RAPID PUBLICATION
`Clinical and Pharmacokinetic Phase I Study
`of Multitargeted Antifolate (LY231514)
`in Combination With Cisplatin
`
`By R. Tho¨dtmann, H. Depenbrock, H. Dumez, J. Blatter, R.D. Johnson, A. van Oosterom, and A.-R. Hanauske
`
`Purpose: Multitargeted antifolate (MTA; LY231514)
`has broad preclinical antitumor activity and inhibits a
`variety of intracellular enzymes involved in the folate
`pathways. This study was designed to (1) determine the
`maximum-tolerated dose (MTD), dose-limiting toxicities
`(DLT), and pharmacokinetics of MTA combined with
`cisplatin; (2) determine a recommended dose for phase
`II studies; and (3) collect anecdotal information on the
`antitumor activity of MTA combined with cisplatin.
`Patients and Methods: Patients with solid tumors re-
`ceived MTA intravenously over 10 minutes and cisplatin
`over 2 hours once every 21 days. In cohort 1, both
`agents were administered on day 1 starting with MTA
`300 mg/m2 and cisplatin 60 mg/m2. In cohort 2, MTA
`(500 or 600 mg/m2) was administered on day 1, fol-
`lowed by cisplatin (75 mg/m2) on day 2.
`Results: In cohort 1, 40 assessable patients received
`159 courses of treatment. The MTD was MTA 600 mg/
`m2/cisplatin 100 mg/m2. DLTs were reversible leukope-
`
`nia/neutropenia and delayed fatigue. Hydration before
`cisplatin therapy did not influence MTA pharmacokinet-
`ics. Eleven objective remissions included one complete
`response in a patient with relapsed squamous cell head
`and neck carcinoma, and partial responses in four of
`ten patients with epithelial pleural mesothelioma. In
`cohort 2, 11 assessable patients received 23 courses of
`treatment. The MTD was MTA 600 mg/m2 and cisplatin
`75 mg/m2. DLTs were neutropenic sepsis, diarrhea, and
`skin toxicity. Two patients died of treatment-related
`complications during the study. Two patients had objec-
`tive remissions (one mesothelioma patient, one colon
`cancer patient).
`Conclusion: The combination of MTA and cisplatin is
`clinically active, and administering both agents on day
`1 is superior to a split schedule. Further development of
`this combination for mesothelioma is warranted.
`J Clin Oncol 17:3009-3016. r 1999 by American
`SocietyofClinicalOncology.
`
`M TA (multitargeted antifolate; LY231514; N-[4-[2-(2-
`
`amino - 3, 4 - dihydro - 4- oxo - 7H - pyrrolo[2, 3-d]pyri-
`midin-5-yl)ethyl]-benzoyl]-L-glutamic acid) is a novel anti-
`folate that was developed during structure/activity studies of
`the lometrexol type of compounds.1,2 After cellular uptake,
`MTA undergoes polyglutamation and predominantly pro-
`duces triglutamates and pentaglutamates.3 Polyglutamation
`results in prolonged intracellular retention of the active
`compound and increases potency against the target enzymes,
`thereby producing more sustained cytotoxic effects.4 MTA
`and its polyglutamates have been shown to inhibit various
`enzymes of the folate pathways,
`including thymidylate
`synthase, dihydrofolate reductase, glycinamide ribonucleo-
`tide formyltransferase, and aminoimidazole carboxamide
`ribonucleotide formyltransferase.3 In CCRF-CEM cells,
`MTA-mediated cytotoxicity was partially, but not com-
`pletely, reversed by the addition of thymidine. An exogenous
`supply of hypoxanthine was required to achieve full rever-
`sal, suggesting that both purine and thymidine syntheses are
`the major sites of action of MTA. The compound arrests
`CCRF-CEM cells at the G1/S transition and has been shown
`to induce apoptosis in these cells.5 MTA has broad antitumor
`activity in a variety of in vitro tumor models and is active
`against lymphoma, colon, lung, pancreas, and breast cancer
`xenografts in vivo. In preclinical toxicology studies, nutri-
`
`tional folate supplementation decreased toxicity of the
`compound while slightly enhancing its activity.6 Folinic acid
`has been used successfully as a rescuing agent in Beagle
`dogs.
`Clinical phase I studies have been performed using three
`different administration schedules (once every 21 days, once
`daily for 5 days every 3 weeks, and once weekly for 4 weeks
`every 6 weeks).7-9 On the basis of the toxicity profile, the
`once-every-21-days schedule was subsequently selected for
`further development of MTA in clinical phase II studies. At
`present, several single-agent phase II studies are in progress
`or under analysis, and MTA seems to be active in non—small-
`cell lung, head and neck, breast, colon, pancreatic, cervical,
`and bladder cancers. The objectives of this study were to
`determine the maximum-tolerated dose (MTD), toxicities,
`
`From the Universitair Ziekenhuis Gasthuisberg, Katholic University
`of Leuven, Leuven, Belgium; Eli Lilly and Company, Bad Homburg,
`Germany; and Lilly Research Laboratories, Eli Lilly and Company,
`Lilly Corporate Center, Indianapolis, IN.
`Submitted September 29, 1998; accepted June 11, 1999.
`Supported in part by Eli Lilly and Company.
`Address reprint requests to A.R. Hanauske, MD, PhD, Universitair
`Ziekenhuis Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium;
`email hanauske.ind-synergen@t-online.de.
`r 1999 by American Society of Clinical Oncology.
`0732-183X/99/1710-3009
`
`JournalofClinicalOncology, Vol 17, No 10 (October), 1999: pp 3009-3016
`
`3009
`
`Downloaded from jco.ascopubs.org on June 7, 2013. For personal use only. No other uses without permission.
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`ACCORD EX 1010
`
`

`

`3010
`
`and pharmacokinetic parameters of MTA when it was
`combined with cisplatin and to derive a dose and schedule
`recommendation for subsequent clinical phase II studies. In
`addition, we have collected anecdotal antitumor information
`about this combination regimen.
`
`PATIENTS AND METHODS
`Patient Selection
`
`Before entry onto the study, each patient underwent a complete
`physical examination, history, and radiologic and laboratory evalua-
`tions. Major eligibility criteria included the following: (1) histologic or
`cytologic diagnosis of cancer for which no proven therapeutic option
`was available; (2) World Health Organization performance status # 2;
`(3) estimated life expectancy of $ 12 weeks; (4) adequate bone marrow
`function (granulocyte value $ 1.5 3 109/L, white blood cell count $
`3.0 3 109/L, platelet count $ 100 3 109/L, hemoglobin value $ 9.0
`g/dL); (5) adequate liver function (serum bilirubin concentration # 1.5
`mg/dL, alanine transaminase or aspartate transaminase value # three
`times the upper normal value [# five times normal in case of known
`disease metastatic to the liver]); (6) prothrombin time and PT and
`activated partial thromboplastin time within normal range; (7) normal
`renal function (creatinine level # 1.5 mg/dL or calculated creatinine
`clearance rate $ 60 mg/min); and (8) provision of written informed
`consent according to institutional guidelines.
`Exclusion criteria included the following: (1) hematologic malig-
`nancy; (2) prior therapy (platinum-based therapy within 6 months
`before entry onto the study, chemotherapy within 3 weeks before entry
`onto the study [6 weeks in case of nitrosoureas or mitomycin C
`therapy]); (3) clinical evidence of brain metastasis; (4) active heart
`disease and/or myocardial infarction within 6 months before entry onto
`the study; (5) pregnancy, current breast-feeding, and/or childbearing
`potential without adequate contraception; (6) active infection; and (7)
`serum calcium concentration above the upper limit of normal.
`
`Treatment Regimen
`
`MTA disodium salt was supplied as lyophilized powder in vials of
`100 mg and was dissolved in physiologic saline. The appropriate dose
`volume was withdrawn and further diluted with physiologic saline to
`yield a total volume of 100 mL. Cisplatin was provided as solution in
`vials of 10 and 50 mg. The appropriate volume was withdrawn and
`further diluted with physiologic saline to yield a total volume of 1,000
`mL. Two treatment schedules were studied. In cohort 1, MTA was
`administered intravenously over 10 minutes after patients were prehy-
`drated with 1,000 mL normal saline. This was followed by a 30-minute
`wash-out with 150 mL normal saline. Subsequently, cisplatin was
`administered intravenously over 120 minutes in a volume of 1,000 mL,
`together with 50 mL mannitol. All patients received posthydration with
`2,000 mL normal saline and glucose, and appropriate substitution with
`potassium chloride, sodium bicarbonate, and magnesium chloride. The
`antiemetic regimen was administered intravenously before the infusion
`of MTA and consisted of dexamethasone 8 mg and tropisetron 5 mg.
`The initial drug doses were MTA 300 mg/m2 and cisplatin 60 mg/m2
`. In
`cohort 2, patients received MTA without hydration or antiemetic
`medication on day 1. This was followed by prehydration, antiemetic
`treatment, cisplatin administration, and posthydration on day 2. The
`hydration schedules and antiemetic regimens were identical in both
`patient cohorts. The initial doses for cohort 2 were MTA 500 mg/m2 and
`cisplatin 75 mg/m2
`. Treatment was repeated every 3 weeks in the
`absence of tumor progression or serious toxicities. At each dose level,
`the initial patients were observed for one full treatment course before
`
`THO¨ DTMANN ET AL
`
`further patients were entered onto the study. On the basis of preclinical
`experience, folinic acid rescue was considered in case of grade 4
`leukopenia/neutropenia lasting longer than 7 days. All serious adverse
`events were reported to the study sponsor (Eli Lilly GmbH, Bad
`Homburg, Germany) and to the local institutional review committees.
`Toxicities were graded according to the National Cancer Institute
`Common Toxicity Criteria.10 Dose-limiting toxicities (DLTs) were
`defined as follows: (1) grade 4 neutropenia lasting more than 5 days; (2)
`febrile neutropenia; (3) grade 4 thrombocytopenia; and (4) grade 3 or
`higher nonhematologic toxicity (except for alopecia or inadequately
`treated nausea or vomiting). The MTD was defined as the dose level at
`which two or more of six patients developed a DLT. The recommended
`dose for subsequent clinical phase II studies was defined as the dose that
`caused moderate and reversible toxicities. Intrapatient dose escalation
`was not allowed. At each dose level, the minimum number of patients
`treated was three. Three additional patients were entered onto the dose
`level if toxicities one grade below the DLT were observed in at least one
`of the initial patients. Patients who experienced DLTs were taken off the
`study unless a benefit from the therapy could be demonstrated, in which
`case treatment was continued at a lower dose at the discretion of the
`investigator. In cohort 1, dose levels (MTA/cisplatin) in mg/m2 were
`300/60, 300/75, 400/75, 500/75, 600/75, and 600/100. On the basis of
`the data generated in cohort 1, cohort 2 received the following dose
`levels: 500/75 and 600/75.
`
`Analytical Method
`
`Blood samples for the analysis of MTA in plasma were collected at
`higher dose levels (500 and 600 mg/m2) for pharmacokinetic assess-
`ments. Plasma MTA concentrations were analyzed by a liquid chroma-
`tography mass spectroscopy/mass spectroscopy method.11 The plasma
`assay was specific for LY231514, and was able to detect concentrations
`with a reliable limit of quantification of 5 ng/mL. Urine was collected
`for the determination of MTA concentrations up to 48 hours after
`administration. The urine assay was specific for LY231514, and was
`able to detect concentrations with a reliable limit of quantification of 50
`ng/mL.
`Pharmacokinetic parameters for MTA were calculated by noncompart-
`mental methods. Maximum plasma concentration and the correspond-
`ing sampling time were identified from the observed data. Concentration-
`time data were plotted on a semilogarithmic scale and the terminal
`log-linear phase was identified by visual inspection. Blood samples
`were obtained up to at least 24 hours after drug administration. The
`terminal slope (lz) was determined by linear regression for the terminal
`log-linear portion of the concentration-time curve up to 24 hours after
`administration. A predicted concentration (Cˆ ) at the last sampling time
`at which the assay value was above the limit of quantification was
`calculated from the regression equation.11
`Area under the plasma concentration versus time curve (AUC0-t) and
`area under the first moment curve (AUMC0-t) were calculated by the
`trapezoidal method and extrapolated to infinite time using the Cˆ at the
`last measurable sampling time (T) and lz values as:
`
`AUC0-‘ 5 AUC02t 1 Cˆ / lZ
`
`AUMC0-‘ 5 AUMC02t 1 Cˆ / lZ · (T1 1/lZ)
`
`(1)
`
`(2)
`
`Mean residence time (MRT), plasma clearance (CLp), fraction of
`drug excreted unchanged in urine (Fe), renal clearance (CLr), and
`volume of distribution at steady state (Vss) were calculated as:
`
`MRT 5 (AUMC0-‘ / AUC0-‘) 2 (t/2)
`
`CLp 5 Dose/AUC0-‘
`
`(3)
`
`(4)
`
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`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`

`

`PHASE I STUDY OF MTA IN COMBINATION WITH CISPLATIN
`
`CLr 5 Ae0-24/AUC0-24
`
`Fe 5 Ae0-24/Dose
`
`VSS 5 CLp x MRT
`
`(5)
`
`(6)
`
`(7)
`
`where t is the duration of infusion (10 minutes) and Ae0-24 is the total
`amount of drug excreted in the urine over 24 hours.
`
`Statistical Analysis
`
`Statistical analysis of the dose-independent parameters (CLp, Vss, and
`CLr) was performed to assess the effect of the two treatment regimens
`on the pharmacokinetics of MTA.
`Pharmacokinetic parameters from each treatment were compared by
`an analysis of variance, using Procedure GLM within SAS (SAS
`Institute, Cary, NC). Dose and treatment regimen were included in the
`model as fixed effects.
`
`Effıcacy
`
`Assessment of antitumor effects was performed every one to two
`courses, using standard response criteria.12 A complete response was
`defined as the absence of all tumor-related signs for more than 4 weeks.
`A partial response was defined as a $ 50% decrease in the sum of the
`products of the largest perpendicular diameters of all measurable lesions
`and required confirmation after at least 4 weeks. Also, no new lesion or
`enlargement of $ 25% of any existing lesion was allowed. Progressive
`disease was defined as either occurrence of a new lesion or an increase
`of $ 25% in an existing lesion. Stable disease was defined as neither
`objective response nor progression.
`
`RESULTS
`Table 1 summarizes the patient characteristics. A total of
`54 patients were entered onto the study. Of these 54, 42
`patients were entered onto cohort 1, and 12 patients were
`entered onto cohort 2. Two patients in cohort 1 were
`registered but did not receive therapy. One patient had a
`rapidly declining performance status, and, on histologic
`review, another patient was found to have small-cell cancer,
`which prompted the choice of another method of first-line
`chemotherapy. One patient with a pleural mesothelioma was
`not assessable for response because he refused a computer-
`ized tomography scan and went off-study after his first cycle.
`One of the patients entered onto cohort 2 was not treated
`because he withdrew his consent before his first course of
`therapy. Of the patients entered onto cohort 1, 35 were male
`and seven were female. Patients’ age range was 42 to 73
`years, and their median performance status was 1 (range, 0
`to 2). Twenty-four patients had received prior chemotherapy
`and 12 had received prior radiotherapy. Sixteen patients
`were chemotherapy-naive. In cohort 2, four patients had had
`not prior treatment, seven had received prior chemotherapy,
`and five had received prior radiotherapy. In cohort 1, doses
`of MTA and cisplatin were increased stepwise to MTA 600
`mg/m2 and cisplatin 100 mg/m2, with three to seven patients
`
`3011
`
`Table 1. Patient Characteristics
`
`Cohort 1
`
`Cohort 2
`
`No. entered
`No. assessable
`Male/female
`Age, years
`Median
`Range
`WHO performance scale
`Median
`Range
`Prior therapy
`None
`Chemotherapy
`Radiation
`Tumor type
`Mesothelioma
`Head and neck
`Non–small-cell lung
`Colorectal
`Esophagus
`Hepatocellular
`Melanoma
`Stomach
`Cervix
`Unknown primary
`Small-cell lung
`Pancreas
`Sarcoma
`Bladder and non–small-cell lung
`
`42
`40
`35/7
`
`57
`42-73
`
`1
`0-2
`
`16
`24
`12
`
`10
`9
`6
`3
`2
`2
`2
`2
`2
`1
`1
`1
`1
`0
`
`12
`11
`9/3
`
`55
`29-73
`
`1
`0-2
`
`4
`7
`5
`
`3
`2
`1
`1
`0
`0
`1
`0
`0
`2
`1
`0
`0
`1
`
`Abbreviation: WHO, World Health Organization.
`
`entered at each dose level. The most common tumor types
`were mesothelioma, head and neck cancer, and non—small-
`cell lung cancer.
`
`Toxicities
`
`Table 2 summarizes the hematologic toxicities for each
`dose level. The DLT of MTA when administered in combina-
`tion with cisplatin on day 1 was myelosuppression, which
`consisted predominantly of leukopenia and neutropenia.
`DLTs did not occur after course one in all patients and
`occasionally were delayed until further cycles were adminis-
`tered. However, there was no evidence for reproducible
`cumulative bone marrow toxicity. The MTD with this
`schedule was MTA 600 mg/m2 and cisplatin 100 mg/m2
`when the first cycle was exclusively evaluated. If all cycles
`were evaluated, the MTD was MTA 600 mg/m2 and cisplatin
`75 mg/m2. Nonhematologic toxicities are summarized in
`Table 3. A total of eight patients developed grade 2 skin
`toxicity, which consisted of a maculopapular rash predomi-
`nantly confined to the trunk. Treatment with dexamethasone
`8 mg resulted in prompt resolution of the rash without
`persistent skin changes. No skin biopsies were performed,
`and the occurrence of this toxicity tended to diminish with
`
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`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`

`

`3012
`
`Table 2. Hematologic Toxicity of MTA and Cisplatin, by Patient
`
`MTA/Cisplatin
`(mg/m2)
`
`Day 1
`300/60
`300/75
`400/75
`500/75
`600/75
`600/100
`Day 1/day 2
`500/75
`600/75
`
`No. of
`Patients
`
`6
`7
`6
`3
`12
`6
`
`7
`4
`
`CTC Grade
`
`WBC
`
`ANC
`
`Hb
`
`PLT
`
`3
`
`1
`3
`1
`1
`7
`3
`
`3
`0
`
`4
`
`0
`0
`0
`0
`0
`3
`
`1
`1
`
`3
`
`2
`3
`0
`1
`5
`1
`
`1
`0
`
`4
`
`1
`1
`0
`0
`2
`3
`
`1
`1
`
`3
`
`0
`1
`1
`0
`6
`1
`
`1
`0
`
`4
`
`0
`0
`1
`1
`2
`1
`
`0
`1
`
`3
`
`0
`0
`0
`0
`0
`0
`
`0
`0
`
`4
`
`0
`0
`0
`0
`0
`0
`0
`
`0
`0
`
`Abbreviations: ANC, absolute neutrophil count; Hb, hemoglobin; PLT,
`platelet.
`
`subsequent cycles. However, the skin toxicity seemed to be
`more pronounced with the split-schedule administration.
`Because of the extensive premedication for the prevention of
`cisplatin-induced emesis, nausea and vomiting were mostly
`mild to moderate. Although diarrhea was occasionally
`observed at higher doses, it did not cause clinical complica-
`tions. Similarly, mild to moderate mucositis was occasion-
`ally observed. The treatment-induced myelosuppression was
`not complicated by higher-grade infections. However, at
`high doses of MTA, a delayed occurrence of fatigue was
`notable.
`Because MTA is renally excreted, it was hypothesized that
`hydrating patients before the administration of cisplatin
`might influence the clearance of MTA and, subsequently,
`may modify the pattern of toxicity or antitumor activity. To
`investigate this possibility, a second cohort of patients
`received MTA on day 1 without prehydration or antiemetic
`medication, followed by cisplatin on day 2 after antiemetic
`premedication and hydration. Using this schedule, seven
`patients were treated with MTA 500 mg/m2/cisplatin 75
`mg/m2, and four patients received MTA 600 mg/m2/cisplatin
`75 mg/m2. At MTA 500 mg/m2/cisplatin 75 mg/m2, three
`patients developed grade 3 and one patient grade 4 leukope-
`nia. One patient each had grade 3 and grade 4 neutropenia.
`No severe anemia or thrombocytopenia was observed.
`However, two patients developed grade 2 and one patient
`grade 3 skin toxicity. The character of skin toxicity observed
`with the split-schedule administration of MTA and cisplatin
`did not differ from that observed when both compounds
`were administered on day 1. Another patient developed
`grade 4 diarrhea followed by severe dehydration and sepsis
`during his second cycle and died because of these treatment-
`related complications. At MTA 600 mg/m2/cisplatin 75
`mg/m2, one patient had grade 4 leukopenia. Another patient
`with recurrent head and neck cancer had a grade 4 mucositis
`
`THO¨ DTMANN ET AL
`
`requiring parenteral nutrition. This patient died while on the
`study, most likely because of a catheter-related bacterial
`sepsis that occurred after the patient had recovered from a
`short-lasting grade 4 neutropenia.
`
`MTA Pharmacokinetics
`The pharmacokinetics of MTA were evaluated in four
`patients who received MTA on day 1 followed by cisplatin
`on day 1 (cohort 1) and in 11 patients who received MTA on
`day 1 followed by cisplatin on day 2 (cohort 2). In cohort 1,
`patients were given an antiemetic regimen and were hy-
`drated before being administered both MTA and cisplatin. In
`cohort 2, patients were given the antiemetic regimen and
`were hydrated on day 2 before being administered cisplatin.
`For comparison purposes, plasma concentrations were
`normalized to a dose of 500 mg/m2
`. Individual normalized
`plasma MTA concentration-time profiles for both cohorts are
`illustrated in Fig 1. Visual inspection of the plots illustrates
`that the normalized MTA plasma concentrations were simi-
`lar between the two cohorts. For patients in cohort 2, blood
`samples were collected up to 96 hours after MTA administra-
`tion. Residual plasma concentrations were low but quantifi-
`able for up to 96 hours in some patients, suggesting the
`presence of a prolonged terminal phase. This prolonged
`terminal phase was not observed in cohort 1 because blood
`samples were not collected beyond 24 hours.
`A summary of mean pharmacokinetic parameters is
`presented in Table 4. The mean CLp, Vss, and CLr values for
`cohort 1 were consistent with those in cohort 2, irrespective
`of the administered dose. Results from statistical analysis
`demonstrated a lack of statistical significance for all three
`parameters with respect to both dose and treatment regimen.
`Therefore, the pharmacokinetics of MTA were independent
`of the timing of cisplatin administration and corresponding
`hydration treatments.
`The relationship between CLp, CLr, and renal function as
`assessed by the calculated creatinine clearance (CLcr) was
`explored. Plots of individual CLp and CLr values as a
`function of CLcr are illustrated in Fig 2. Visual inspection of
`the plots shows that there was no relationship between CLp,
`CLr, and CLcr. Results from regression analyses demonstrate
`that the slopes of both lines were not significantly different
`from zero (P 5 .76 for CLp v CLcr and P 5 .74 for CLr v
`CLcr). Therefore, for this treatment combination, MTA
`elimination did not seem to be related to renal function over
`the range of creatinine clearance values obtained in this
`study.
`
`Antitumor Activity
`Eleven objective antitumor responses were observed in
`cohort 1 and are listed in Table 5. Throughout all dose levels,
`clinical antitumor activity of MTA/cisplatin was notable.
`
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`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`

`

`PHASE I STUDY OF MTA IN COMBINATION WITH CISPLATIN
`
`3013
`
`Table 3. Nonhematologic Toxicity of MTA and Cisplatin, by Patient
`
`Table 3. Nonhematologic Toxicity of MTA and Cisplatin, by Patient (Cont’d)
`
`Toxicity/Grade*
`
`300/60 300/75 400/75 500/75 600/75 600/100
`
`Toxicity/Grade*
`
`300/60 300/75 400/75 500/75 600/75 600/100
`
`MTA/Cisplatin Dose (mg/m2)
`
`MTA/Cisplatin Dose (mg/m2)
`
`0
`0
`0
`
`1
`0
`0
`
`0
`1
`1
`
`1
`0
`0
`
`1
`0
`0
`
`0
`1
`0
`
`0
`0
`0
`
`1
`0
`0
`
`0
`0
`0
`
`3
`1
`0
`
`3
`0
`0
`
`3
`0
`0
`
`2
`2
`0
`
`0
`0
`0
`
`0
`1
`0
`
`2
`0
`0
`
`0
`0
`0
`
`5
`1
`0
`
`0
`0
`0
`
`1
`0
`0
`
`2
`1
`0
`
`1
`0
`0
`
`0
`0
`0
`
`2
`0
`0
`
`0
`0
`0
`
`2
`0
`0
`
`2
`0
`0
`
`0
`0
`0
`
`1
`0
`0
`
`0
`1
`0
`
`0
`0
`0
`
`0
`0
`0
`
`Day 1 schedule
`Anorexia
`2
`3
`4
`Nausea
`2
`3
`4
`Vomiting
`2
`3
`4
`Diarrhea
`2
`3
`4
`Fatigue
`2
`3
`4
`Infection
`2
`3
`4
`Mucositis
`2
`3
`4
`Skin
`2
`3
`4
`Day 1/day 2 schedule
`Anorexia
`2
`3
`4
`Nausea
`2
`3
`4
`Vomiting
`2
`3
`4
`Diarrhea
`2
`3
`4
`Fatigue
`2
`3
`4
`Infection
`2
`3
`4
`
`1
`1
`0
`
`9
`2
`0
`
`4
`4
`0
`
`0
`1
`0
`
`4
`1
`0
`
`2
`1
`0
`
`2
`0
`0
`
`0
`0
`0
`
`1
`0
`0
`
`6
`1
`0
`
`4
`1
`0
`
`0
`0
`1
`
`3
`0
`0
`
`0
`0
`1
`
`0
`0
`0
`
`4
`1
`0
`
`3
`1
`0
`
`0
`1
`0
`
`3
`2
`0
`
`0
`0
`0
`
`1
`0
`0
`
`3
`0
`0
`
`0
`0
`0
`
`2
`0
`0
`
`1
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`
`0
`0
`1
`
`Mucositis
`2
`3
`4
`Skin
`2
`3
`4
`
`1
`0
`0
`
`2
`1
`0
`
`0
`0
`1
`
`0
`1
`0
`
`NOTE. Two deaths occurred during the study period due to neutropenic
`sepsis (diarrhea, pneumonia).
`*National Cancer Institute common toxicity criteria grade.
`
`Most importantly, one patient with a relapsed squamous cell
`carcinoma of the head and neck developed a complete,
`although short-lasting, response. A further two patients with
`head and neck cancer had partial responses. Four patients
`with pleural mesothelioma developed partial remissions.
`These responses have been confirmed by an independent
`reviewer with a specialty in radiology. The reviewer verified
`that three of the four patients had lesions that were bidimen-
`sionally measurable and one patient had unidimensionally
`measurable thickening of the pleura. In cohort 2, one patient
`with an adenocarcinoma of the submandibular gland devel-
`oped a minimal response after one cycle of treatment, but
`her disease progressed after the third cycle. Two patients
`(one mesothelioma patient, one colon cancer patient) had a
`confirmed partial response. The overall activity of MTA/
`cisplatin against mesothelioma indicates marked clinical
`activity in this difficult-to-treat disease.
`
`DISCUSSION
`From previous clinical phase I studies, the every-21-days
`schedule has been chosen for further development of MTA
`single-agent phase II and combination phase I studies.7-9 The
`results of the study presented here indicate that it is clinically
`feasible and safe to combine MTA with cisplatin using a
`once-every-21-days administration schedule. When both agents
`are administered on day 1, the acute DLTs consist of leukopenia
`and neutropenia. In addition, delayed fatigue may be observed
`at high doses of MTA. No other phase I combination studies
`with MTA have yet been completed, but our results are in
`agreement with observations from single-agent phase I
`studies with this compound.7-9 Rinaldi et al, using the same
`once-every-21-days administration schedule of MTA, re-
`ported neutropenia, thrombocytopenia, and fatigue as DLTs.
`However, we have not observed significant thrombocytope-
`nia in our patients. This difference might be because Rinaldi
`et al escalated the dose of MTA to 700 mg/m2
`, whereas in the
`study presented here, the highest MTA dose was 600 mg/m2
`.
`
`Downloaded from jco.ascopubs.org on June 7, 2013. For personal use only. No other uses without permission.
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`

`

`3014
`
`Fig 1. Comparison of plasma MTA concentration-time profiles following
`administration of MTA and cisplatin on day 1 (A) and after the administration
`of MTA on day 1 and cisplatin on day 2 (B).
`
`In contrast to other single-agent clinical phase I and phase
`II studies, we did not observe serious skin toxicity in cohort
`1. This may be because of the routine use of dexamethasone
`as antiemetic regimen before the administration of cisplatin
`in our patients. We hypothesize that the use of corticoste-
`roids as part of the antiemetic prophylaxis regimen for
`cisplatin has prevented the high incidence of severe skin
`toxicities described by others. This conclusion is supported
`by the observation that administration of corticosteroids 24
`hours after the administration of MTA in patient cohort 2
`
`THO¨ DTMANN ET AL
`
`was accompanied by the occurrence of grade 3 skin reac-
`tions. Subsequent use of dexamethasone in patients who had
`developed a skin rash after treatment with MTA resulted in
`the resolution of skin toxicity within 48 hours.
`The combination of MTA and cisplatin has shown antitu-
`mor activity at various dose levels and in different tumor
`types. Of particular interest is the activity against mesothe-
`lioma. A total of five of 11 assessable patients with pleural
`mesothelioma had a partial response, and an additional four
`patients had stabilization of their disease. Although the
`design of a phase I study generally does not allow for the
`estimation of response rates, all of the responses that we
`observed occurred at the top dose levels, indicating an
`estimated response rate of 45% for this narrow dose range.
`In addition, we would predict from our data (five partial
`responses in eight patients with epithelial histologies) that
`the epithelial subtype of pleural mesothelioma will be most
`sensitive to MTA/cisplatin treatment. Further clinical studies
`of MTA/cisplatin in patients with mesothelioma therefore
`are of high interest. In addition, the activity observed with
`this combination regimen against head and neck cancer also
`warrants further investigation.
`The pharmacokinetics of MTA in this study were evalu-
`ated in two separate treatment regimens. Although the
`sample size in each treatment regimen was small,
`the
`pharmacokinetic parameters were similar in both treatments.
`The MTA plasma concentration-time profile for cohort 2
`displayed a long terminal elimination half-life (t1/2). Because
`blood samples were only collected for up to 24 hours for
`cohort 1, the long terminal t1/2 was not observed for this
`cohort. Nevertheless, the effect of the long terminal elimina-
`tion t1/2 on the overall elimination of MTA was minimal. The
`total extrapolated area under the plasma concentration-time
`curve due to the terminal phase was generally less than 1%
`of the AUC0-‘. Therefore, in conclusion, the administration
`of cisplatin and its pretreatment regimen within the same
`time frame as MTA did not seem to alter the pharmacokinet-
`ics of MTA.
`MTA is eliminated primarily by renal excretion of un-
`changed drug when it is administered as a single agent, using
`a similar dosing regimen as that used for MTA administra-
`tion in this combination.9 Approximately 80% of a single-
`agent MTA dose is excreted unchanged in the urine.
`However, when administered with cisplatin in this combina-
`tion, the fraction of the MTA dose excreted unchanged in
`urine (, 40%) was approximately 50% less than that
`observed after single-agent administration. Despite the ob-
`served discrepancy in Fe values, CLr values obtained after
`administration of this combination were consistent with
`those obtained after single-agent administration. The MTA
`CLp in this combination was observed to be approximately
`
`Downloaded from jco.ascopubs.org on June 7, 2013. For personal use only. No other uses without permission.
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`

`

`PHASE I STUDY OF MTA IN COMBINATION WITH CISPLATIN
`
`3015
`
`Parameter
`
`Arithmetic Mean
`
`CV (%)
`
`Arithmetic Mean
`
`CV (%)
`
`Arithmetic Mean
`
`CV (%)
`
`Cohort 1 (600 mg/m2) (n 5 4)
`
`Cohort 2 (500 mg/m2) (n 5 6)
`
`Cohort 2 (600 mg/m2) (n 5 5)
`
`Table 4. Summary of MTA Pharmacokinetic Parameters
`
`Cmax, mg/mL
`AUC0-‘, mg · h/mL
`AUC extrapolation,* %
`CLp, mL/min/m2
`Fe
`CLr, mL/min
`Vss, L/m2
`t1/2, h
`
`83.1
`158
`0.6
`67.2
`0.32
`25.0
`13.0
`3.6
`
`21
`25
`
`31
`80
`107
`32
`
`72.2
`122
`0.7
`88.8
`0.38
`31.1
`19.1
`31.5
`
`NOTE. Cohort 1, MTA day 1/cisplatin day 1; cohort 2 MTA day 1/cisplatin day 2.
`*Ranges: cohort 1, 0.2-0.9; cohort 2, 0.2-1.5; cohort 2, 0.1-0.9.
`
`49
`47
`
`63
`32
`61
`62
`
`97.1
`147.3
`0.4
`76.3
`0.48
`38.0
`13.9
`19.7
`
`21
`44
`
`33
`48
`58
`26
`
`twice that obtained after single-agent administration. Be-
`cause CLr is the product between CLp and Fe (CLr 5 Fe 3
`CLp) the apparent twofold increase in CLp coupled with a
`50% reduction in Fe translated into CLr values that remained
`consistent between the two treatments. Therefore, it seems
`that a greater percentage of the total clearance of MTA can
`be attributed to unknown extrarenal elimination pathways
`when MTA is administered with cisplatin.
`The terminal elimination t1/2 of MTA after administration
`of this combination was observed to be consistent with that
`occurring after single-agent administration.9 The lack of
`change in t1/2 may be attributed to an apparent increase in Vss
`when MTA was administered with cisplatin. The volume of
`distribution of MTA after the administration of this combina-
`tion was observed to be approximately twice that which
`occurred single-agent administration. Because t1/2 is propor-
`
`Table 5. Objective Tumor Responses Observed After Treatment
`With MTA and Cisplatin
`
`MTA/Cisplatin
`Dose Level (mg/m2)
`
`Tumor Type
`
`Response
`
`Duration
`(months)
`
`Both agents administered on
`day 1 of each treatment
`course
`300/60
`300/60
`400/75
`400/75
`600/75
`600/75
`600/75
`600/75
`600/75
`600/100
`600/100
`MTA administered on day 1,
`cisplatin administered
`on day 2 of each treat-
`ment course
`500/75
`600/75
`
`Non–small-cell lung
`Colorectal
`Cancer of unknown primary
`Head and neck
`Mesothelioma
`Melanoma
`Head and neck
`Head and neck
`Mesothelioma
`Mesothelioma
`Mesothelioma
`
`Mesothelioma
`Colorectal cancer
`
`PR
`PR
`PR
`PR
`PR
`PR
`CR
`PR
`PR
`PR
`PR
`
`PR
`PR
`
`2
`7
`7
`41
`81
`2
`4
`31
`5
`31
`21
`
`21
`21
`
`Abbreviations: CR, complete response; PR, partial response.
`
`Fig 2. Relationship between total plasma clearance (A), renal clearance
`(B), and calculated creatinine clearance.
`
`Downloaded from jco