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Phase II Study of Oral Platinum Drug JM216 as First-Line Treatment in Patients With Small-Cell Lung Cancer

From the University Hospital Groningen, Groningen, the Netherlands; Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzerland; Clinical Cancer Research Unit, Bristol-Myers Squibb, Brussels, Belgium, and Princeton, NJ; and the Royal Marsden Hospital, Surrey, United Kingdom.

Address reprint requests to H.J.M. Groen, MD, PhD, Department of Pulmonary Diseases, University Hospital Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands; email h.j.m.groen{at}int.azg.nl

	ABSTRACT

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PURPOSE: This multicenter phase II trial was performed to determine tumor efficacy and tolerance of the oral platinum drug JM216 in patients with small-cell lung cancer (SCLC).

PATIENTS AND METHODS: Patients with SCLC limited disease unfit for intensive chemotherapy or those with extensive disease received JM216 120 mg/m²/d for 5 consecutive days every 3 weeks. Individual dose escalation to 140 mg/m²/d was allowed if toxicity was grade 2 according to the National Cancer Institute Common Toxicity Criteria. Tumor response was evaluated according to World Health Organization criteria.

RESULTS: Twenty-seven patients were assessable for toxicity and 26 for tumor response. Eighty-eight cycles were administered. Common Toxicity Criteria grade 3 and 4 hematologic toxicities were neutropenia in 15.9% and 3.7%, lymphocytopenia in 47.6% and 17.1%, and thrombocytopenia in 19.5% and 10.3% of cycles, respectively. One patient suffered from neutropenic fever. Nausea, vomiting, and diarrhea were the most common nonhematologic toxicities. Except for grade 4 diarrhea in one patient, no grade 4 nonhematologic toxicity was observed. No severe neurotoxicity or nephrotoxicity was observed. Tumor response rate was 10 of 26 (38%; 95% confidence interval, 19% to 58%), excluding five unconfirmed partial responses. No complete responses were observed. Median overall time to progression was 110 days (range, 5 to 624 days). Median overall survival time was 210 days (range, 5 to 624 days).

CONCLUSION: Oral JM216 is active in previously untreated patients with SCLC and shows mild toxicities.

	INTRODUCTION

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JM216 [BISACETATO-ammine-dichloro-cyclohexamine-platinum(IV)] is a novel oral platinum(IV) drug. It has shown activity against several platinum-sensitive and -resistant human cell lines derived from lung cancer,¹ cervical squamous tumor,² ovarian carcinoma,³ and murine leukemia cell lines.⁴ In these cell lines, JM216 can partly circumvent platinum resistance. In vivo oral JM216 showed activity comparable to intravenous cisplatin against human ovarian carcinoma xenografts and showed even better activity against murine ADJ/PC6 plasmacytoma in mice.⁵ Furthermore, JM216 seemed to be less toxic and emetogenic than cisplatin. No nephrotoxicity or neurotoxicity was found in rodents or humans.^6-9 In mice, leukopenia was the dose-limiting toxicity for JM216.¹⁰ In human phase I studies, the major toxicities were moderate and severe leukopenia and thrombocytopenia.^6,9,11

In mice, different dosing schedules of JM216 were investigated. Optimal dosing with respect to activity, toxicity, and pharmacokinetics occurred with a once-daily administration for 5 days every 21 or 28 days.¹² In humans, a once-daily administration for 5 days was preferable over single- or twice-daily dosing and showed a maximum-tolerated dose of 140 mg/m²/d. The recommended dose for previously untreated patients was 120 mg/m²/d for 5 consecutive days every 3 weeks.^9,11

To establish efficacy and toxicity of JM216 in SCLC, we performed a multicenter study with JM216 in chemotherapy-naive patients with SCLC with either limited disease unfit for intensive combination treatment or extensive disease.

	PATIENTS AND METHODS

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Patients
Patients with histologically confirmed SCLC were accrued at the University Hospital of Groningen (Groningen, the Netherlands), the Center Pluridisciplinaire d'Oncologie (Lausanne, Switzerland), and the Royal Marsden Hospital (Surrey, United Kingdom). Patients with either limited disease considered unfit for intensive combination chemotherapy or extensive disease were eligible. Further inclusion criteria were as follows: no prior chemotherapy; Eastern Cooperative Oncology Group performance status 2; measurable disease; life expectancy 3 months; and normal liver, renal, and bone marrow functions. Prior radiotherapy was allowed if completed at least 4 weeks before study entry and if the radiation area did not include assessable or measurable lesions. Patients with serious concurrent medical disorder, symptomatic brain metastases, major gastrointestinal absorption impairment, or a history of prior malignancy, except curatively treated carcinoma of the cervix or localized epithelial skin cancer, were excluded. Pregnant and breast-feeding women were also excluded.

Ethics
The study was approved by all local medical ethics committees, and written informed consent was obtained from all patients.

Study Drug and Dosing
JM216 was provided by Bristol-Myers Squibb (Brussels, Belgium) in capsules containing 10, 50, and 200 mg with excipients (microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate). Patients received oral JM216 120 mg/m²/d at home in the evening during 5 consecutive days, repeated every 21 days, for a maximum of six cycles. No intravenous or oral hydration schedule was used. Treatment was stopped when patients experienced progressive disease or unacceptable toxicity defined as grade 3 according to National Cancer Institute Common Toxicity Criteria (CTC), except nausea, vomiting, and alopecia, or by patient's wish. Dose escalation to 140 mg/m²/d for subsequent cycles was permitted if CTC toxicity was grade 2 in the first cycle. Dose was reduced by 20% if absolute neutrophil count less than 0.5 x 10⁹/L or platelet count less than 50 x 10⁹/L occurred, or if nonhematologic toxicity exceeded CTC grade 2. Treatment delay was allowed for up to 2 weeks if absolute neutrophil and platelet counts were 1.5 x 10⁹/L and 100 x 10⁹/L, respectively, or if creatinine clearance was 60 mL/min at the end of a cycle. If no recovery had occurred after 2 weeks of delay, drug treatment was discontinued.

Antiemetics
The antiemetic regimen consisted of oral dexamethasone 8 mg given 1 hour before treatment and 4 mg every 6 hours thereafter, and oral metoclopramide 20 mg given every 4 hours. Both were administered for 5 consecutive days. No HT₃ antagonists were used in this study.

Evaluation
Before treatment, physical examination, electrocardiogram, and laboratory tests (complete blood count, differential, electrolytes, liver and renal function tests, total protein, albumin, and urine analysis) were performed. A complete medical history was also assessed. Creatinine clearance was calculated from a 24-hour urine collection and performed once every cycle. All other laboratory tests and physical examination were repeated weekly during treatment. Patients were asked to record time of dosing and experienced toxicities on a diary card during the 5-day treatment period at each cycle. Before treatment and soon after the end of study, audiometry was performed to assess whether ototoxicity had occurred. Tumor measurements were performed by chest radiograph or computed tomography scan of the chest before treatment and were repeated every second cycle and at the end of treatment. Tumor response was assessed according to standard World Health Organization criteria.¹³ Lesions that could be measured in two perpendicular diameters were considered measurable. Tumor response was classified as complete response when all detectable disease disappeared for at least 4 weeks, as partial response when a decrease of 50% in the sum of the products of perpendicular diameters of all lesions was determined by two consecutive observations at least 4 weeks apart, and as progressive disease when there was 25% increase in size of any assessable lesion or when a new lesion appeared. Otherwise, tumor response was classified as stable disease. Toxicities were graded according to the National Cancer Institute CTC.

During the first cycle, plasma total platinum was measured in 12 consecutive patients before JM216 administration and 12 hours after dosing during the first 9 days, except days 5 and 6. Plasma total platinum was assessed on days 5 and 6 in only two patients. Plasma total platinum concentration was measured by atomic absorption spectrophotometry as previously described.¹⁴ The lower detection limit was 0.1 mg/L.

Statistics
A two-stage design was adopted in this study. The objective response rate was the primary efficacy end point. After the first 15 patients assessable for response, response status was assessed. If extreme results ( one responder or five responders) were observed, the study would have been terminated. If at first-stage analysis two to four responders were observed, 15 additional patients could be included so that the maximum number of response-assessable patients would be 30. Response rates were calculated as the ratio between the number of responders (complete response + partial response) and number of patients assessable for tumor response. Duration of response, time to progression, and survival were estimated using the Kaplan-Meier method.¹⁵ Survival was calculated from the date of randomization to death. Patients still alive were censored at the last day the patient was known to be alive. Time to progression was calculated from the randomization date to the date that disease progression was reported. Patients without disease progression were censored at the last day they were known to be alive or at their date of death. Duration of response was calculated for all responders (complete response + partial response) from the date of first treatment until the date that progressive disease was noted. The same conventions for censoring were used as for time to progression.

	RESULTS

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Patients
Between October 1994 and April 1996, 27 patients were enrolled onto the study in three different centers. Patient characteristics are listed in Table 1. A total of 88 cycles of oral JM216 was administered. Dose was escalated to 140 mg/m² after the first cycle in 13 patients, and a total of 31 escalated cycles was given. Fourteen cycles were reduced because of myelosuppression (n = 13), especially thrombocytopenia, and because of diarrhea (n = 1) experienced in the previous cycle. Thirty-three cycles were delayed, mainly because of late hematologic (n = 30) or nonhematologic recovery (n = 2) or logistics (n = 1).

Hematologic Toxicity
Myelosuppression was the main toxicity of JM216. For all cycles, CTC grade 3/4 lymphocytopenia, neutropenia, and thrombocytopenia occurred in 23 (85%), 10 (37%), and 18 (67%) patients, respectively. The median nadir platelet and neutrophil counts occurred on day 19 at all cycles. Recovery from nadirs was usually rapid, within a few days. CTC grading of hematologic toxicity by patient is listed in Table 2. One patient recovered completely from febrile neutropenia with antibiotics. Cumulative toxicity was not observed.

Nonhematologic Toxicity
The most notable nonhematologic toxicities are listed in Table 3. Mild nausea was common; severe nausea (CTC grade 3/4) occurred in two patients. Vomiting did not exceed CTC grade 2 and was limited to one or a few episodes during the 5-day treatment period. If nausea and/or vomiting occurred, it usually started several hours after oral administration of JM216. Diarrhea usually occurred during the last days of oral treatment; CTC grade 1/2 diarrhea was observed in 14 patients and grade 3/4 in two patients. Maximum neurotoxicity was grade 2 paresthesia (n = 1). No severe nephrotoxicity (grade 3/4) was observed. One patient showed CTC grade 2 elevation in serum creatinine concentration, whereas five patients experienced CTC grade 1 toxicity. Audiometry showed no ototoxicity. Four patients completed treatment as planned. One early death was related to the disease, and two early deaths were not disease-related: one patient died from gastrointestinal bleeding and one from a neutropenic sepsis as a consequence of subsequent chemotherapy after JM216 treatment was stopped. All other patients were taken off treatment because of disease progression (n = 10), incomplete hematologic recovery (n = 2), patient's wish (n = 4), death (n = 1), or renal dysfunction (n = 3). One of the latter three patients already had a grade 1 elevation in creatinine concentration at baseline. Treatment was discontinued when grade 2 elevation of creatinine concentration occurred after the second cycle. The other two patients showed a glomerular filtration rate less than 60 mL/min that did not recover after a 2-week treatment delay. Three additional patients with a baseline grade 1 elevation of creatinine concentration did not experience any further nephrotoxicity during treatment.

Tumor Response
Response rates are listed in Table 4. No complete responses were observed. The overall response rate was 10 of 26 (38%; 95% confidence interval, 19% to 58%). Twelve patients had stable disease, five of whom showed a partial response that could not be confirmed by later assessments. In these patients, treatment was stopped because of patient's request (n = 2), JM216 toxicity (n = 2), and death (n = 1). The median duration of the 10 confirmed responses was 161 days (range, 99 to 289 days). Median overall time to disease progression was 110 days (range, 5 to 624 days), and median overall survival time was 210 days (range, 5 to 624 days; Fig 1).

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of time to progression and survival of 27 patients with SCLC after treatment with oral single-agent JM216.

Plasma Platinum Levels
Plasma total platinum was measured in the last 12 patients treated. With oral JM216, total plasma platinum reached levels of 0.5 mg/L 4 days after the start of treatment and decreased on days 8 and 9. Plasma platinum levels during and after oral administration of JM216 are shown in Fig 2.

View larger version (12K): [in this window] [in a new window]   Fig 2. Plasma total platinum concentrations (milligrams per liter) after oral administration of single-agent JM216 in 12 patients with SCLC. The horizontal bar indicates the treatment period. Error bars indicate SD.

	DISCUSSION

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This study shows that oral administration of single-agent JM216 in a 5-day schedule every 21 days is an active first-line treatment in patients with SCLC, with a tumor response rate of 38%. Previous investigations with platinum drugs showed that single-agent cisplatin treatment in patients with SCLC yielded response rates up to 36%.^16-18 These studies included previously treated patients as well. For single-agent carboplatin, previously untreated patients with SCLC showed a response of 50% to 79%.^19-22 In previously treated patients with SCLC, tumor response rate was 41%. Of 26 previously treated patients, nine had failed to respond, and 17 had relapsed after various types of initial therapy that did not contain any platinum product.^21,22 A Japanese phase II study reported a response rate of 28% in 67 previously treated and untreated patients with SCLC.²³ In another study, patients with SCLC who relapsed after previous chemotherapy were randomized to treatment with either carboplatin or iproplatin as single agents. Only one of 18 and none of 16 patients responded to carboplatin and iproplatin, respectively.²⁴ Tumor response rate for JM216 in previously untreated patients presented in the present study is comparable to the level of activity reported for carboplatin. However, JM216 is an oral drug, and this may be an advantage over intravenously administered carboplatin. Another well-known oral drug for SCLC is etoposide. Two studies with oral etoposide administered over 5 days in previously untreated patients with SCLC older than 70 years showed response rates of 79% and 71%, respectively, although other trials with oral etoposide showed lower response rates.^17,25,26 Two randomized trials with single-agent etoposide versus triple chemotherapy did not show any advantage of single-agent etoposide.^27,28 Therefore, combinations of oral cytotoxic drugs should be explored. The combination of oral JM216 and etoposide already showed synergy in a mouse leukemia model.²⁹

The most important toxicity of JM216 was myelosuppression, especially lymphocytopenia, neutropenia, and thrombocytopenia, with a rapid recovery. These findings are in agreement with data from the phase I studies by McKeage et al^6,9 and Beale et al.¹¹ The hematologic toxicity profile of JM216 resembles that of carboplatin, as reported in phase I and II studies.^20-23,30-34 Nausea, vomiting, and diarrhea are the most common nonhematologic toxicities of JM216 in the present study. Their frequency and severity seem similar to previously reported results.^6,9,11 Vomiting may theoretically limit the uptake of JM216 from the intestine. However, it is usually mild and does not occur until several hours after ingestion of JM216. Plasma platinum detected as early as 10 to 20 minutes after JM216 ingestion in previous studies^6,9 and during subsequent days suggests a good availability of JM216. Therefore, it is not likely that biologic availability of JM216 is limited by vomiting. After oral administration in humans, JM216 was rapidly and completely converted into at least seven different platinum-containing compounds. JM118 and JM383 seemed to be the major metabolites. JM216 itself could not be detected in plasma samples. Concentrations of JM118 in human plasma were in the cytotoxic range as established by incubation of ovarian tumor cell lines with JM118.³

Phase I studies with single and twice-daily dosing of JM216 showed that absorption of JM216 was predictable, and platinum pharmacokinetics were linear up to dose levels of 200 mg/m².^6,11 In our study, during the 5-day oral intake of JM216, plasma total platinum concentrations showed a linear increase up to day 4 and a decrease on day 7. Maximum plasma platinum levels were slightly lower in the present study compared with the study by McKeage et al.⁹ Nevertheless, they were still well within the cytotoxic range as established for lung cancer cell lines.¹

In conclusion, oral JM216 given as single agent is active in treatment of patients with SCLC, with moderate and manageable hematologic and gastrointestinal toxicities but without clinical relevant nephrotoxicity or neurotoxicity. Because best results in the treatment of SCLC are obtained with combinations of drugs, such as cisplatin and etoposide^35-38 or carboplatin and etoposide,^22,39-42 JM216 may be a good alternative platinum compound when combined with other active drugs.

	ACKNOWLEDGMENTS

 
We thank Bristol-Myers Squibb, Brussels, Belgium, for supplying the JM216 and supporting data management.

	REFERENCES

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Submitted June 16, 1999; accepted July 22, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fokkema, E. Articles by Smith, I. E. Search for Related Content PubMed PubMed Citation Articles by Fokkema, E. Articles by Smith, I. E. Social Bookmarking                            What's this?