Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days

Our plain-English summary of Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days, by C. Sessa, C. Minoia, A. Ronchi, et al (Annals of Oncology, 1998).

The study

• Authors: C. Sessa, C. Minoia, A. Ronchi, M. Zucchetti, J. Bauer, M. Borner, J. de Jong, O. Pagani, J. Renard, C. Weil, M. D'Incalci
• Journal: Annals of Oncology
• Published: 1998;9(12):1315-22
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients.

Patients And Methods: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS).

Results: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d x 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities.

Conclusions: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.

In plain English

This was a phase I study of JM216, an experimental oral platinum cancer drug. It was not a study of asbestos exposure. Forty-six adults with solid tumours not suited to standard treatment were scheduled to take JM216 once a day for 14 days, repeated every four to five weeks, at daily doses from 10 to 50 mg/m2; seven received fewer than 13 days in the first cycle. The dose-limiting side effect was neutropenia (a drop in infection-fighting white blood cells), which was delayed and varied between patients. Moderate to severe vomiting occurred in 22% of cycles at doses of 35 mg/m2 or more, diarrhea in 28% of cycles, and drug-related fever in 15 patients (32%). One patient with locally advanced malignant mesothelioma, given eight cycles at 50 mg/m2 as first treatment, had stable disease on chest CT, with complete resolution of pericardial effusion and control of tumour-related pain and fever lasting nine months. Blood platinum levels varied widely between patients. The authors selected 40 and 45 mg/m2 a day, depending on prior treatment, for further (phase II) testing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I clinical and pharmacokinetic (dose-finding) study of an oral drug
• Who was studied: 46 adult patients (32 men, 14 women; median age 57, range 29 to 74) with solid tumours not amenable to conventional treatment; most often colorectal cancer (14) and non-small-cell lung cancer (11); one patient had malignant mesothelioma
• Exposure: No asbestos exposure was studied. Patients were given the oral platinum drug JM216 on a schedule of once daily for 14 days, every four to five weeks, at daily doses from 10 to 50 mg/m2
• Main results:
  • Seven patients (15%) received fewer than 13 days of treatment in the first cycle and were left out of the analysis of blood toxicity for that cycle
  • The dose-limiting toxicity was neutropenia, which was delayed and variable among patients
  • Maximum tolerated doses were 45 mg/m2/d (patients with extensive prior treatment) and 50 mg/m2/d (limited or no prior treatment), given for 14 days every five weeks
  • Moderate to severe vomiting occurred in 22% of cycles at doses of 35 mg/m2/d or more
  • Diarrhea occurred in 28% of cycles
  • Drug-related fever occurred in 15 patients (32%)
  • One patient with locally advanced malignant mesothelioma received eight cycles at 50 mg/m2 as first treatment. The patient had stable disease on chest CT, with complete resolution of pericardial effusion and control of tumour-related pain and fever lasting nine months
  • Pharmacokinetics were studied in 15 patients at 20 to 50 mg/m2/d
  • Peak levels and total exposure (Cmax and AUC) of total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients
  • Only the peak level (Cmax) on day 1 was linearly related to dose
  • Total and ultrafiltrable platinum were still detectable two weeks after the last dose
  • In one patient with mesothelioma who had pleural drainage, the platinum concentration in pleural fluid was half the corresponding plasma total platinum concentration
• The authors' conclusion: The authors selected daily doses of 40 mg/m2 (extensive prior treatment) and 45 mg/m2 (limited or no prior treatment) for 14 days every five weeks, with oral anti-sickness prophylaxis, for phase II evaluation
• Limitations the authors state:
  • No pharmacokinetic data were available for patients who had diarrhea or were taking loperamide
  • The ultrafiltration filters used may have overestimated ultrafiltrable platinum
  • The dose range studied was smaller than in an earlier study, which might have amplified overlap of exposure values between doses

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Carboplatin, Neutropenia, Chemotherapy, Malignant Mesothelioma.

Related studies

• Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors — R. Bahleda, M.C. Le Deley, et al. (2018)
• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)
• A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours — D. Jamieson, M.J. Griffin, et al. (2016)
• Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion — I. Rassmann, R. Thödtmann, et al. (1998)
• Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients — T. Takahashi, Y. Nakamura, et al. (2011)
• Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer — K. Fizazi, M. Ducreux, et al. (2000)

Browse more research in Annals of Oncology, or return to medical research.