Phase I Trial of Esorubicin (4'Deoxydoxorubicin)
`
`By Harinder S. Garewal, Aurelia Robertone, Sydney E. Salmon, Stephen E. Jones, David S. Alberts, and
`Robert Brooks
`
`A phase I study of 4'deoxydoxorubicin (esorubicin)
`was performed on an every-21-day bolus intravenous
`(IV) schedule in 36 patients with advanced cancer.
`Thirty-four patients were evaluable for toxicity analy-
`sis. Toxicity included mild nausea, occasional local
`skin reactions, and mild to moderate alopecia. Myelo-
`suppression was dose limiting. Clinically evident con-
`gestive heart failure was not observed. However, two
`patients developed premature ventricular contrac-
`tions. Overall, esorubicin was better tolerated than
`doxorubicin at equally potent doses. Although re-
`sponse analysis was not the primary objective of this
`
`phase I study, minor responses were observed
`in
`melanoma, breast cancer, lymphoma, and gastric
`cancer. On the basis of this study, a starting dose of 30
`mg/m2 IV every 21 days is recommended for good-risk
`patients with escalation to 32.5 mg/m 2 depending on
`bone marrow tolerance. For patients with poor bone
`marrow reserve, a starting dose of 25 mg/m 2 every 21
`days is recommended. Phase II trials with esorubicin
`in this dosage schedule are clearly warranted in a
`wide variety of metastatic neoplasms including a
`substantial population of patients who have not re-
`ceived prior chemotherapy.
`
`SINCE its introduction over a decade ago, the
`
`anthracycline antibiotic doxorubicin has
`proved to be one of the most effective anticancer
`agents currently in use. However, its prolonged
`use is limited by cardiac toxicity especially after
`the cumulative dose by bolus injection exceeds
`500 to 550 mg/m2. Consequently, new anthracy-
`cline analogs have been developed in an effort to
`decrease or eliminate cardiac toxicity while re-
`taining anticancer activity. Structure-activity re-
`lationship studies have shown that the C-4' posi-
`tion in the sugar moiety can be modified
`to
`provide analogs that may possess a more fa-
`vorable
`therapeutic
`index
`than doxorubicin.
`4'Deoxydoxorubicin (esorubicin) is a derivative
`of doxorubicin obtained by removal of the hy-
`droxyl group from the 4' position on the amino
`sugar (Fig 1). It was synthesized by Arcamone et
`al.' This chemical modification increases the ba-
`sicity of the compound.
`
`From the Section of Hematology and Oncology. Department
`of Internal Medicine, and the Cancer Center, University of
`Arizona College of Medicine, Tucson, Ariz.
`Submitted November 22. 1983: accepted April 27. 1984.
`Supported in part by grant no. CA-17094 from the National
`Cancer Institute and a grant from Farmitalia Carlo Erba.
`Address reprint requests to Sydney E. Salmon, MD. Universi-
`ty ofArizona College of Medicine, Department ofInternal Medi-
`cine and the Cancer Center, Section Hematology/Oncologyv,
`Arizona Health Sciences Center, Tucson. AZ 85724.
`© 1984 by American Society of Clinical Oncology.
`0732-183X/84/0209-0010$3.00/0
`
`Esorubicin is at least as active as doxorubicin
`in several murine tumor models (L1210, P388,
`gross, and solid sarcoma 180).'
`It is slightly
`less active than doxorubicin in B16 melanoma
`and early and late mammary mouse carcino-
`ma, but is more active in the colon 38 tumor. 2
`It appears to be very active against several hu-
`man colon tumor xenografts in nude mice.2.6
`In this system, its activity appears to be superior
`to both 5-fluorouracil and BCNU.7 Overall, it
`appears to have greater antitumor potency than
`doxorubicin.
`In vitro phase II studies of esorubicin, per-
`formed at the University of Arizona Cancer Cen-
`ter against a number of different human tumors
`using the human tumor stem cell assay, have also
`shown significantly increased antitumor potency
`of this drug against some tumors as compared to
`doxorubicin or daunorubicin. 8 ,9 However, sig-
`nificant in vitro antitumor activity was not ob-
`served against human colon cancer. In the stem
`cell assay, esorubicin appears to be noncross-
`resistant with doxorubicin.
`In general, toxicology studies in animals have
`shown a pattern of toxicity that is similar to pre-
`viously studied anthracycline drugs.' These in-
`clude dose-dependent weight loss, myelosup-
`pression, and gastrointestinal toxicity (vomiting,
`diarrhea and spontaneous hemorrhage). Liver
`and kidney toxicity was seen only at the highest
`doses used. Of great importance is the finding
`
`1034
`
`Journal of Clinical Oncology, Vol 2, No 9 (September) 1984
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1038-0001
`
`

`
`PHASE I TRIAL OF ESORUBICIN
`
`1035
`
`.COC H2 OH
`"OH
`
`CH3 0 0 0 H 6
`0
`CH3
`H -
`
`NH2
`R1 H2
`
`doxorubicin
`
`R1 = OH
`
`4'deoxydoxorubicin R1 = H
`Fig 1. The structure of doxorubicin and esorubicin.
`that, in comparison to doxorubicin, esorubicin
`markedly reduces or eliminates cardiac toxicity
`in all three animal models studied (ie, mouse,
`rabbit, and dog). 2' 3 The LDIO in mice was 8.5
`mg/kg and one tenth of this dose induced only
`mild toxicity in dogs. 2
`In November 1982, we initiated a phase I trial
`of esorubicin. Case accrual was completed in
`August 1983 after 36 patients had been entered
`on this study. Results of the phase I trial and a
`recommended dose schedule for phase II study
`are reported in this paper.
`
`MATERIALS AND METHODS
`Patient Selection
`All patients entered into the study had histologic proof of
`cancer and were refractory to conventional methods of treat-
`ment. All patients had an estimated life expectancy of at least
`eight weeks, a Karnofsky performance status of >50, and had
`recovered from the effects of previous chemotherapy or radio-
`therapy. Patients were required to have adequate liver function
`(total bilirubin <2 mg/dL) and adequate renal function (serum
`creatinine <1.5 mg/dL or a creatinine clearance >80 mL/min).
`Adequate bone marrow function was required, ie, a peripheral
`absolute granulocyte count >1,500/pL and a platelet count
`>100,000/pL. Patients with a previous history of congestive
`heart failure or serious arrhythmia as well as those with prior
`total dose of doxorubicin >350 mg/m 2 were excluded. One
`exception to this was a patient with a total doxorubicin dose of
`363 mg/m 2 who had a normal nuclear medicine cardiac ejection
`fraction of 62%. Patients who had received between 300 to 350
`mg/m 2 of doxorubicin were evaluated with a nuclear medicine
`cardiac ejection fraction that was required to be normal prior to
`initiation of the drug.
`
`Parameters Evaluated During Study
`Pretreatment evaluation consisted of a history and physical
`examination, complete blood cell (CBC) count, electrolytes,
`blood sugar, calcium, phosphorus, uric acid,
`liver function
`tests, thyroxine, amylase, prothrombin time, partial thrombo-
`plastin time, and urinalysis. An initial chest roentgenogram and
`other radiographs as needed were obtained. A baseline electro-
`cardiogram was obtained on all patients. During the study,
`weekly vital signs and CBC counts were measured. Prior to each
`course, CBC counts, serum chemistries, chest roentgenogram or
`other appropriate roentgenograms, and electrocardiogram were
`performed. During the first course of treatment, an electrocar-
`diogram was obtained at one hour, 24 hours, and one week after
`drug administration. In subsequent courses, an electrocardio-
`gram was obtained one hour after each drug infusion. Nuclear
`medicine ejection fractions were measured after every eight
`courses of treatment in patients with <200 mg/m 2 of prior dox-
`orubicin and five courses in patients who had previously re-
`ceived 200 to 350 mg/m 2 of doxorubicin. If a nuclear medicine
`injection fraction became abnormal, an endomyocardial biopsy
`was planned; however, this was not required in any patient.
`
`Toxicity Criteria
`Toxicity criteria were essentially those of the Southwest On-
`cology Group. Those criteria pertinent to this study are summa-
`rized in Table 1. Alopecia was graded as mild (<25% hair loss),
`moderate (25% to 75%), or severe (>75%).
`Although primarily a phase I study, patients were observed
`for response according to the following criteria: complete re-
`sponse, total disappearance of all clinical evidence of disease for
`at least two measurements separated by at least four weeks;
`partial response, at least a 50% reduction in the size of all
`measurable tumor areas as measured by the sum of the products
`of the greatest length and the maximum width; and minor re-
`sponse, a decrease in size of measurable tumor areas, but less
`than that required for a partial response. Patients who failed to
`show any reduction in tumor size or showed tumor progression
`were considered nonresponders.
`
`Drug Information and Schedule
`Esorubicin (NSC #267469; IMI-58; 4'deoxydoxorubicin)
`was supplied in 5-mg vials as a red powder by Farmitalia Carlo
`Erba, Milan, Italy. It was reconstituted in 5 mL of 5% dextrose
`in water for injection. The drug was given by intravenous (IV)
`injection over five minutes every three weeks. The lowest start-
`ing dose for the phase I trial was 10 mg/m. 2 Patients without
`evidence of myelosuppression or other toxicity at three weeks
`after drug administration were eligible to reenter the study at the
`same dose or at a higher dose level. Patients were classified as
`"new patients" only for the initial dosage level and not on
`reentry. If severe toxicity was encountered, dose reduction was
`permitted at the next treatment cycle. Treatment was discontin-
`ued if disease progression became clearly evident.
`
`RESULTS
`
`Patient Characteristics
`The total number of patients entered was 36;
`their characteristics are shown in Table 2. Two
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1038-0002
`
`

`
`1036
`
`GAREWAL ET AL
`
`Table 1. Summary of Relevant Toxicity Criteria
`
`0
`
`1
`
`Grade
`
`2
`
`3
`
`4
`
`>1,500
`>100,000
`
`<1,500
`75,000-99,999
`
`<250
`<500
`<1,000
`50,000-74,999 25,000-49,999 <25,000
`
`Toxicity
`
`Hematologic
`Granulocytes//tL
`Platelets/4LL
`Gastrointestinal
`Stomatitis
`
`Normal
`
`Erythema
`
`Nausea and vomiting
`
`None
`
`Nausea, no
`vomiting
`
`Unable to eat because of
`Ulcers, able to
`ulcerations
`eat
`Vomiting can be Vomiting >6 times/d in spite
`prevented by
`of antiemetics
`therapy (<6
`times/d)
`
`patients were inevaluable for toxicity analysis
`since they failed to obtain follow-up evaluation
`after the first course. Five patients are currently
`inevaluable for response. These include the two
`mentioned above as well as three others who
`the first
`to continue treatment after
`refused
`course.
`The median number of courses of esorubicin
`per patient was 2.5 (range, 1 to 11). Five patients
`were given one course, 13 received two, seven
`received three, seven received four, two received
`six, one received ten, and one received 11
`courses of treatment. The median total dose per
`patient was 62.5 mg/m2 (range, 25 to 222 mg/
`m 2). Table 3 lists the doses and courses adminis-
`tered during this study. Patients entered at 17.5
`and 22.5 mg/m2 received these doses after expe-
`riencing toxicity at higher doses. These were,
`therefore, not part of the planned dose escala-
`tion. The 27.5 mg/m 2 dose was also not part of
`the planned dose escalation schedule, with pa-
`
`tients being entered at this dose either because of
`toxicity at a higher dose or because they were
`considered to have poor bone marrow reserve by
`their primary physicians and, thus, given a lower
`starting dose than 30 mg/m2.
`
`Toxicity
`Table 4 lists the toxicity encountered after a
`single dose of the drug. Only grade I nausea (ie,
`nausea, but no vomiting) was observed. One pa-
`tient developed grade I stomatitis at her entry
`dose of 35 mg/m2 as well as at a reduced dose of
`27.5 mg/m2. This was transient, lasting only two
`to four days each time. Local reactions consisted
`of hives at the injection site, occasionally extend-
`ing proximally along the venous track. Once en-
`countered, these reactions tended to recur in the
`same patients. In one patient, recurrent local re-
`actions led to a decrease in the administered
`dose. Since local reactions tended to recur in
`patients, subsequent doses in the same patient
`
`Table 2. Patient Characteristics
`
`Table 3. Doses and Courses of Esorubicin
`
`Characteristic
`
`Total no. of case entries
`No. evaluable for toxicity
`No. evaluable for response
`Sex
`Male
`Female
`Age in yr (range)
`Median Karnofsky performance status
`(range)
`No. with prior chemotherapy
`Median no. of prior chemotherapy
`regimens (range)
`Prior doxorubicin
`Prior radiotherapy
`
`No.
`
`36
`34
`31
`
`13
`23
`21-73
`
`80 (50-100)
`33
`
`2 (0-5)
`20
`19
`
`Dose
`(mg/n 2)
`10
`15
`17.5
`20
`22.5
`25
`27.5
`30
`32.5
`35
`Total
`
`No. of Patients
`Evaluable/
`No. Entered
`
`4/4
`7/7
`3/3
`6/7
`2/2
`10/10
`3/4
`16/16
`9/10
`1/1
`61/64 (95.3%)
`
`Total No.
`of Courses
`Evaluable/Total
`No. Courses
`
`6/6
`13/14
`3/3
`20/21
`2/3
`19/19
`3/4
`24/24
`13/16
`1/1
`104/111 (94%)
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1038-0003
`
`

`
`PHASE I TRIAL OF ESORUBICIN
`
`1037
`
`Dose
`Level
`(mg/m2)
`
`10
`15
`
`Nausea
`
`1/6
`3/13
`
`17.5*
`
`0/3
`
`2/6
`1/13
`
`1/3
`
`20
`
`1/20
`
`3/20
`
`22.5*
`
`2/2
`
`25
`
`3/19
`
`0/2
`
`0/19
`
`27.5*
`
`0/3
`
`1/3
`
`0/3
`
`30
`
`9/24
`
`2/24
`
`32.5
`
`2/13
`
`1/13
`
`35
`
`0/1
`
`0/1
`
`4/24
`(2 mild,
`2 moderate)
`
`3/13
`(2 mild,
`1 moderate)
`
`1/1
`(moderate)
`
`Table 4. Toxicity After a Single Dose of Esorubicin
`
`Local
`Reactions Alopecia
`
`Granulo-
`cytopenia
`
`Thrombo-
`cytopenia
`
`0/6
`0/13
`
`0/3
`
`0/20
`
`1/2
`(mild)
`3/19
`(2 mild,
`1 moderate)
`
`0/6
`2/13
`(both grade 2)
`1/3
`(grade 2)
`3/20
`(2 grade 1,
`1 grade 2)
`1/2
`(grade 2)
`10/19
`(7 grade 1,
`2 grade 2,
`1 grade 3)
`3/3
`(1 grade 3,
`2 grade 4)
`14/24
`(2 grade 1,
`3 grade 2,
`5 grade 3,
`4 grade 4)
`11/13
`(3 grade 1,
`5 grade 2,
`3 grade 3)
`1/1
`(grade 4)
`
`0/6
`0/13
`
`0/3
`
`7/20
`(6 grade 1,
`1 grade 3)
`0/2
`
`1/19
`(grade 1)
`
`3/3
`(2 grade 3,
`1 grade 4)
`5/24
`(2 grade 1,
`2 grade 3,
`1 grade 4)
`
`2/13
`(1 grade 2,
`1 grade 3)
`
`1/1
`(grade 2)
`
`Cardiac
`
`0/6
`0/13
`
`0/3
`
`1/20 (PVCs)
`
`0/2
`
`1/19
`(PVCs, trigeminy)
`
`0/3
`
`0/24
`
`0/13
`
`0/1
`
`The data in this table show the No. of courses in which the indicated toxicity was encountered/total No. of
`NOTE.
`courses at that dose. PVC = premature ventricular beats.
`*These doses were not part of the planned dose escalation (see text).
`
`were always preceded with premedication. Con-
`sequently, Table 4 probably underestimates the
`total frequency of local reactions that would have
`been encountered in the absence of premedica-
`tion with diphenhydramine and/or steroids,
`which usually prevented or reduced the intensity
`of the reactions. Regional skin cooling may also
`block local reactions. Overall, 22% (8/36) of the
`patients experienced local reactions.
`Myelosuppression was the dose-limiting tox-
`icity. Granulocyte and platelet nadirs usually oc-
`curred at the two-week measurement, but could
`be seen as early as one week after drug adminis-
`tration. Recovery usually followed within four to
`seven days after the nadir. Two patients devel-
`oped fevers during the granulocytopenic period
`and received broad-spectrum antibiotic treat-
`ment. One of these two was a previously untreat-
`ed patient with adenocarcinoma of unknown ori-
`
`gin with metastases to the liver who received the
`highest dose tested in this study (35 mg/m2).
`Table 5 shows the hematologic toxicity after the
`first course of esorubicin in new patient entries at
`the planned dose levels.
`Congestive heart failure was not encountered
`in any patient. One patient with metastatic colon
`cancer and massive ascites developed premature
`ventricular beats and occasional
`trigeminal
`rhythm within 24 hours after receiving one
`course of treatment. A second patient developed
`premature ventricular beats after receiving 222
`mg/im 2 of esorubicin over ten courses. He had
`previously been treated with doxorubicin-con-
`taining regimens to a total doxorubicin dose of
`240 mg/m2. Three patients fulfilled the planned
`criteria for measurement of cardiac ejection frac-
`tion. They had received 90 mg/m 2, 240 mg/im 2,
`and 250 mg/im 2 of doxorubicin prior to entry and
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1038-0004
`
`

`
`1038
`
`GAREWAL ET AL
`
`Table 5. First-Course Hematologic Toxicity of
`Esorubicin in New Patients
`
`No. of
`New
`Patients
`Evaluable
`(No.
`Dose
`(mg/m2) Escalated)
`
`Nadir Counts After First Course*
`
`Granulocytes
`
`Platelets
`
`370 (326-374)
`6.2 (4.8-19.6)
`3 (2)
`10
`246 (141-396)
`1.6 (0.6-4.7)
`3 (0)
`15
`176 (175-177)
`1.35 (1.1-1.6)
`2 (0)
`20
`323 (197-458)
`2.1 (0.8-2.7)
`4 (0)
`25
`0.61 (<0.25-4.2) 134 (3-665)
`13 (1)
`30
`0.85 (<0.25-1.8) 230 (44-282)
`6 (0)
`32.5
`1 (0) <0.025
`74
`35
`* x 103/gL.
`
`had normal follow-up ejection fractions (58%,
`61%, and 65%). One patient had an acute myo-
`cardial infarction
`two weeks after his fourth
`course at the 30 mg/m2 dose level. However, this
`was not considered to be related to the drug. He
`recovered uneventfully and subsequently
`re-
`ceived additional chemotherapy with other
`agents.
`
`Therapeutic Activity
`Although not the primary objective of this
`study, patients were monitored for tumor re-
`sponse. No complete or partial responses were
`observed. However, clearly documented minor
`responses were seen in 29% (9/31) of the evalua-
`ble patients. Eight of these nine responding pa-
`tients had received prior doxorubicin. Table 6
`summarizes the tumor types of patients studied
`
`Table 6. Therapeutic Activity of Esorubicin (Phase I
`Trial)
`
`and response information on patients who were
`evaluable for response. Table 7 lists previous
`treatment received by the responding patients
`and the dose of esorubicin at which the minor
`response occurred.
`
`DISCUSSION
`On the basis of this phase I trial, the dose-
`limiting toxicity of esorubicin appears to be
`myelotoxicity. Since CBC counts were only
`measured at weekly intervals, the exact day of
`hematologic nadir could not be precisely estimat-
`ed. The nadirs usually occurred at the 14-day
`measurement, but occasionally were seen seven
`days after a dose. Thus, the nadir occurred be-
`tween one to 14 days for the majority of patients.
`It appears that esorubicin is about twice as
`potent as doxorubicin with respect to myelo-
`suppression. For phase II trials, we would rec-
`ommend a starting dose of 30 mg/m, 2 given ev-
`ery 21 days for good-risk patients. If this dose is
`tolerated without myelosuppression, escalation
`to 32.5 mg/m 2 should be considered. For pre-
`viously untreated patients, higher doses may
`prove tolerable. For patients with poor bone mar-
`row reserve (ie, heavily pretreated with chemo-
`therapy and/or radiation therapy), we would rec-
`ommend a starting dose of 25 mg/m. 2
`There is too little clinical information at pres-
`ent on cardiac toxicity, but preclinical data sug-
`gest that this will be significantly less than that
`seen with doxorubicin. More information on this
`issue will be obtained in phase II trials wherein
`
`Table 7. Characteristics of Responding Patients
`
`Tumor Type
`
`Hypernephroma
`Sarcoma
`Melanoma
`Colon
`Breast
`Lymphoma (non-Hodgkin's)
`Lymphoma (Hodgkin's)
`Gastric
`Carcinoid (thymic)
`Lung (non-small cell)
`Mesothelioma
`Unknown primary
`Total
`
`No.
`Evaluable
`Patients
`
`1
`3
`4
`5
`5
`3
`4
`2
`1
`1
`1
`1
`31
`
`Response
`
`...
`1 (minor)
`...
`2 (minor)
`2 (minor)
`3 (minor)
`1 (minor)
`
`Diagnosis
`
`Melanoma
`Breast
`Breast
`Non-Hodgkin's lymphoma
`Non-Hodgkin's lymphoma
`Hodgkin's disease
`Hodgkin's disease
`Hodgkin's disease
`Gastric
`
`No.
`Previous
`Chemo-
`therapy
`Regimens
`
`5
`1
`4
`3
`2
`3
`4
`2
`1
`
`Dose of
`Esorubicin
`Producing
`Response
`(mg/m2 )
`32.5
`25
`30
`15
`30
`20
`25
`32.5
`27.5
`
`9 minor (29%)
`
`NOTE. All patients except the one with melanoma had
`received prior doxorubicin. All responses were classified as
`minor responses.
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`Ex. 1038-0005
`
`

`
`PHASE I TRIAL OF ESORUBICIN
`
`1039
`
`responsive patients are maintained on the drug
`and studied serially for cardiac function. Nausea,
`vomiting, and alopecia were by-and-large negli-
`gible with esorubicin, but hives during infusion
`did require premedication with antihistamines.
`We did note minor responses in several pa-
`tients. Objective responses have been noted by
`other investigators in preliminary reports of their
`phase I trials. 10,"' Since 92% of our patients were
`heavily pretreated, these results are very encour-
`aging, especially in view of the relative lack of
`nonhematologic toxicity of this new agent when
`
`compared with doxorubicin at equally myelo-
`suppressive doses. Phase II trials in a broad vari-
`ety of solid tumors are clearly warranted. Further
`clinical trials should determine whether esorubi-
`cin is a "second generation" anthracycline with
`enhanced antitumor activity, reduced cardiac
`toxicity, and other nonhematologic side effects
`that impair quality of life.
`
`ACKNOWLEDGMENTS
`We thank Drs Thomas Miller and Frank L. Meyskens, Jr for
`patient referral, and Toni Meinke for secretarial support.
`
`REFERENCES
`
`1. Arcamone F, Bernardi L, Patelli B, et al: Synthesis and
`antitumor activity of new daunorubicin and Adriamycin ana-
`logs. Experientia 34:1255-1257, 1978
`2. Cagnasso M (ed): Summary of preclinical studies of IMI-
`58 (4'deoxydoxorubicin) up to April 1981. Farmitalia Carlo
`Erba
`3. Casazza AM: Experimental evaluation of anthracycline
`analogs. Cancer Treat Rep 63:835-844, 1979
`4. Henry DW: Structure-activity relationship among dauno-
`rubicin and Adriamycin analogs. Cancer Treat Rep 63:845-854,
`1979
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