEDs may
`result in increased clearance of CCI-779, the appropri-
`ate phase II dose in patients on enzyme-inducing anti-
`epileptic agents was established first [9]. The agent was
`well tolerated, with side effects as described at a similar
`dosing schedule in solid cancers [11].
`This phase II study sought to evaluate the efficacy of
`CCI-779 as defined by 6-month progression-free survival
`in patients with recurrent GBM irrespective of the use
`of EIAEDs. Unfortunately, despite good tolerance of the
`agent, CCI-779 did not demonstrate sufficient antitumor
`activity to warrant further study as a single agent. There
`are possibly several reasons for this lack of efficacy. Al-
`though the pharmacokinetic results suggested adequate
`systemic concentrations of the drug to block mTOR [9],
`actual drug concentration within the tumors had not been
`documented. The presence of the blood-brain barrier and
`inadequate penetration of the agent to the infiltrative tu-
`mor cells may be a barrier for drug delivery. This em-
`phasizes the challenges of performing clinical trials of
`novel agents in patients with malignant glioma [12]. A
`small pilot study being performed by the North Ameri-
`can Brain Tumor Consortium involves 10 patients who
`will be administered CCI-779 prior to planned surgical
`resection of a recurrent malignant glioma. In addition to
`evaluation of inhibition of mTOR, measurements of tumor
`drug levels are planned and may help in answering this
`question.
`
`Figure 1. Kaplan Meier estimate for time to progression for 41 patients with recurrent GBM treated with CCI-779.
`
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`PTEN status of the tumors at the time of enrollment
`was not required or mandated. As with any ‘targeted’
`therapy, enrollment of patients lacking the specific ge-
`netic abnormality may cause underestimation of the true
`efficacy of the agent. This poses a significant challenge in
`the selection of patients, given the invasive nature of tis-
`sue acquisition. Retrospective analysis of tissue samples
`is also fraught with potential for misinterpretation, as the
`specimens analyzed tend to be representative of the tumor
`at the time of initial diagnosis and not at the time of recur-
`rence following therapy with radiation and/or chemother-
`apy. Changes in the molecular targets could theoretically
`occur with time, and the most informative sample would
`be at the time of treatment with the targeted agent.
`It is well accepted that many cell-signaling pathways
`overlap, and there may actually be an interdependence of
`activity within these pathways. Targeting only one aspect
`of a pathway may be successful in proof-of-principle stud-
`ies; however, this may unfortunately not translate into a
`benefit of clinical significance for the patient. An example
`of this is the recent demonstration of the alterations in cy-
`clin D1/c-myc expression as critical determinants of cell
`sensitivity to mTOR inhibitors, which suggested that ex-
`cessive transcription of these genes in tumors may inhibit
`the effectiveness of mTOR inhibitors [13]. Other rela-
`tionships between signaling molecules have been demon-
`strated in vivo by Choe et al., using human GBM tissue mi-
`croarrays [14]. In addition to the well-accepted relation-
`ship of the PTEN and PI3K pathways, the authors show
`correlation of PTEN with the family of forkhead tran-
`scription factors as well as the mutant epidermal growth
`factor receptor vIII. Others have also described the re-
`lationship of epidermal growth factor receptor (EGFR)
`with this particular signaling pathway [15]. This is partic-
`ularly relevant for GBM, as frequent mutation of EGFR
`is seen and is known to confer an unfavorable prognosis
`[16]. There may be a scientific rationale for the combi-
`nation of EGFR inhibitors with mTOR inhibitors given
`these findings. These studies also suggest that the signal-
`ing abnormalities specific to the individual patient may be
`important information for stratification into clinical trials
`of these targeted agents.
`In addition to these reasons for the limited efficacy of
`CCI-779 observed in this study, potential mechanisms of
`resistance to rapamycin and its analogs include mutation
`of the binding proteins FKBP-12, alteration of the down-
`stream effectors of mTOR, and mutation of mTOR itself
`[17, 18]. Many of these mechanisms are being elucidated,
`but their clinical significance needs to be further studied.
`It is anticipated that many of these cytostatic agents
`that target specific signaling pathways are unlikely to have
`durable control of tumor growth as single agents because
`of the reasons described above. There is the danger of
`discarding a potentially useful agent that could be used
`
`in combined modality therapy because of its lack of ef-
`ficacy as a single agent. Preclinical data support the use
`of mTOR inhibitors in combination with radiation and
`chemotherapy [19–21]. The current paradigm of evaluat-
`ing the efficacy of these drugs as single agents first rather
`than in combination with radiation therapy, chemother-
`apy, or other targeted therapies may inherently delay ap-
`propriate use of these novel compounds. Given that the
`agent is well tolerated, proceeding with the study of these
`combinations may be worthy of further study.
`
`Conclusions
`
`This phase II study of CCI-779 in patients with recurrent
`GBM on and off enzyme-inducing anti-epileptic drugs
`failed to demonstrate any efficacy as a single agent. Be-
`cause CCI-779 was well tolerated, further combination
`strategies may merit evaluation.
`
`Acknowledgments
`
`Research support
`
`Institution
`
`Member/Affiliate
`Grant Number
`
`GCRC Grant
`Number
`
`NABTC # CA62399 M01-RR00079
`University of California,
`Member #CA62422
`San Francisco
`University of Texas, M.D. CA62412
`Anderson Cancer Center
`Dana Farber Cancer
`Center
`University of Texas,
`Southwestern
`Medical Center
`University of Texas,
`San Antonio
`University of California,
`Los Angeles
`
`CA16672
`
`U01CA62407-08
`
`N/A
`
`CA62455-08
`
`M01-RR00633
`
`CA62426
`
`N/A
`
`U01 CA62399
`#022330 for
`NABTC98-03 only
`U01CA62399
`5-U01CA62399-09
`
`M01-RR0865
`
`M01-RR00042
`
`U01CA62421-08
`
`M01 RR03186
`
`University of Michigan
`Memorial Sloan-Kettering
`Cancer Center
`University of Wisconsin
`Hospital
`
`The authors thank Sharon Reynolds, Department of Neu-
`rological Surgery, University of California, San Francisco
`for editorial support.
`
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`Address for offprints: Susan M. Chang, M.D., Neuro-Oncology Ser-
`vice, University of California, San Francisco, 400 Parnassus Ave, A808,
`San Francisco, CA 94143. Tel.: 415 353 2966; Fax: 415 353 2167;
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