Cancer Chemother Pharmacol (1999) 43: 385–388
`
`(cid:211) Springer-Verlag 1999
`
`O R I G I N A L A R T I C L E
`
`Mark D. DeMario Æ Mark J. Ratain
`Nicholas J. Vogelzang Æ Sridhar Mani
`Everett E. Vokes Æ Gini F. Fleming Æ Kimberly Melton
`Sheryl Johnson Æ Steven Benner Æ David Lebwohl
`A phase I study of oral uracil/ftorafur (UFT) plus leucovorin
`and bis-acetato-ammine-dichloro-cyclohexylamine-platinum IV
`(JM-216) each given over 14 days every 28 days
`
`Received: 5 March 1998 / Accepted: 3 September 1998
`
`Abstract Purpose: To determine the feasibility, maximal
`tolerated doses, and response rates for a combined reg-
`imen of the platinum and 5-fluorouracil oral analogues
`bis-acetato-ammine-dichloro-cyclohexyl-amine
`plati-
`num(IV) (JM-216) and uracil/ftorafur (UFT) coadmin-
`istered as a 14 consecutive-day every 28-day schedule.
`Methods: Of 20 patients enrolled in this investigation, 17
`on the following dose escalation scheme were evaluable
`for toxicity and/or response: I UFT 300 mg/day, JM-
`216 5 mg/day (three patients), II UFT 300 mg/day, JM-
`216 10 mg/day (four patients), III UFT 300 mg/day,
`JM-216 20 mg/day (ten patients). Results: All 17 evalu-
`able patients were evaluable for toxicity. At dose level
`III, dose-limiting nausea and emesis were observed in
`one patient despite maximal antiemetic support. Im-
`portantly, neurotoxicity and nephrotoxicity were not
`observed at the JM-216 dose levels examined in this
`study. This observation is consistent with results seen
`with single agent JM-216. Conclusion: For JM-216 and
`UFT administered at 20 mg/day and 300 mg/day over
`14 days, nausea and emesis were observed as the prin-
`cipal dose-limiting toxicities. These doses are consider-
`ably below the maximally tolerated doses of single agent
`JM-216 and UFT. Shorter administration schedules
`should be explored in an attempt to increase the dose
`
`M.D. De Mario Æ M.J. Ratain Æ N.J. Vogelzang Æ S. Mani
`E.E. Vokes Æ G.F. Fleming Æ K. Melton Æ S. Johnson
`Section of Hematology/Oncology, Department of Medicine,
`The University of Chicago, Medical Center, Chicago, IL, USA
`M.J. Ratain (&)
`Committee on Clinical Pharmacology
`and Cancer Research Center,
`The University of Chicago Medical Center,
`5841 S. Maryland Avenue, MC2115,
`Chicago, IL 60637-1470, USA
`Tel.: +1773-702-4400; Fax: +1-773-702-0963
`
`S. Benner Æ D. Lebwohl
`Bristol Myers Squibb Pharmaceutical Research Institute,
`Richard L Gelb Center for Pharmaceutical
`Research and Development, 5 Research Parkway,
`P.O. Box 5100 Wallingford, CT 06492-7660, USA
`
`intensity and minimize the toxicity of this combination
`oral regimen.
`
`Key words Oral chemotherapy Æ JM-216 Æ UFT Æ
`Hyperemesis Æ Advanced cancer
`
`Introduction
`
`Therapeutic combination regimens of cisplatin and
`5-fluorouracil (5-FU) have been used extensively in the
`treatment of head and neck, esophageal, gastric, lung
`and squamous cell skin carcinomas. The e€ectiveness
`of such regimens may be due in part to synergy be-
`tween the two agents. Preclinical models suggest mul-
`tiple mechanisms for synergism,
`including (1) 5-FU
`depletion of intracellular glutathione, which can pro-
`duce CDDP resistance at high levels, (2) 5-FU incor-
`poration
`into RNA with
`subsequent
`impaired
`transcription of DNA repair enzymes for cisplatin ad-
`ducts, and (3) enhanced 5-FU e(cid:129)cacy through a
`schedule-dependent, cisplatin-mediated increase in in-
`tracellular folate levels [2, 3, 14].
`Ftorafur (UFT) is an orally bioavailable fluoropy-
`rimidine composed of 1-(2-tetrahydrofuryl)-5-fluoro-
`uracil (tegafur) and uracil complexed at a molar ratio. of
`1:4 UFT is a prodrug, metabolized to 5-FU by target
`tumor tissues and by hepatic cytochrome P450 [1]. Phase
`I studies of UFT on a 28-day schedule with high-dose
`leucovorin (150 mg/day) suggest a maximal tolerated
`dose (MTD) of 350 mg/day, with the principal toxicities
`being diarrhea, nausea, and emesis [7]. Similarly, UFT
`has been safely coadministered with low-dose leucovorin
`(15 mg/day) on a 28-day schedule at a dose of 350 mg/
`day [13]. UFT has been used extensively in Japan, where
`pooled phase II data at doses from 300 to 600 mg/day
`suggest response rates of 25 to 32% in patients with
`colorectal cancer, cholangiocarcinoma, and gastric and
`breast carcinomas [8].
`Bis-acetato-ammine-dichloro-cyclohexylamine-plati-
`num(IV)
`(JM-216)
`is a novel platinum analogue
`
`Ex. 1081-0001
`
`

`

`386
`
`bioavailable by the oral route. JM-216 is rapidly bio-
`transformed following oral administration into at least
`six species [12]. Preclinically, JM-118 has been identified
`as the major cytotoxic species in ovarian carcinoma cell
`lines [12]. Single-dose pharmacokinetic studies of JM-
`216 suggest saturable absorption at doses exceeding
`200 mg/m2 [5]. Phase I JM-216 studies with 5 and 14
`consecutive-day schedules suggest MTDs of 140 mg/m2
`and 40 mg/m2, respectively [6, 9]. The dose-limiting
`toxicity in each study was myelosuppression. Phase II
`data are notable for a 31% response rate in therapy-
`naive small-cell lung cancer patients treated on a 120–
`140 mg/m2/day · 5 schedule [4], while 42% of patients
`with hormone-refractory prostate cancer had a reduc-
`tion of serum prostate-specific antigen (PSA) on this
`schedule [11].
`Recognizing the single-agent MTDs of JM-216 and
`UFT with prolonged administration, we investigated
`their combination on a 14 consecutive-day every 28-day
`schedule.
`
`Patients and methods
`
`This single-institution phase I trial was initiated in November
`1996 to determine the MTDs of JM-216 and UFT with leucovorin
`which could be safely coadministered on a 14-day schedule every
`28 days. Disease response was assessed as a secondary endpoint.
`All patients had pathologic confirmation of a nonhematologic
`malignancy which was refractory to standard therapies or for
`which no standard therapy existed. All patients had measurable
`or evaluable disease. Eligibility requirements, determined within 2
`weeks of study entry, included (1) Karnofsky performance status
`>70%, (2) adequate bone marrow function (ANC >2 · 109/l
`and platelet count >100 · 109/l), (3) serum creatinine <1.4 mg/
`dl or calculated creatinine clearance >60 ml/min, (4) adequate
`liver function (total serum bilirubin <1.5 mg/dl, ALT and alka-
`line phosphatase <1.25 · the upper limit of normal values, and
`(4) the ability to swallow pill medications. No patient had re-
`ceived previous chemotherapy or radiotherapy within 4 weeks
`prior to study entry. Patients with serious concurrent medical
`disorders, history of gastrectomy, or previous
`radiotherapy
`to >30% of bone marrow were not eligible. This investigation
`was approved by the investigational review board of the Uni-
`versity of Chicago. All patients gave written informed consent
`prior to study entry.
`For each cycle, all patients received a 14-day supply of UFT,
`leucovorin, and JM-216 tablets. JM-216 (5- or 10-mg tablets) was
`given as a single daily oral dose. UFT (100-mg tablets) was ad-
`ministered on a three times daily schedule at 7 a.m., 3 p.m. and 11
`p.m. Leucovorin was administered concomitantly with UFT at a
`fixed dose of 30 mg three times daily. Instructions were given to
`take no food within 1 h before or after UFT or JM-216 dosing.
`The dose escalation scheme was as follows: I JM-216 5 mg/day,
`UFT 300 mg/day; II JM-216 10 mg/day, UFT 300 mg/day; III
`JM-216 20 mg/day, UFT 300 mg/day. The trial design called for
`three evaluable patients per dose level. Dose escalation proceeded
`in the absence of dose-limiting toxicities, as defined below. If a
`dose-limiting toxicity was observed, that dose level cohort was
`expanded to six patients. The MTD was defined as one dose level
`below that at which two or more dose-limiting toxicities were
`observed.
`Patients had complete blood counts checked weekly. Dose-
`limiting toxicities, defined by common toxicity criteria, were as
`follows: (1) grade 3 or higher GI toxicity with the exception of
`nausea, diarrhea, and vomiting; (2) nausea, emesis, or diarrhea
`
`were dose-limiting only if grade 3 or higher following maximal
`medical intervention (for nausea and emesis, this was defined as
`symptoms refractory to prochlorperazine and ondansetron given
`every 6 and 8 h, respectively); (3) grade 3 or higher anemia or
`thrombocytopenia or grade 4 neutropenia; (4) nonhematologic
`toxicities grade 2 or higher; or (5) missing four or more doses of
`JM-216 and/or 12 or more doses of UFT or leucovorin due to
`toxicity.
`Dose delays were allowed in the event of granulocyte or platelet
`counts less than 1000/mm3 and 50 000/mm3, respectively, at any
`time during the 14-day period of drug administration. Medications
`were readministered when granulocytes reached > (cid:136) 1500/mm3
`and platelets > (cid:136) 100 000/mm3. Dose delays were allowed for
`nonhematologic toxicities of grade 2 or higher. Medications were
`readministered only after these toxicities had resolved to grade 1 or
`less. Medication withheld due to dosage delay was not administered
`beyond the planned 14-day schedule.
`Patients were evaluated for response to treatment after every
`two courses of therapy. Response criteria were defined according to
`UICC criteria: CR, complete radiographic disappearance of all
`tumor lesions for at least 4 weeks; PR, >50% decrease in the sum
`of perpendicular diameters of all measurable lesions over two cy-
`cles, PD, a >25% increase in the size of any measurable or
`evaluable lesions or the appearance of new lesions; SD, a disease
`assessment not fulfilling any of the above criteria. Patients with
`stable or responsive disease and acceptable toxicity were eligible for
`additional treatment cycles.
`
`Results
`
`A total of 20 patients were treated in this study. Ten
`patients received at least two complete cycles and were
`fully evaluable for toxicity and response. An additional
`seven patients were evaluable for toxicity. Three patients
`were not considered for toxicity or response, having
`received only a fraction of their first cycle of therapy.
`Two of these patients were noncompliant with medica-
`tion and the third required radiation therapy for spinal
`metastasis. A total of 40 cycles of JM-216 and UFT with
`leucovorin were administered to the 17 patients evalu-
`able for toxicity and/or response. Of these evaluable
`patients, three were treated in dose escalation cohort I,
`four were treated in cohort II, and ten were treated in
`cohort III.
`
`Toxicity
`
`treatment-related toxicities.
`Table 1 summarizes all
`Table 2 summarizes gastrointestinal toxicities with re-
`spect to dose escalation cohort. Nausea and emesis
`were the most frequently observed adverse events, oc-
`curring in 38% and 28% of all cycles administered,
`respectively. Although protocol design allowed for
`prochlorperazine and ondansetron medications, they
`were utilized by only 1 of 12 patients experiencing
`grade 1 nausea or emesis. A dose level III patient ex-
`perienced grade 3 nausea and grade 3 emesis on her
`first cycle of therapy. She was hospitalized on cycle day
`11 for these toxicities, but had taken no antiemetics
`prior to receiving intravenous prochlorperazine and
`ondansetron as an inpatient. After a 24-h delay, JM-
`216 and UFT were restarted with the implementation
`
`Ex. 1081-0002
`
`

`

`Table 1 Summary of toxicities during 40 treatment cycles
`
`Adverse event
`
`Gastrointestinal
`Nausea
`
`Emesis
`
`Anorexia
`Diarrhea
`
`Mucositis
`Hematologic
`Neutropenia
`Thrombocytopenia
`Hepatic
`Total bilirubin
`Transaminase
`Renal
`Creatinine
`Neurologic
`Dizziness
`Other
`Fatigue
`
`NCI
`grade
`
`% of cycles
`
`No. of
`patients
`
`1
`2
`3
`1
`2
`3
`3
`1
`2
`1
`
`2
`3
`
`3
`2
`
`2
`
`1
`
`1
`2
`3
`
`32.5
`0
`5.0
`25.0
`0
`2.5
`2.5
`2.5
`5.0
`2.5
`
`2.5
`5.0
`
`2.5
`2.5
`
`2.5
`
`2.5
`
`22.5
`15.0
`2.5
`
`9
`0
`2
`7
`0
`1
`1
`1
`2
`1
`
`1
`2
`
`1
`1
`
`1
`
`1
`
`3
`1
`1
`
`of 8 mg ondansetron every 8 h and 10 mg proc-
`hlorperazine every 6 h as prophylaxis. Less than 24 h
`following chemotherapy readministration, the patient
`experienced recurrent nausea and emesis and was re-
`moved from study. Two patients subsequently treated
`at dose level III received the aforementioned prophy-
`lactic ondansetron and prochlorperazine medications at
`the initiation of therapy. These patients su€ered no
`nausea or emesis in excess of grade 1.
`Hematologic toxicity was infrequent, being observed
`in only 2 of 17 evaluable patients. Each of these patients
`had comorbid conditions which may have completely or
`in part contributed to the observed toxicity. A dose level
`I patient with prostate cancer who experienced grade 3
`thrombocytopenia and grade 2 neutropenia following
`treatment cycle 6 had biopsy-proven tumor infiltration
`
`387
`
`of the bone marrow. A dose level II patient who devel-
`oped grade 3 thrombocytopenia on the 27th day fol-
`lowing the start of treatment cycle 1 had concomitant
`non-neutropenic sepsis.
`Other significant toxicities included fatigue, which
`was observed in 40% of treatment cycles. One patient
`treated at dose level II experienced a grade 2 creatinine
`elevation on the 14th day of his first treatment cycle.
`This toxicity may have been related to decreased fluid
`intake during the acute phase of an ongoing cerebro-
`vascular accident. While the renal toxicity was judged as
`not definitively related to study therapy, it nevertheless
`prompted an expansion of patient cohort III. No other
`renal toxicities were observed in the expanded cohort.
`One patient treated at dose level III had an isolated
`episode of grade 3 hyperbilirubinemia (2.1 mg/dl) on
`day 14 of his first treatment cycle. The serum bilirubin
`had normalized without intervention by the next anal-
`ysis of laboratory parameters, on the 27th day following
`initiation of cycle 1. The patient received cycle 2 of
`therapy at a reduced dose (level II); no recurrent hype-
`rbilirubinemia was observed.
`One dose level III patient had an isolated episode of
`grade 2 hepatic transaminase elevation during her first
`treatment cycle, but also had rapidly progressive he-
`patic-based metastatic disease at that time.
`
`Response
`
`A patient with hormone-refractory prostate cancer was
`treated at dose level I for a total of six cycles. The patient
`had a sustained decrease in serum PSA, which was first
`noted after the second cycle of therapy. Serum PSA was
`reduced from 509 ng/ml pretreatment to 67 ng/ml fol-
`lowing cycle 6. The patient had a clear improvement in
`pain symptoms as well, but was subsequently removed
`from study due to PD (bone marrow metastasis).
`Two patients with treatment-refractory malignancies
`had stabilization of disease on this regimen. A patient
`with endometrial carcinoma and PD following four
`previous chemotherapy regimens had stable radio-
`graphic disease for four cycles of JM-216 and UFT. A
`patient with pseudomyxoma peritonei had stable disease
`over six cycles of therapy.
`
`Table 2 Summary of gastrointestinal toxicities by dose escalation
`cohort
`
`Discussion
`
`Dose level cohort
`
`Adverse event
`
`NCI grade
`
`Nausea
`
`Emesis
`
`Anorexia
`Diarrhea
`
`Mucositis
`
`1
`2
`3
`1
`2
`3
`3
`1
`2
`1
`
`I
`
`3
`–
`–
`1
`–
`–
`–
`–
`–
`–
`
`II
`
`III
`
`2
`–
`–
`2
`–
`–
`–
`–
`–
`1
`
`4
`–
`2
`4
`–
`1
`1
`1
`2
`–
`
`With this combination of JM-216 and UFT given over a
`14 consecutive-day schedule, nausea and emesis were the
`dose-limiting toxicities at 20 mg/day and 300 mg/day,
`respectively. These doses are substantially below the 14-
`day single-agent MTDs of JM-216 (40 mg/m2) and UFT
`with leucovorin (400 mg/m2) [9, 10]. A relationship be-
`tween dose escalation and gastrointestinal toxicity was
`suggested (Table 2). Nausea and emesis did not exceed
`grade 1 in any dose level I or II patient. No dose level I
`or II patient utilized prophylactic odansetron or proc-
`hlorperazine. All grade 3 nausea and emesis occurred in
`
`Ex. 1081-0003
`
`

`

`388
`
`dose level III patients. Sustained nausea and emesis were
`present in one patient treated at this dose level, despite
`every 8-h ondansetron and every 6-h prochlorperazine
`prophylaxis initiated after treatment delay. While two
`other patients treated at this dose level had no nausea or
`emesis with this prophylactic schedule initiated at the
`beginning of therapy, it is not clear whether this degree
`of antiemetic support would be practical in an outpa-
`tient schedule. Also, the cost of this intensive prophy-
`laxis would further limit the widespread application of
`this regimen.
`Consistent with previous clinical studies of JM-216
`given on 5-d and 14-day schedules, recurrent neurotox-
`icity and nephrotoxicity were not observed. Hematologic
`toxicities were significant in two patients, but each had a
`significant comorbid disease process. Therefore none of
`the hematologic toxicities observed in this investigation
`could be definitively ascribed to therapy-induced myelo-
`suppression.
`Our results do not demonstrate the feasibility of ad-
`ministration of a concomitant oral regimen of JM-216 and
`UFT given for 14 consecutive days of a 28-day cycle. The
`historic e(cid:129)cacy of 5-fluorouracil and cisplatin regimens
`and the absence of clear myelotoxicity, nephrotoxicity
`and neurotoxicity observed in this investigation suggest a
`rationale for additional evaluation of JM-216 and UFT
`combination regimens. Di€erent dose schedules may be
`explored in an attempt to increase dose intensity while
`minimizing significant toxicity, primarily dose-limiting
`nausea and emesis. Groen et al. noted grade 2/3 nausea
`and emesis in only 2% (1 of 50) JM-216 cycles adminis-
`tered on a 5-day schedule (120 mg/m2per day) with pro-
`phylactic antiemetics [4]. Using an identical dose and 5
`consecutive-day schedule, McKeage et al. noted severe
`(grade 3 or higher) nausea and emesis in up to 13% of JM-
`216 cycles, despite aggressive antiemetic prophylaxis [6].
`These symptoms were routinely delayed, with a median
`onset at 24 h for nausea and 75 h for emesis. These in-
`vestigators noted a substantial accumulation of platinum
`species with this 5-day administration schedule; day 5
`platinum ultrafiltrate AUC averaged 1.7 times that ob-
`served on day 1 [6]. It was asserted that nausea and emesis
`may be related to the accumulation of platinum species
`with repetitive daily dosing. It follows that this e€ect
`might be accentuated on the 14 consecutive-day schedule
`used in our investigation. Given the additive gastrointes-
`tinal toxicity manifest with coadministered UFT, it may
`be valuable to consider a shorter 5-day JM-216 adminis-
`tration schedule for future combination studies of JM-216
`and UFT.
`
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`Ex. 1081-0004
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`