Original Article
`
`A Phase 2 Study of Temsirolimus (CCI-779)
`in Patients With Soft Tissue Sarcomas
`
`A Study of the Mayo Phase 2 Consortium (P2C)
`
`Scott Okuno, MD1; Howard Bailey, MD2; Michelle R. Mahoney, MS1; Douglas Adkins, MD3; William Maples, MD4;
`Tom Fitch, MD5; David Ettinger, MD6; Charles Erlichman, MD1; and Jann N. Sarkaria, MD1
`
`BACKGROUND: The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus (CCI-779),
`a mammalian target of rapamycin in patients with advanced soft tissue sarcomas (STS). METHODS: Patients 18
`years with measurable advanced STS, no prior chemotherapy for metastatic disease (adjuvant and neoadjuvant
`chemotherapy allowed), adequate organ function, and performance status of 2 were eligible. After premedication
`with an antihistamine, CCI-779 was given intravenously at 25 mg over 30 minutes on Days 1, 8, 15, and 22, repeated
`every 4 weeks. The primary endpoint was confirmed response rate per Response Evaluation Criteria in Solid Tumors.
`RESULTS: Between June 2004 and November 2005, a total of 41 patients were enrolled and began treatment; 40
`patients are evaluable for response and adverse events. The median age was 62 years (range, 28-72 years) with 56%
`women. Eighty percent had high-grade STS, and 22% had prior adjuvant chemotherapy. There were 2 patients (5%;
`95% confidence interval [CI], 1-17) (undifferentiated fibrosarcoma and uterine leiomyosarcoma) who achieved a
`confirmed partial response lasting 3 and 17 months, respectively. Thirty-nine (95%) patients have progressed, with
`a median time to progression of 2.0 months (95% CI, 1.8-3.5). The median overall survival was 7.6 months (95%
`CI, 6.1-15.9). Forty-three percent experienced grade 3þ adverse events that were possibly related to therapy.
`CONCLUSIONS: Temsirolimus in this patient population of STS had limited clinical activity and had moderate toxic-
`ities. Cancer 2011;117:3468–75. VC 2011 American Cancer Society.
`
`KEYWORDS: soft tissue sarcoma, mammalian target of rapamycin, temsirolimus, toxicities..
`
`Soft tissue sarcomas (STS) are a heterogeneous group of cancers with various biologic activities. It is estimated that there
`will be 10,520 new cases of STS diagnosed in 2010, with an estimated mortality of 37%.1 Despite activity of certain agents
`for histologic-specific STS such as of imatinib and sunitinib for gastrointestinal stromal sarcomas2,3 or gemcitabine and
`docetaxel for uterine leiomyosarcoma,4 for the vast majority of the other STS, treatment with palliative doxorubicin- or
`ifosfamide-based therapy is toxic and has marginal activity.5,6
`Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates numerous cellular functions.
`mTOR functions within 2 distinct signaling complexes, denoted as mTOR complex 1 (mTOR complex 1) and mTOR
`complex 2. In the presence of adequate nutrient and energy stores, mTOR complex 1 integrates signals from mitogenic
`signaling pathways and controls downstream signaling cascades that regulate translation of a subset of mRNAs with com-
`0
`0
`plex 5
`untranslated regions or 5
`polypyrimidine tracts. Many of these transcripts encode proteins involved in promoting
`cell proliferation, angiogenesis, and cell survival. Key downstream targets that modulate protein translation include eu-
`karyotic initiation factor 4E and p70S6 kinase, the latter of which phosphorylates ribosomal S6 protein.7 Several potent
`inhibitors of mTOR complex 1 signaling have been developed, including sirolimus (rapamycin, Rapamune) and the
`related ester temsirolimus (CCI-779, sirolimus 42-ester with 2,2-bis[hydroxymethyl] propionic-acid). CCI-779
`
`Corresponding author: Scott Okuno, MD, Department of Oncology, Mayo Clinic, Rochester, MN 55905; Fax: (507) 284-1803; Okuno.scott@mayo.edu
`
`1Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota; 2Division of Oncology, University of Wisconsin Comprehensive Cancer Center,
`Madison, Wisconsin; 3Division of Oncology, Washington University School of Medicine, St Louis, Missouri; 4Division of Oncology, Mayo Clinic, Jacksonville, Florida;
`5Department of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona; 6Department of Oncology, Bunting Blaustein Cancer Research Building, Baltimore,
`Maryland
`
`Presented at the 42nd American Society of Clinical Oncology Annual Meeting, Atlanta, Georgia, June 2-6, 2006, abstract 9504.
`
`We thank Kristina Laumann for her statistical support and Ann Mladek for expert analysis of S6 phosphorylation in peripheral blood mononuclear cell samples.
`
`DOI: 10.1002/cncr.25928, Received: September 21, 2010; Revised: November 8, 2010; Accepted: November 29, 2010, Published online February 1, 2011 in
`Wiley Online Library (wileyonlinelibrary.com)
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`inhibition has growth inhibitory effects on a wide range of
`histologically diverse tumor cells, including STS.8,9 The
`primary goal of this phase 2 study was to determine con-
`firmed response rate of CCI-779 in STS.
`
`MATERIALS AND METHODS
`Eligibility
`Patients with histologically confirmed STS were eligible
`for the study. Patients had Eastern Cooperative Oncology
`Group (ECOG) performance status (PS) of 2, and life
`expectancies of 12 weeks. The inclusion criteria
`included: absolute neutrophil count (ANC) 1500/
`mm3, platelet count 100,000/mm3, hemoglobin 10.0
`g/dL, direct bilirubin 1.5 the institutional upper limit
`of normal (ULN), aspartate aminotransferase 2.5 the
`institutional ULN or5 the ULN if there were liver me-
`tastases, alanine aminotransferase 2.5 ULN or5
`the ULN if there were liver metastases, creatinine 1.5
`the institutional ULN (or creatinine clearance 50mL/
`min for patients with creatinine levels >1.5 institutional
`ULN), fasting serum cholesterol 350 mg/dL, fasting tri-
`glycerides 400 mg/dL, age 18 years, and negative
`pregnancy test for women of childbearing potential. All
`patients were required to have at least 1 lesion that could
`be accurately measured, with the longest diameter meas-
`uring 2.0 cm. Exclusion criteria included: chemother-
`apy for metastatic disease (exceptions: patients with
`gastrointestinal stromal tumors [GIST] who fail Gleevec
`are eligible; patients who have had adjuvant/neoadjuvant
`chemotherapy are also eligible), pregnancy or lactation,
`uncontrolled intercurrent illness, central nervous system
`metastases unless treated and stable symptoms for 1
`month, history of allergic reactions attributed to com-
`pounds similar to temsirolimus (CCI779), and known
`human immunodeficiency virus-positive patients receiv-
`ing combination antiretroviral therapy.
`
`Treatment Administration and Evaluation
`CCI-779 was administered intravenously at 25 mg over
`30 minutes on Days 1, 8, 15, and 22, repeated every 4
`weeks. Premedication with antihistamines was given
`intravenously 30 minutes before CCI-779. Doses were
`held for grade 3-4 hematologic and nonhematologic tox-
`icities. Treatment was resumed at 5 mg dose reduction
`once the nonhematologic toxicity resolved to grade 2,
`ANC 1000/mm3, and platelets 75,000/mm3. A maxi-
`mum of 3 dose modifications were allowed.
`
`Temsirolimus for STS/Okuno et al
`
`Baseline evaluations were done within 7 days of
`treatment, including history and physical, complete blood
`count (CBC), albumin, alkaline phosphatase, bicarbon-
`ate, blood urea nitrogen, calcium, chloride, creatinine,
`glucose, lactate dehydrogenase, phosphorus, potassium,
`total protein, aspartate aminotransferase, alanine amino-
`transferase, sodium, total and direct bilirubin, cholesterol,
`triglycerides, and pregnancy test. CBC were done weekly
`before treatment in addition to chemistry, cholesterol,
`and triglycerides done every other week. Adverse events
`were collected via National Cancer Institute Common
`Terminology Criteria for Adverse Events version 3.0. Pre-
`treatment and post-treatment blood samples were proc-
`essed to evaluate
`sirolimus blood levels
`and S6
`phosphorylation to document inhibition of mTOR com-
`plex 1 signaling.
`The study was approved by the institutional review
`board at each treating site. Toxicity stopping rules were in
`place. Specifically, if at any time 4 of the initial 20 patients
`or 20% of all patients experienced a grade 4 or 5 adverse
`event (at least possibly related to study treatment), then
`accrual to the study would have been halted for full review
`of the data by the study team.
`
`Disease Assessment
`Disease assessment by computed tomography scan or
`magnetic resonance imaging was performed within 21
`days of registration. Tumor evaluations were done after 2
`cycles of therapy and then every other cycle (ie, every 8
`weeks). Tumor response was assessed using Response
`Evaluation Criteria in Solid Tumors (RECIST), with re-
`evaluation every 8 weeks.10 Total disappearance of target
`lesions constituted a complete response (CR), whereas a
`minimum of a 30% decrease in the sum of the longest di-
`ameter of the target lesions was classified as a partial
`response (PR). New lesions or a 20% increase in the sum
`of the longest diameters of the target lesions were consid-
`ered progressive disease (PD). Patients were re-evaluated
`for disease status 4 weeks after initial documentation of
`CR or PR to confirm the assessment. Similarly, stable dis-
`ease (SD) was reassessed at a minimum interval of 8
`weeks. Patients with global deterioration of health status
`requiring discontinuation of treatment without objective
`evidence of disease progression at that time, and not
`related to study treatment or other medical conditions,
`were considered to have PD because of symptomatic
`deterioration.
`Duration of response was calculated from the first
`date of a patient’s objective status of either CR or PR to
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`the date of PD (or last tumor assessment). Duration of
`SD was calculated from the date of registration to the date
`of PD (or last tumor assessment if no PD) for patients
`having achieved a best response of SD. Patients were cen-
`sored for progression (survival) at their date of last assess-
`ment (last contact) if no progression (death) occurred.
`Time to PD was calculated from the date of registration to
`the date of PD. Survival or time to death was calculated
`from the date of registration to the date of death. All
`patients were followed until death or a maximum of 5
`years after registration, whichever was earlier.
`
`Laboratory Correlative Studies
`Peripheral blood mononuclear cells (PBMC) were iso-
`lated from blood samples obtained before and 24 hours
`after the first infusion of CCI-779. Samples were proc-
`essed as described in detail previously.11 Briefly, fresh
`PBMC were divided into aliquots, spiked with or without
`rapamycin, and then stimulated with phytohemagglutinin
`and phorbol 12-myristate 14-acetate before freezing. Fro-
`zen samples then were batch processed for Western blot-
`ting with phospho- and total-S6 antibodies. NIH Image J
`(http://rsbweb.nih.gov/ij/) was used to measure optical
`density of individual bands, and the ratio of phospho-S6
`versus total S6 was calculated for each sample. The differ-
`ence in the phospho-S6 intensity between the spiked and
`unspiked pretreatment blood sample was considered the
`dynamic range of S6 phosphorylation with and without
`effective mTOR complex 1 inhibition, respectively, and a
`75% or greater reduction in this dynamic range in the
`post-treatment blood sample was considered effective in-
`hibition of S6 phosphorylation. Blood samples for siroli-
`mus
`serum levels 24 hours after
`treatment were
`determined in the Mayo Medical Laboratories.
`
`Statistical Methods
`The primary endpoint for this trial was the proportion of
`confirmed tumor responses. All eligible patients who have
`initiated study treatment and signed consent were consid-
`ered evaluable for the primary endpoint. Confirmed tu-
`mor response to treatment is defined as a CR or PR on 2
`consecutive evaluations, at least 4 weeks apart. The pri-
`mary endpoint was estimated by the number of confirmed
`responses divided by the total number of evaluable
`patients. Five percent was the threshold used for clinical
`inactivity (Ho) in regard to confirmed tumor response
`rate, whereas an observed confirmed response rate of 20%
`was considered promising (Ha) in this population. To test
`these hypotheses and in recognition of the lack of benefi-
`
`cial treatments in this population, a single-stage phase 2
`study design with a planned interim analysis was used; no
`suspension of accrual between stages was allowed unless
`there was excessive toxicity. Here, 2 confirmed responses
`within the initial 20 patients expanded enrollment to 50
`patients. Six of 50 patients with confirmed tumor
`responses was considered evidence that this treatment
`could be recommended for further testing in subsequent
`studies in this patient population. This single-stage Flem-
`ing design12 yielded 91% power to detect a true con-
`firmed response rate of at least 20%, at a .09 level of
`significance. Confidence intervals (CIs) for the primary
`endpoint were calculated by the method of Duffy and
`Santner.13
`Summary statistics and frequency tables were used
`to summarize baseline patient characteristics and adverse
`events. Adverse events were reported as a maximum sever-
`ity per patient and type, across all cycles of treatment. All
`attributions collected for adverse events were reported
`unless otherwise noted. The Kaplan-Meier14 method was
`used to estimate distributions of time to progression and
`time to death. All analyses were conducted using SAS ver-
`sion 9.0 (SAS Institute, Cary, NC).
`Laboratory correlatives were investigated using
`graphical techniques and summary statistics (eg, mean,
`median). Serum sirolimus was measured post-treatment
`only, whereas all other correlates were measured at both
`pretreatment and post-treatment. Changes over time were
`assessed using percentage change from baseline, as well as
`categorical methods (eg, using frequency tables to identify
`changes in the patterns of phosphorylation intensity).
`Clinical characteristics (eg, sex, age) and patient outcome
`(eg, progression, death, response) were assessed relative to
`laboratory correlatives to look for possible associations (or
`lack thereof). These analyses were considered hypothesis
`generating in nature.
`
`RESULTS
`Demographics
`Patient characteristics are presented in Table 1. Between
`June 2004 and November 2005, the study enrolled 41
`patients from 4 sites (Mayo Clinic [n ¼ 23], University of
`Wisconsin Comprehensive Cancer Center [n ¼ 12],
`Washington University [n ¼ 4], and Johns Hopkins [n ¼
`2]). One patient did not return after receiving 1 dose of
`therapy. The median age was 62 years (range, 28-79),
`with 85% of patients having an ECOG performance sta-
`tus of 0 or 1. Seventy-two percent of patients presented
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`Table 2. Patient Outcomes (N ¼ 41)
`
`Frequency (%)
`
`Outcome
`
`Frequency/Estimate
`
`Table 1. Patient Characteristics
`
`Characteristic
`
`Age, median y (range)
`Sex, women
`
`ECOG performance status
`0
`1
`2
`
`62 (28-79)
`23 (56)
`
`15 (36)
`20 (49)
`6 (15)
`
`Response ratea
`No. of responders (PR)
`Time to response, median mo
`
`Overall survival, median mob
`6 months
`12 months
`18 months
`
`Time to disease progression,
`median mob
`2 months
`3 months
`4 months
`6 months
`
`5% (95% CI, 1-17)
`2
`2.7 mo (range, 2-4)
`
`7.6 mo (95% CI, 6.1-15.9)
`66% (95% CI, 53-82)
`39% (95% CI, 27-57)
`34% (95% CI, 22-52)
`
`2.0 (95% CI, 1.8-3.5)
`
`54% (95% CI, 41-72)
`41% (95% CI, 28-60)
`22% (95% CI, 12-40)
`13% (95% CI, 6-31)
`
`CI indicates confidence interval; PR, partial response.
`a n ¼ 40; response sustained for at least 2 consecutive evaluations.
`b Kaplan-Meier method.
`
`with lung metastases. Eighty percent had high-grade STS
`based on local pathology review.
`
`Treatment Efficacy
`Forty (98%) of 41 patients were considered evaluable for the
`primary endpoint of confirmed tumor response. Accrual was
`rapid, and at the time response data were available for the
`first 20 evaluable patients, only 1 patient achieved a con-
`firmed PR. This failed to meet the criteria to complete full
`accrual of 50 patients; thus, the trial was closed at Patient 41.
`Overall, 2 (5%; 95% CI, 1-17) patients achieved a con-
`firmed PR (Table 2). A 63-year-old man, with undifferenti-
`ated fibrosarcoma of the thigh and metastases to the lung,
`achieved a PR after 2 cycles of therapy, which was sustained
`for 17 months until progression in the lung at Cycle 19. He
`died 10 months later of his cancer. The other PR was a 42-
`year-old woman, with leiomyosarcoma of the uterus and me-
`tastases in the lymph nodes, bone, and lung, achieved a PR
`in Cycle 4. She had progression in the lymph nodes and lung
`in Cycle 7 (duration of response, 3 months). She died 22
`months later of her cancer.
`Thirty-nine (95%) patients progressed; the most
`common site of progression was the lung (58%). Figure 1
`and Table 2 indicate time to progression (TTP) and over-
`all survival (OS), as well as duration of response. The me-
`dian time to progression was 2.0 months (95% CI, 1.8-
`3.5). All patients have died. The median time to death
`(OS) was 7.6 months (95% CI, 6.1-15.9).
`
`Time from diagnosis to going on study,
`median mo (range)
`
`10.9 (0.9-137.1)
`
`Distant metastasesa
`Nodal
`Subcutaneous
`Bone
`Lung
`Liver
`Abdominal
`Brain
`Otherb
`
`Histological type
`MFH
`Sarcoma, NOS
`Fibrosarcoma, NOS
`Myxosarcoma
`Liposarcoma, NOS
`Leiomyosarcoma
`Endometrial stromal sarcoma
`Synovial sarcoma
`Hemangiosarcoma/angiosarcoma
`Hemangiopericytoma, NOS
`Neurofibrosarcoma
`
`Sarcoma site
`Pelvis
`Head (skull, face)
`Extremities
`Intra-abdominal, NOS
`Genitourinary, NOS
`Vascular, NOS
`Cardiac, muscle
`Fallopian tube
`Uterus
`Skin
`Pulmonary, lung
`Truncal, chest wall
`
`Differentiation (grade)
`High (grade 3 or 4)
`Low (grade 1 or 2)
`
`Status of primary tumor site
`Resected with no residual
`Resected with known residual
`Unresected
`Recurrent
`
`Prior adjuvant therapy, yes
`
`6 (19)
`2 (6)
`5 (16)
`23 (72)
`4 (13)
`5 (16)
`2 (6)
`3 (9)
`
`8 (20)
`9 (22)
`3 (7)
`1 (2)
`5 (12)
`9 (22)
`1 (2)
`1 (2)
`2 (5)
`1 (2)
`1 (2)
`
`3 (8)
`2 (5)
`16 (40)
`5 (13)
`1 (2)
`2 (5)
`1 (3)
`1 (3)
`5 (13)
`1 (3)
`1 (3)
`2 (5)
`
`33 (80)
`8 (20)
`
`13 (32)
`7 (17)
`8 (19)
`13 (32)
`
`9 (22)
`
`ECOG indicates Eastern Cooperative Oncology Group; MFH, malignant
`fibrous histiocytoma; NOS, not otherwise specified.
`a Overall, 13 (32%) patients had multiple metastasis sites.
`b Other sites included right chest wall
`in rib cage, adrenal mass, and left
`lower thoracic paraspinal mass.
`
`Tolerability
`Forty-one patients completed a total of 143 cycles of treat-
`ment (median, 2; range, 1-19). Nine patients had dose
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`Figure 1. Kaplan-Meier survival curves are shown.
`
`reductions in 9 cycles for nonhematologic (6 patients) and
`hematologic (3 patients) toxicities. CCI-779 was held in
`19 patients (Day 8, 9 patients; Day 15, 9 patients; Day
`22, 18 patients). Table 3 describes the number of doses
`omitted per cycle. All patients have completed study treat-
`ment. Reasons for discontinuing treatment include: dis-
`ease progression (85%); adverse event (7%); refusal (3%),
`and surgical debulking (3%).
`
`Toxicity
`Table 4 describes the maximum severity of treatment-
`related adverse events. Forty-three percent experienced
`grade 3þ adverse events at least possibly related to treat-
`ment during all cycles of therapy. The most common tox-
`icities
`(adverse events at
`least possibly related to
`treatment) included (number of patients with grade 3-4):
`stomatitis (n ¼ 3), fatigue (n ¼ 2), and anemia (n ¼ 1).
`Two patients experienced grade 4 adverse events; these
`included hyperglycemia, hypocalcemia, and peripheral
`motor neuropathy.
`
`Translational Correlates
`Sample collection was optional for this study. Samples for
`sirolimus testing were available for 23 patients; samples
`for PBMC testing were available for 37 patients. Siroli-
`mus is the active metabolite of temsirolimus, and as
`related in Table 5, 23 patients had sirolimus levels ranging
`from 23.9 to 171 ng/mL, with a median serum level of
`51.8 ng/mL (Fig. 2). Although the limited pharmacoki-
`netic sampling limits the interpretation of the drug-level
`data, the therapeutic range for effective mTOR complex 1
`suppression in the transplant setting is trough levels of 4
`to 12 ng/mL sirolimus, and thus, all patients had drug
`
`Table 3. Number of Omitted Doses per Cycle
`
`Cycle
`
`No.
`
`Omits
`Day 8
`
`Omits
`Day 15
`
`Omits
`Day 22
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`
`41
`36
`17
`13
`7
`6
`5
`4
`3
`
`2
`2
`2
`1
`1
`0
`0
`0
`0
`
`4
`1
`3
`1
`0
`0
`0
`0
`0
`
`6
`4
`5
`1
`1
`0
`0
`0
`1
`
`levels above this range 24 hours after the first infusion of
`CCI-779. Inhibition of mTOR complex 1 signaling was
`assessed in PBMC samples by comparing phosphoryla-
`tion levels of ribosomal protein S6 in pretreatment and
`post-treatment PBMC. Pretreatment and post-treatment
`blood samples were available from 32 of 37 patients and
`were processed in this assay. Of these 32, results from 10
`patients were inconclusive (no P-S6 and/or total S6 signal
`for at least 1 sample), 1 patient’s samples were insensitive
`to the rapamycin spike, and 1 patient had equivocal
`results. Of the remaining 20 interpretable paired patient
`samples, 16 (80%) of 20 patients had robust suppression
`of S6 phosphorylation exceeding a 75% reduction in
`PBMC P-S6 signal. Thus, potentially therapeutic drug
`levels were achieved in all patients, and mTOR signaling
`in PBMC was effectively suppressed in approximately 2=3
`of patients. Both sirolimus and PBMC samples were avail-
`able for 18 patients. Patients experiencing robust suppres-
`sion of S6 phosphorylation (median, 50.6; range, 23.9-
`171) did not have significantly different sirolimus values
`from those who did not (median, 62.9; range, 41.5-76.4;
`Wilcoxon rank sum test P ¼ .71). In addition, the patient
`having a 17-month duration of response demonstrated P-
`S6 inhibition, showing a 75% drop at 24 hours. The other
`patient having a 3-month response showed only a 36%
`drop at 24 hours (ie, no P-S6 inhibition).
`
`DISCUSSION
`This phase 2 study of CCI-779 demonstrated possible ac-
`tivity in fibrosarcoma and leiomyosarcoma, but showed
`no activity in the other histologies of STS treated in our
`study. grade 3þ toxicities related to therapy occurred in
`43% of patients. The most common grade 3þ symptom
`possibly related to therapy was stomatitis, which occurred
`in 3 patients, followed by fatigue, nausea, vomiting, and
`dyspnea, which each occurred in 2 patients. This toxicity
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`Table 4. Maximum Severity of Adverse Eventsa for All Patients (N ¼ 40)
`
`Body System
`
`Toxicityb
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Grade 3-4
`
`Temsirolimus for STS/Okuno et al
`
`Constitutional symptoms
`Dermatology/skin
`Gastrointestinal
`
`Hematology
`
`Hepatic
`
`Metabolic/laboratory
`
`Neurology
`
`Pulmonary
`
`Renal/genitourinary
`
`Fatigue
`Acne
`Stomatitis
`Anorexia
`Diarrhea
`Nausea
`Vomiting
`Taste alteration
`Anemia
`Thrombocytopenia
`Leukopenia
`Neutropenia
`ALT
`AST
`Hypoalbuminemia
`Bilirubin
`Hypertriglyceridemia
`Hypercholesterolemia
`Hyperglycemia
`Bicarbonate
`Alkaline phosphatase
`Hypocalcemia
`Hypokalemia
`Hypophosphatemia
`Hyperkalemia
`Hyponatremia
`Neurosensory
`Neuromotor
`Cough
`Dyspnea
`Creatinine
`
`15 (38%)
`18 (45%)
`19 (48%)
`13 (33%)
`11 (28%)
`6 (15%)
`4 (10%)
`5 (13%)
`15 (38%)
`17 (43%)
`8 (20%)
`0
`13 (33%)
`14 (35%)
`7 (18%)
`4 (10%)
`13 (33%)
`13 (33%)
`10 (25%)
`12 (30%)
`10 (25%)
`9 (23%)
`4 (10%)
`2 (5%)
`4 (10%)
`4 (10%)
`4 (10%)
`0
`10 (25%)
`3 (8%)
`5 (13%)
`
`9 (23%)
`3 (8%)
`5 (13%)
`2 (5%)
`5 (13%)
`3 (8%)
`0
`0
`5 (13%)
`1 (3%)
`5 (13%)
`5 (13%)
`5 (13%)
`2 (5%)
`2 (5%)
`0
`4 (10%)
`3 (8%)
`3 (8%)
`1 (3%)
`1 (3%)
`0
`0
`2 (5%)
`0
`0
`0
`0
`1 (3%)
`2 (5%)
`0
`
`ALT indicates alanine aminotransferase; AST, aspartate aminotransferase.
`a These have an attribution of possible, probable, or definite.
`b National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
`
`2 (5%)
`0
`3 (8%)
`1 (3%)
`1 (3%)
`2 (5%)
`2 (5%)
`0
`1 (3%)
`0
`1 (3%)
`2 (5%)
`2 (5%)
`2 (5%)
`0
`0
`0
`0
`1 (3%)
`0
`0
`0
`2 (5%)
`1 (3%)
`0
`0
`0
`0
`0
`2 (5%)
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`1 (3%)
`0
`0
`1 (3%)
`0
`0
`0
`0
`0
`1 (3%)
`0
`0
`0
`
`2 (5%)
`0
`3 (8%)
`1 (3%)
`1 (3%)
`2 (5%)
`2 (5%)
`0
`1 (3%)
`0
`1 (3%)
`2 (5%)
`2 (5%)
`2 (5%)
`0
`0
`0
`0
`2 (5%)
`0
`0
`1 (3%)
`2 (5%)
`1 (3%)
`0
`0
`0
`1 (3%)
`0
`2 (5%)
`0
`
`Table 5. Translational Results
`
`Correlative
`
`PBMC, inhibited
`No. of samples
`
`Sirolimus, therapeutic levels
`No. of samples
`Median (range)
`
`Frequency/Estimate
`
`16 (73%)
`
`22
`
`23 (100%)
`
`23
`51.8 (23.9-171)
`
`PBMC indicates peripheral blood mononuclear cells.
`
`is similar to that found in studies using CCI-779 in other
`patient populations.15–18
`STS are a rare heterogenous group of cancers, each
`with its own natural history and response to chemother-
`apy. In the past several years, systemic treatment for STS
`has been tailored more to the histological subtype of sar-
`coma
`rather
`than broad-based chemotherapy. For
`instance, histology-specific options are available for GIST
`with imatinib and sunitinib2,3; for uterine leiomyosar-
`coma with docetaxel and gemcitabine4 as well as dacarba-
`
`Figure 2. Sirolimus values are shown by patient.
`
`regimens19,20;
`angiosarcoma with
`for
`zine-based
`taxanes21; and for myxoid round cell liposarcoma with
`trabectedin.22–24 Despite these histology-specific options,
`the vast majority of the sarcoma subtypes do not have
`effective specific therapies, and broad-based treatment
`
`Cancer
`
`August 1, 2011
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`
`Original Article
`
`with single-agent doxorubicin or combination with ifosfa-
`mide is still the standard chemotherapy option.
`mTOR inhibition is an attractive target for cancer
`and especially for STS, as many of the signal transduction
`networks in STS are affected by mTOR. In our study, we
`tested CCI-779 in a broad variety of STS in the first-line
`metastatic setting. We chose to use standard confirmed
`response rate by RECIST as our primary endpoint. Other
`endpoints such Choi criteria25 and progression-free sur-
`vival26 were just being developed during the inception of
`this trial. Moreover, Choi criteria were developed for
`GIST and have not been validated in all STS.25 We also
`performed ancillary testing to confirm that we were
`obtaining inhibition of mTOR signaling.
`Although CCI-779 was overall well tolerated, we
`only had 2 (5%) confirmed responses, with a response du-
`ration of 3 and 17 months. The median TTP was short at
`2 months, and the median OS was 7.6 months. Inhibition
`of pS6 was achieved in 80% of the cases, and therapeutic
`levels of sirolimus were seen all cases tested. The relation-
`ship between TTP with the inhibition of pS6 and siroli-
`mus was explored; results were not significant. According
`to the European Organization for Research and Treat-
`ment of Cancer, progression-free rates for first-line ther-
`apy at 6 months of 30% to 56% would suggest an active
`compound. Our 6-month progression-free rate of 13%
`would suggest that CCI-779 is not an active agent.
`Our patient population would be considered a standard
`STS cohort. They had a good ECOG PS (85% with a PS of
`0 or 1), had mainly lung metastasis (72%), had high-grade
`STS (80%), had common histologies of malignant fibrous
`histiocytoma (pleomorphic sarcoma), liposarcoma, leiomyo-
`sarcoma, and sarcoma not otherwise specified along with
`some less common histologies, and received the planned tar-
`geted dose of therapy (CCI-779 >80% of the time).
`The use of CCI-779 in the first-line setting is not jus-
`tified based on this study. However, further study in fibro-
`sarcoma
`and leiomyosarcoma histologies
`could be
`considered, given the PRs observed in our study. It is
`unknown what role the other mTOR inhibitors have in
`STS or what role the mTOR inhibitors have in maintaining
`response rates, and results from ongoing studies are awaited.
`
`CONFLICT OF INTEREST DISCLOSURES
`Supported by N01-CM62205 and CA15083.
`
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