1543
`
`A Phase II Study of High-Dose Paclitaxel in Patients
`with Advanced Neuroendocrine Tumors
`
`Stephen M. Ansell, M.D., Ph.D.1
`Henry C. Pitot, M.D.1
`Patrick A. Burch, M.D.1
`Larry K. Kvols, M.D.2
`Michelle R. Mahoney, M.S.3
`Joseph Rubin, M.D.1
`
`1 Division of Medical Oncology, Mayo Clinic, Roch-
`ester, Minnesota.
`
`2 GI Tumor Program, H. Lee Moffitt Cancer Center,
`Tampa, Florida.
`
`3 Division of Statistics, Mayo Clinic, Rochester,
`Minnesota.
`
`Supported in part by Grant RR00585.
`
`Address for reprints: Joseph Rubin, M.D., Division
`of Medical Oncology, Mayo Clinic, 200 First Street
`SW, Rochester, MN 55905; Fax: (507) 284-1803;
`E-mail: rubin.joseph@mayo.edu
`
`Received July 21, 2000; accepted December 27,
`2000.
`
`© 2001 American Cancer Society
`
`BACKGROUND. New agents with antitumor activity in patients with neuroendocrine
`tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with
`metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic.
`Granulocyte– colony-stimulating factor (GCSF) also was administered to amelio-
`rate neutropenia.
`METHODS. Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors,
`and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel
`given as a 24-hour continuous infusion at a dose of 250 mg/m2 every 3 weeks plus
`GCSF at a dose of 5 mg/kg/day subcutaneously, beginning 24 hours after the
`completion of the paclitaxel dose and continuing until the absolute neutrophil
`count was . 10,000/mL.
`RESULTS. All 24 patients were evaluable for analysis. The overall response rate was
`8% (95% confidence interval [95% CI], 0 – 0.11). At last follow-up all patients except
`1 had developed disease progression, with an estimated median time to disease
`progression of 3.2 months (95% CI, 1.6 – 6.0 months). The estimated median sur-
`vival was 1.5 years (95% CI, 1.0 –1.8 years). Hematologic toxicity was significant
`with 12 of 24 patients developing Grade 4 (according to the National Cancer
`Institute Common Toxicity Criteria scale) neutropenia; however, there were no
`septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12
`patients and the duration of these events ranged from 2–5 days. More common
`nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients),
`nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients).
`CONCLUSIONS. Given the lack of antitumor activity of paclitaxel and the significant
`hematologic toxicity observed despite the use of GCSF support in the current study
`cohort of patients with neuroendocrine tumors, further studies of this combination
`in this particular patient population are not recommended. Cancer 2001;91:
`1543– 8. © 2001 American Cancer Society.
`
`KEYWORDS: paclitaxel, neuroendocrine tumors, carcinoid tumor, islet cell tumor.
`
`Gastrointestinal neuroendocrine tumors are rare human malignan-
`
`cies and may present as a constellation of nonspecific symptoms
`mimicking more common diseases. These tumors can be divided
`between the gastrointestinal submucosal carcinoid tumors and the
`endocrine islet cell tumors of the pancreas. A smaller subset of tumors
`with anaplastic histology are classified as anaplastic carcinomas. They
`are derived from the enterochromaffin or Kulchitsky cells1 and are
`classified histologically as APUDomas (amine precursor uptake and
`decarboxylation) but are indistinguishable from one another by light
`microscopy. They may be found anywhere in the human body but
`traditionally are described as originating from the foregut, midgut, or
`hindgut.2 Neuroendocrine tumors commonly present with dissemi-
`nated disease. Although the disease may have an indolent course in
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`
`many patients, the overall survival of patients corre-
`lates significantly with the stage of disease. Patients
`with unresectable abdominal metastases and hepatic
`metastases fare poorly, with median survivals of 5
`years and 3 years, respectively.
`Paclitaxel is derived from the bark of the Pacific
`yew, Taxus Brevifolia, and is one of a group of com-
`pounds with a unique mechanism of cytotoxicity as a
`promoter of microtubular assembly and stabiliza-
`tion.3,4 Paclitaxel binds to microtubules and causes
`cells to form abundant arrays of disorganized and
`dysfunctional microtubules. Treated cells have a rep-
`lication block in the G2- and M-phases of the cell
`course. Paclitaxel has shown activity against ovarian
`carcinoma and breast carcinoma3,5 and also has dem-
`onstrated effective single agent activity against non-
`small cell lung carcinoma.6,7 In human trials, the pri-
`mary dose-limiting toxicity associated with paclitaxel
`has been neutropenia. The administration of granulo-
`cyte– colony-stimulating factor (GCSF) after intensive
`chemotherapy has been shown to reduce the duration
`of neutropenia and was administered in the current
`trial in an effort to minimize the need for dose reduc-
`tions secondary to myelosuppression.
`The goal of the current study was to determine the
`therapeutic activity and toxicity of paclitaxel given
`with GCSF support in patients with advanced neu-
`roendocrine carcinoma.
`
`MATERIALS AND METHODS
`Eligibility/Evaluation
`Patients with histologic or cytologic proof of a neu-
`roendocrine tumor who were seen at the Mayo Clinic
`were eligible for the current study. All patients had
`radiologically documented evidence of extensive stage
`disease. All patients had measurable or evaluable dis-
`ease and had an Eastern Cooperative Oncology Group
`(ECOG) performance score of 0, 1, or 2. Preenrollment
`staging tests included a history and physical examina-
`tion; complete blood count; standard blood chemis-
`tries; serum levels of either insulin, gastrin, glucagon,
`or adrenocorticotropic hormone (ACTH), or vasoac-
`tive intestinal peptide or 24-hour urine 5-hydroxyin-
`doleacetic acid (5-HIAA)
`levels; chest radiograph;
`computed tomography (CT) scan or magnetic reso-
`nance imaging of the abdomen; and an electrocardio-
`gram.
`Contraindications to protocol entry included a
`leukocyte count , 4000/mL, a platelet
`count
`, 130,000/mL, a hemoglobin level , 10 g/dL, liver
`function tests . 3 times the institutional upper limit of
`normal, or a total bilirubin greater than the institu-
`tional upper limit of normal. Other contraindications
`to protocol entry included more than two prior che-
`
`motherapy regimens, radiation therapy to the axial
`skeleton or pelvis, pregnant or nursing women, and
`patients with significant cardiac disease. The cardiac
`exclusions included a history of angina or congestive
`heart failure, cardiac arrhythmias, myocardial infarc-
`tion occurring within the previous 6 months, or elec-
`trocardiographic evidence of a right or left bundle
`branch block. Patients with a prior history of cancer
`other than skin cancer, superficial bladder carcinoma,
`American Joint Committee on Cancer (AJCC) Stage I
`colon or rectal carcinoma, or in situ cervical carci-
`noma were excluded unless they had a 5-year disease-
`free interval without treatment. Patients with a history
`of allergic reactions to cremophor-containing or Esch-
`erichia coli-derived drugs were excluded. Informed
`consent was obtained from all patients.
`Tumor responses were classified as a complete
`response (CR) or a partial response (PR). A measurable
`lesion was defined as a lesion apparent on physical
`examination, CT scan, or radiography with clearly
`measurable perpendicular dimensions. CR was de-
`fined as the total disappearance of all tumor. PR was
`defined as a reduction of $ 50% in the sum of the
`products of the longest perpendicular dimensions of
`the indicator lesion(s). All patients were required to
`have measurable tumor or definite hormonal abnor-
`malities that would serve as indicators of response to
`therapy. Elevated serum levels of either insulin, gas-
`trin, glucagon, ACTH, or vasoactive intestinal peptide
`or elevated 24-hour urine 5-HIAA levels were required
`for entry onto the study if no other measurable lesions
`were found.
`
`Treatment
`All patients received pretreatment with dexametha-
`sone, 20 mg orally, at 12 hours and 6 hours before the
`initiation of paclitaxel. In addition, patients received
`diphenhydramine, 50 mg intravenously, and cimeti-
`dine, 300 mg intravenously, 30 minutes before the
`administration of paclitaxel. The administration of
`paclitaxel took place over 24 hours by intravenous
`infusion at a dose of 250 mg/m2 in normal saline or 5%
`dextrose. Treatment was administered in the hospital
`setting or General Clinical Research Center and re-
`peated every 21 days. GCSF was given subcutaneously
`at a dose of 5 mg/kg/day until the absolute neutrophil
`count (ANC) was . 10,000/L after the nadir. GCSF was
`initiated 24 hours after the completion treatment with
`paclitaxel. Patients who achieved a PR or stable dis-
`ease continued treatment until disease progression,
`unless they experienced undue toxicity. The dose of
`paclitaxel was decreased by 30% in patients with an
`ANC , 500/mL for 5 days or an ANC , 500/mL with
`fever/sepsis or a platelet count , 25,000 with associ-
`
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`TABLE 1
`Design Considerations
`
`Parameter
`
`Carcinoid
`
`Islet cell and anaplastica
`
`Subgroup
`
`Null hypothesis
`Alternative hypothesis
`Power, significance level
`Stage I accrual
`Responses needed in Stage
`I to proceed to Stage II
`Stage II accrual
`Responses needed in Stage
`I and Stage II combined
`to declare activity
`
`0.20
`0.40
`(0.90, 0.09)
`17
`
`0.20
`0.50
`(0.89, 0.10)
`9
`
`4
`20
`
`11
`
`3
`9
`
`6
`
`a Identical designs were used for these two subgroups.
`
`ated bleeding. Treatment was discontinued in any pa-
`tients experiencing $ Grade 3 cardiac arrhythmia, al-
`lergic reaction, and/or neuropathy (grades of toxicity
`based on the National Cancer Institute Common Tox-
`icity Criteria scale).
`If
`the leukocyte count was
`, 4000/mL or the platelet count was , 100,000/mL at
`the time of retreatment, treatment then was delayed
`until the counts recovered. Similarly, any patient with
`Grade 3/4 mucositis/stomatitis at the time of retreat-
`ment had their treatment delayed until this toxicity
`resolved and the dose was decreased by 30% for sub-
`sequent courses.
`
`Evaluation
`Patients were evaluated at study entry and after every
`course of therapy by physical examination, chest ra-
`diography, complete blood count, and a chemistry
`profile. If the indicator lesion was measurable or as-
`sessable by CT scan only, the scan then was repeated
`with every other course of therapy. The incidence of
`toxicity was monitored at each evaluation and toxici-
`ties were evaluated according to the National Cancer
`Institute Common Toxicity Criteria scale. In particu-
`lar, patients were monitored for any signs or symp-
`toms of cardiac toxicity.
`
`Study Design
`Patients were classified as having carcinoid, islet cell,
`or anaplastic carcinoma. Due to the anticipated dif-
`ference in the responses of these patient populations
`to the chemotherapy regimens, we designed the cur-
`rent study as three sub-Phase II studies with the same
`primary endpoint of therapeutic activity (i.e., response
`rate). The study was not designed nor powered for
`direct comparisons between the three subgroups of
`patients. Table 1 provides a summary of the two-stage
`
`Paclitaxel in Neuroendocrine Tumors/Ansell et al.
`
`1545
`
`Simon8 designs and power considerations for the
`three substudies. A patient was classified as having a
`confirmed tumor response if a CR or PR was sustained
`for at least 2 consecutive evaluations that were at least
`3 weeks apart.
`All patients were followed for disease progression,
`duration of response, and survival. Patients who died
`(or were lost to follow-up) without disease progression
`were considered to have disease progression at the
`date of death (or last contact) unless documentation
`proved otherwise, in which case they would be con-
`sidered as having no disease progression at the date of
`last tumor evaluation. The duration of response was
`calculated from the earliest date of tumor response
`(i.e., CR or PR) to the date of disease progression. Time
`to progression was calculated from the date of study
`entry to the date of disease progression. Time to death
`(i.e., survival) was calculated from the date of study
`entry to the date of death or last follow-up contact.
`
`Statistical Analysis
`Summary statistics (e.g., mean, median, quartiles) and
`Wilcoxon tests were used to describe and compare the
`distributions of continuous variables (e.g., age, leuko-
`cyte count nadirs). Hematologic toxicity was summa-
`rized as a lowest value (i.e., nadir) per patient and
`course. Nonhematologic toxicity was reported as the
`maximum grade (i.e., severity) for a given type of
`event. The chi-square and Fisher exact tests were used
`to compare the frequency distributions of categoric
`data. Exact binomial confidence intervals were used
`for estimating the confirmed response rate. Kaplan–
`Meier9 methodology was used to estimate the distri-
`butions of duration of response, time to progression,
`and survival.
`
`RESULTS
`This study accrued a total of 24 patients, all of whom
`were evaluable for response and toxicity. A tabulation
`of patient characteristics at study entry is shown in
`Table 2. Only one patient with an anaplastic tumor
`was accrued and this patient’s data were combined
`with those of the group of patients with islet cell
`carcinoma. All patients had advanced disease with
`88%(21 of 24 patients) presenting with liver metasta-
`ses and 29% (7 of 24 patients) presenting with lung
`metastases. The median age of the patients was 55
`years; however, the patients in the carcinoid tumor
`group were significantly older than those in the islet
`cell/anaplastic tumor group (P 5 0.0025).
`Patients received a total of 83 courses of paclitaxel
`plus GCSF (median, 3 courses; range, 1–7 courses).
`One patient did not receive the third course of GCSF
`because of a skin rash. The primary hematologic tox-
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`TABLE 2
`Patient Characteristics
`
`Factor
`
`Carcinoid
`
`Subgroup
`
`Islet cell and
`anaplastic
`
`No. of patients
`Age (yrs)
`Median
`Range
`Gender (M/F)
`ECOG PS
`0
`1
`2
`Prior doxorubicin-
`containing therapy
`Metastatic disease site
`Bone
`Liver
`Lung
`Two sites
`Three sites
`Previous treatment
`
`14
`
`60.5
`41–71
`8/6
`
`1
`12
`1
`
`2
`
`1
`8
`1
`3
`1
`5
`
`10
`
`47.5
`26–60
`3/7
`
`2
`7
`1
`
`6
`
`0
`5
`0
`4
`1
`7
`
`M: male; F: female; ECOG PS: Eastern Cooperative Oncology Group performance score.
`
`TABLE 3
`Toxicitya: Maximum Severity per Patient (N 5 24)
`
`Type
`
`Allergy
`Alopecia
`Anorexia
`Diarrhea
`Infection
`Myalgia
`Nausea
`Neurosensory
`Stomatitis
`Emesis
`Skin
`Neuromotor
`Arthralgia
`Leukopenia
`Neutropeniab
`Thrombocytopenia
`
`1/2
`
`0
`22 (92)
`13 (54)
`11 (46)
`0
`13 (54)
`12 (50)
`13 (54)
`7 (29)
`9 (38)
`5 (21)
`5 (21)
`17 (71)
`7 (29)
`—
`15 (63)
`
`Grade (%)
`
`3
`
`1 (4)
`NA
`2 (8)
`0
`1 (4)
`2 (8)
`3 (13)
`1 (4)
`1 (4)
`0
`1 (4)
`0
`4 (17)
`8 (33)
`—
`1 (4)
`
`Overall
`
`24
`
`55
`26–71
`11/13
`
`3
`19
`2
`
`8
`
`1
`13
`1
`7
`2
`12
`
`4
`
`1 (4)
`NA
`0
`2 (8)
`0
`0
`0
`0
`1 (4)
`1 (4)
`0
`0
`0
`3 (13)
`12 (50)
`0
`
`NA: not applicable.
`a Toxicity was determined according to National Cancer Institute Common Toxicity Criteria, Version 2.
`b Data were collected if the absolute neutrophil count was , 500/mL.
`
`icity was neutropenia (Table 3). The ANC values and
`duration were recorded for analysis purposes if they
`were , 500/mL. Patients with carcinoid tumors expe-
`rienced more myelosuppression; however, the differ-
`ence in the average hematologic nadir between the
`
`two groups was not statistically significant. Approxi-
`mately 61% of patients (14 of 23 patients) experienced
`either at least Grade 3 leukopenia or Grade 4 neutro-
`penia (ANC , 500/mL). Neutropenia was reported to
`have occurred 17 times in 12 patients and the duration
`of these events ranged from 2–5 days. Nine of the 12
`events reported in the carcinoid tumor group (75%)
`involved Grade 3 leukopenia. Leukopenia and neutro-
`penia occurred together in three of five patients in the
`islet cell/anaplastic group. Four cases of Grade 3/4
`leukopenia occurred in the absence of Grade 4 neu-
`tropenia. One patient with a carcinoid tumor experi-
`enced Grade 4 neutropenia over three treatment
`courses in conjunction with stomatitis, arthralgia,
`neurosensory toxicity, and anorexia. This patient devel-
`oped disease progression within 3 courses and died 3
`months later. Another carcinoid tumor patient experi-
`enced Grade 4 neutropenia in four of six courses. Severe
`thrombocytopenia was unremarkable; only 1 patient ex-
`perienced an overall low platelet count of 48,000/mL.
`Nonhematologic toxicity (Table 3) primarily in-
`cluded diarrhea, anorexia, allergic reactions, nausea,
`and arthralgia. Toxicity patterns were similar between
`the two groups with the exception of neuropathy and
`diarrhea. Fifty percent of the patients in the islet cell/
`anaplastic tumor group (5 of 10 patients) experienced
`Grade 1/2 neurologic toxicity. Approximately 64% of
`the patients with carcinoid tumors (9 of 14 patients)
`experienced neurotoxicity, 1 of which was Grade 3.
`Seventy percent of patients with islet cell/anaplastic
`tumors (7 of 10 patients) experienced Grade 1/2 diar-
`rhea versus 36% of patients in the carcinoid tumor
`group (5 of 14 patients).
`All 24 patients were considered to be evaluable for
`confirmed tumor response. Only two PRs were ob-
`served that failed to meet the criteria to proceed to the
`second stage of accrual for the study design. The over-
`all response rate was 8% (95% confidence interval
`[95% CI], 0 –11%). One patient with a carcinoid tumor
`experienced a PR, albeit nonsustained (i.e., lasting one
`course). Similarly, one patient with an islet cell tumor
`was classified as having a “biochemical” PR (i.e., a
`. 50% decrease in 5HIAA, but stable CT scans and liver
`examinations over 2 of 7 treatment courses). A majority
`of patients (83%) discontinued treatment due to disease
`progression and 3 patients discontinued treatment due
`to toxicity or patient refusal to continue.
`At last follow-up, 23 patients had developed dis-
`ease progression. Two patients were alive off-study
`and 22 patients (92%) had died. The median survival
`and the median time to disease progression was 1.5
`years (95% CI, 1.0 –1.8 years) and 3.2 months (95% CI,
`1.6 – 6.0 months), respectively (Figs. 1 and 2). Esti-
`mates of the median survival and time to disease
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`1547
`
`but it generally is reserved for those patients with
`severe symptomatology or those who develop poor
`prognostic signs.10,11 Single cytotoxic agents used in
`this disease are associated with variable response
`rates. To our knowledge, doxorubicin, 5-fluorouracil
`(5-FU), dacarbazine, and interferon-a have produced
`the best objective response rates reported to date in
`patients with advanced disease (17–21%).10 –17 Unfor-
`tunately, combination chemotherapy has not
`im-
`proved the outlook significantly for patients with ad-
`vanced carcinoid tumors, although the response rate
`has been reported to vary between 20 – 40%.13,18 –19
`The combination of streptozocin and 5-FU, used by
`ECOG12 and the Mayo Clinic,10 demonstrated a 33%
`objective response rate in patients with metastatic
`carcinoid tumors. Unfortunately, this regimen pro-
`duced substantial side effects such as nausea, emesis,
`and anorexia, which limited its prolonged application,
`and the response duration was reported to be only 7
`months. Two other trials18,19 showed a slightly better
`response rate (35– 40%) when using different combi-
`nations (5-FU, doxorubicin, cyclophosphamide, and
`streptozocin and streptozocin and doxorubicin, re-
`spectively) in patients with advanced carcinoid tu-
`mors, although no firm conclusions can be drawn
`because of the extremely small number of patients.
`Recent trials investigating new agents have been
`disappointing. Phase II trials of dacarbazine and mitox-
`antrone demonstrated minimal activity for
`these
`drugs.17,20,21 Likewise, the Italian Medical Oncology
`Group studied the combination of dacarbazine, 5-FU,
`and epirubicin and found it to have no more activity
`than any one of the single agents used alone.22 Efforts to
`biologically modulate 5-FU with the addition of inter-
`feron-a are reported to have been met with mixed suc-
`cess in three recent reports. Although the regimens had
`tolerable toxicity and produced biochemical responses,
`the objective tumor responses were , 20%.23–25 Again,
`because these response rates are similar to the response
`rates of the agents used individually and because toxicity
`was increased, we believe the use of combination che-
`motherapies cannot be recommended routinely and fur-
`ther studies of cytotoxic therapies are needed.
`However, patients with aggressive variants of carci-
`noid tumors as well as those with islet cell tumors appear
`to have higher response rates to therapy.26 –28 Moertel et
`al.27 reported 45 patients with metastatic neuroendo-
`crine tumors who were treated with etoposide and cis-
`platin. Among 27 patients with well-differentiated carci-
`noid tumors or islet cell carcinomas, only 2 objective PRs
`were observed (7%). However, among 18 patients pro-
`spectively classified as having anaplastic neuroendo-
`crine carcinomas, there were 9 PRs and 3 CRs, giving an
`overall regression rate of 67%. The median duration of
`
`FIGURE 1. Overall survival
`for patients with metastatic neuroendocrine
`tumors who were treated with paclitaxel.
`
`FIGURE 2. Time to progression in patients with metastatic neuroendocrine
`tumors who were treated with paclitaxel.
`
`progression for patients with carcinoid tumors was 1.8
`years (95% CI, 0.7–3.2 years) and 3.4 months (95% CI,
`1.3– 6.0 months), respectively. Estimates of the median
`survival and time to disease progression for patients
`with anaplastic/islet cell tumors was 1.1 years (95% CI,
`0.6 –1.6 years) and 3.2 months (95% CI, 1.5–9.5
`months), respectively. It should be noted that a formal
`comparison between the two subgroups was not sta-
`tistically appropriate because the underlying disease
`process and small sample sizes were believed to ac-
`count for any significant differences observed.
`
`DISCUSSION
`In general, gastrointestinal neuroendocrine tumors
`are not overly sensitive to cytotoxic chemotherapy.
`Chemotherapy can be used to reduce tumor burden,
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`disease regression was 8 months. In a study of patients
`with metastatic islet cell tumors,28 the combination of
`streptozocin plus doxorubicin was found to be superior
`to the combination of streptozocin plus 5-FU with re-
`gard to the rate of tumor regression (69% vs. 45%), time
`to tumor progression (20 months vs. 6.9 months), and
`survival (2.2 years vs. 1.4 years). However, this result has
`been challenged by a subsequent retrospective review
`that found only a 6% response rate in 16 patients with
`metastatic islet cell tumors.29
`Due to the limited efficacy and substantial toxicity of
`previous treatment regimens, we have assessed the effi-
`cacy and toxicity of a high-dose paclitaxel regimen com-
`bined with GCSF support to ameliorate the neutropenia
`expected to occur with such therapy. The results of the
`current study have shown that paclitaxel at this dose has
`limited antitumor efficacy in patients with carcinoid and
`islet cell tumors. There also was substantial hematologic
`toxicity with 50% of patients experiencing Grade 4 neu-
`tropenia despite the use of GCSF. Given the lack of
`antitumor activity of paclitaxel at this dose and the sig-
`nificant hematologic toxicity despite GCSF support, we
`do not recommend further studies of this combination
`in patients with neuroendocrine tumors.
`
`4.
`
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`NOVARTIS EXHIBIT 2045
`Par v. Novartis, IPR 2016-01479
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