Eur J Cmccr C/h Od, Vol. 25, No 3, pp. 563-564, 1989.
`Printed in Great Britain
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`
`Short Communication
`
`4’-Epidoxorubicin
`II Study of High-dose
`Phase
`the Treatment
`of Advanced Gastrointestinal
`
`in
`Cancer
`
`FALKSON
`and GEOFFREY
`DANIEL A. VOROBIOF
`Department of Medical Oncology, Universily of Pretoria, Private Bag ‘Y169, Pretoria, 0001, Republic of South Africa
`
`rec-
`the
`at
`tolerated
`4’-EPIDOXORUBICIN
`is well
`ommended
`dose of 60-90 mg/m* 3 weekly. The
`maximal
`tolerated
`dose
`(MTD)
`of 4’-epidoxoru-
`bicin
`in untreated
`patients
`is, however,
`150-165
`mg/m*
`i.v. every 3 weeks
`[l-8].
`from 10 to
`4’-Epidoxorubicin,
`at doses ranging
`an overall
`3 weeks,
`gives
`105 mg/m*
`every
`response
`rate of 8%
`in patients with colon cancer
`and of 25%
`in previously
`untreated
`patients with
`rectosigmoid
`carcinoma
`[9]. 4’-Epidoxorubicin,
`at
`doses
`ranging
`from 75 to 90 mg/m*
`i.v. every 3
`weeks, gives a response
`rate of 18-26%
`in patients
`with advanced
`stomach
`cancer
`[lo].
`to evaluate
`This present
`study was undertaken
`the efficacy
`and
`toxicity
`of 4’-epidoxorubin
`150
`3 weekly
`in patients
`with
`advanced
`mg/m*,
`stomach
`and colorectal
`cancer.
`cancer
`colorectal
`Sixteen patients with advanced
`cancer
`stomach
`and
`six patients with advanced
`were entered on study. There were eight males and
`14 females with a median
`age of 54.5 years
`(range,
`20-70).
`Performance
`status
`(PS)
`[ 1 l] was 0 in
`three,
`1 in 11, 2 in seven and 3 in one patient.
`Five had one metastatic
`site, and 17 patients
`had
`two or more metastatic
`sites. Sites of metastases
`[ 151, peritoneum
`[ 131 and
`lung
`[5]
`were
`the liver
`(see Table
`1).
`chemo-
`no prior
`included
`Eligibility
`criteria
`therapy, PS < 3, measurable
`and/or
`evaluable
`dis-
`ease, adequate
`hematologic
`reserve
`(WBC 2 4000/
`
`1988.
`29 September
`Accepted
`and reprints: GeofTrey Falkson, MD,
`for correspondence
`Address
`Department Medical Oncology, University
`of Pretoria, Private
`Bag X169, Pretoria, 0001, Republic of South Africa.
`Supported in part by a grant
`from the National Cancer Associ-
`ation of South Africa.
`
`functions
`hepatic
`3 100,000/mm”),
`mm:‘, platelets
`(normal bilirubin,
`SGOT and alkaline phosphatase
`s 2 times
`the upper
`limit of normal)
`and
`renal
`functions.
`Patients with cardiac disease were not
`eligible.
`in 200 ml of nor-
`150 mg/m*
`4’-Epidoxorubicin
`mal
`saline was administered
`as an
`intravenous
`infusion
`in 30 min 3 weekly. The dose was modi-
`fied for toxicity. ECOG
`toxicity and response
`cri-
`teria were used
`[ 111.
`tox-
`for either
`Three patients were unevaluable
`icity or response:
`one patient with rectum
`cancer
`
`Table 1. Patient characteristics
`
`Number ofpatients
`With stomach Ca
`With colon Ca
`With rectal Ca
`
`Sex
`Male
`Female
`
`Median qe
`
`PS
`0
`1
`2
`3
`
`Number of metastatic sites
`1
`32
`
`Site of meta.5ta.w
`Liver
`Abdominal
`Lung
`Pelvic cavity
`Bone
`
`cavity
`
`563
`
`22
`6
`10
`6
`
`8
`14
`
`54.5
`
`(20-70)
`
`3
`11
`7
`1
`
`5
`17
`
`15
`13
`5
`3
`1
`
`NPC02237298
`
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`
`

`
`564
`
`Short Communication
`
`disease died 2
`with a PS of 3 and very advanced
`weeks after receiving
`one dose of treatment.
`Two
`patients with colon cancer
`refused
`further
`treat-
`ment after the first dose of 4’-epidoxorubicin.
`Four
`patients
`received
`one dose,
`.6 two doses, 5 three
`doses, 3 four doses and 1 patient
`received 5 doses.
`The median
`total dose administered
`to
`the 19
`evaluable
`patients
`was
`300 mg/m2
`(range,
`150-682 mg/m2).
`(see
`Two patients developed Grade 4 leukopenia
`Table
`2). Ten of the 18 patients who
`received
`more
`than
`two doses of 4’-epidoxorubicin
`and/or
`who were on study more
`than 3 months had base-
`line and follow-up gated radionuclide
`scanning
`for
`the assessment
`of the left ventricular
`cjcction
`func-
`tion
`(LVEF).
`Four of these 10 patients
`had an
`absolute LVEF decrease
`of 11, 12, 30 and 39%
`at 4’-epidoxorubicin
`doses of 300, 454, 545 and
`600 mg/m*
`respectively.
`(see
`No objective
`response was documented
`and
`Table
`3). Eleven
`patients
`(eight
`colorectal
`three
`stomach
`cancer)
`had disease
`stabilization
`with a median
`duration
`of 6 weeks
`(range, 4-24
`weeks). The median
`survival
`time of patients with
`
`Table 2. Toxicity: 150 mg/m’ 4’-epidoxorubicin
`
`ECOG grade*
`
`1
`
`7
`5
`0
`
`7
`2
`6
`5
`0
`5
`
`2
`
`4
`8
`1
`
`10
`1
`3
`1
`2
`13
`
`3
`
`2
`5
`0
`
`1
`0
`2
`0
`0
`0
`
`4
`
`0
`2
`0
`
`0
`0
`0
`0
`0
`0
`
`Hematologic toxicity
`Anemia
`Leukopenia
`Thombocytopenia
`
`Non-hematologic toxici(v
`Nausea and vomiting
`Diarrhea
`Stomatitis
`Anorexia
`Infection
`Alopecia
`
`*See Ref. [l l]
`colorectal
`cancer was 19 weeks and of patients
`with stomach
`cancer
`10 weeks.
`further dose
`As this dose
`is close
`to the MTD
`escalation
`is not practical
`and
`it is improbable
`that
`this anthracycline
`analog will be of significant
`value
`for patients with
`advanced
`stomach
`and
`colorectal
`cancers.
`
`Table 3. Therapeutic response to 150 mglm’
`
`4’-epidoxorubicin
`
`Disease
`stabilization
`
`Progressive
`disease
`
`Unevaluable
`
`Total
`
`Colon Ca
`Rectum Ca
`Stomach Ca
`
`Total
`
`5
`3
`3
`
`11
`
`3
`2
`3
`
`8
`
`2
`1
`
`3
`
`10
`6
`6
`
`22
`
`1.
`
`2.
`
`3.
`
`8.
`
`9.
`
`10.
`
`11.
`
`trial with epirubicin
`
`in
`
`REFERENCES
`JA, Murillo E, Duque A et al. Phase
`II
`Nogueira
`Moreno
`measurable
`advanced
`rectal cancer. Proc ECCO
`1987, 4, 42.
`Blackstein ME, Meharchand
`J, Pater J, Wilson K, Holloway C, Lassus M. High dose
`epirubicin
`in metastatic
`breast
`cancer. A phase
`I study
`in CMF
`failures. PYOC ECCO
`1987, 4, 133.
`Simonsen E, Bengtsson C, Hogberg T et al. A phase
`II study of the effect of 4’-epi-
`doxorubicin
`administered
`in high dose 150 mg
`in 24 hours
`intravenous
`infusion
`in
`advanced
`ovarian
`carcinoma.
`1987, 4, 226.
`Proc ECCO
`Blackstein M, Wilson K, Meharchand
`J, Shepherd
`F, Fontaine B, Lassus M. Phase
`study of epirubicin
`in metastatic
`breast cancer. Proc ASCO 1988, 7, 23.
`untreated
`Walde D, Case A, Lassus M, Betello P. High dose epirubicin
`in previously
`I study. Proc ASCO 1988, 7, 73.
`patients with advanced metastatic
`cancer. A phase
`Holdener EE, Jungi WJ, Fiebig HH et al. Phase
`I study of high dose epirubicin
`in non-
`small cell lung cancer. Proc ASCO 1988, 7, 208.
`4’-
`S. High-dose
`Kolaric K, Eckhardt S, Kaplan E, Intini C, Schoket Z, Kerpel-Fronius
`epi-doxorubicin
`(4-EpiDx)
`in untreated
`patients with small cell lung cancer. Preliminary
`trial. Proc ASCO 1988, 7, 212.
`results of phase
`II
`Banham SW, Henderson AF, Milroy R, Monie RD. Phase II study of high dose epirubicin
`in poor prognosis
`small cell lung cancer
`(SCLC). Proc ASCO 1988, 7, 2 17.
`Falkson G, Vorobiof DA. Epirubicin
`in colorectal
`cancer.
`In: Bonadonna G, ed. Advances
`in Anthracycline Chemotherapy: Epirubicin. Milano, Masson
`Italia Editori,
`1984, 10.+109.
`Kolaric K. Studies with epirubicin
`in gastric cancer.
`In: Bonadonna G, ed. Advances
`in
`Anthracycline Chemotherapy:
`Epirubicin. Milano, Masson
`Italia
`Editori,
`1984,
`111-118.
`Oken MM, Creech RH, Tormey DC et al. Toxicity
`and
`response
`criteria
`of the Eastern
`Am J Clin Oncol 1982, 5, 649-655.
`Cooperative
`Oncology
`Group.
`
`I
`
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