Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients

Fokkema, Eelco; Vries, de Elisabeth G. E.; Meijer, S; Groen, Harry J.M.

doi:10.1007/pl00006749

Cited by 20 publications

(5 citation statements)

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“…Subsequently, a daily schedule for five consecutive days was developed, with the dose utilized for phase II and III studies varying between 100 and 120 mg/m 2 / day (15)(16)(17)(18)(19)(20). The drug has a favorable side-effect profile, with myelosuppression (neutropenia and thrombocytopenia) as the doselimiting toxicity, and manageable nausea and vomiting (15,17,21,22). Satraplatin has shown preliminary evidence of activity in lung, ovarian, and prostate cancer, and seems to have good efficacy in combination with radiation for lung and head and neck cancer (18,(22)(23)(24)(25).…”

mentioning

confidence: 99%

Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study

Ricart

Sarantopoulos

Calvo

et al. 2009

Clinical Cancer Research

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Purpose: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors. Experimental Design: Satraplatin was administered orally at 80 mg/m 2 once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state. Results: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed. Conclusions: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.Platinum analogs form the mainstay of treatment for a number of cancers, including bladder, head and neck, lung, ovarian, and testicular cancer, and a usual first option against colorectal and esophagogastric cancer. All approved platinum anticancer drugs are administered i.v., with aggressive hydration to avoid acute nephrotoxicity in the case of cisplatin (1, 2). In addition, their efficacy is often limited by cumulative toxicity, particularly neurotoxicity and ototoxicity (1,3,4). Satraplatin [bisacetatoammine-dichloro-cyclohexylamine-platinum(IV)] is a novel, orally bioavailable, platinum agent (5). It was selected from a series of oral platinum compounds because of promising preclinical features including in vitro antitumor activity, in vivo antitumor activity at least comparable with cisplatin and carboplatin in a diversity of murine and human tumor models, and finally its ability to partially circumvent intrinsic and acquired resistance to cisplatin (5-12).When satraplatin was administered every three to four weeks, nonlinear pharmacokinetics, probably due to saturable absorption, were observed (13,14). Subsequently, a daily schedule for five consecutive days was developed, with the dose utilized for phase II and III studies varying between 100 ...

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confidence: 99%

Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study

Ricart

Sarantopoulos

Calvo

et al. 2009

Clinical Cancer Research

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“…Although prolongation of progression-free survival, reduction of pain, decreases in PSA levels and tumor responses were reported, treatment with satraplatin did not result in significantly prolonged survival [40]. In a phase II study of satraplatin in SCLC ten out of 26 patients exhibited a partial response [36]. Furthermore, satraplatin monotherapy showed little activity in advanced NSCLC [41].…”

Section: Satraplatinmentioning

confidence: 96%

“…Satraplatin displayed variable, nonlinear pharmacokinetics in clinical trials [32][33][34][35]. Dose-limiting toxicities are reversible and noncumulative thrombocytopenia and neutropenia [9,36]. Satraplatin therapy is associated with mostly gastrointestinal side effects while high-grade nephrotoxicity is absent [32].…”

Section: Satraplatinmentioning

confidence: 99%

A Better Platinum-Based Anticancer Drug Yet to Come?

Olszewski

Hamilton²

2010

ACAMC

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In attempts to overcome the drawbacks of cisplatin - severe toxicity, drug resistance and poor oral bioavailability - the development of platinum-based drugs has progressed from carboplatin and oxaliplatin to the newest generation of drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin). Despite encouraging preclinical in vitro and in vivo results, outcomes of clinical trials of these coordination complexes remained below expectations. Biased rationale underlying the drug design along with in vitro and in vivo preclinical tests with inadequate predictive power seem to have eventually resulted in the selection of drug candidates of limited clinical activity. The nature of the active species generated in vivo, uptake, efflux, intracellular trafficking and detailed mechanisms involved in chemoresistance of platinum drugs in vivo are topics that need further investigation to provide clues for the rational formulation of new drugs. Insufficient diffusion in tumor tissues is likely to constitute an important limiting step in the treatment of solid tumors with platinum compounds. Preclinical assays with improved predictive power for the clinical outcome of the compounds should be based on more representative tumor models, such as resistant primary cancer cell lines, spheroids and orthotopic xenograft models, respectively. Finally, use of new pharmaceutical formulations and bifunctional complexes, as well as their selection by decisive preclinical tests, are expected to result in the generation of platinum-based anticancer drugs with the potential to achieve clinical activity even in multidrug-resistant tumors.

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“…There was no neurotoxicity, ototoxicity and nephrotoxicity observed. Fokkema and colleagues studied satraplatin at doses of 120 mg/m 2 /day for 5 consecutive days repeated every 21 days with a maximum of six cycles among lung cancer patients [40]. They found no nephrotoxicity of JM-216.…”

Section: Clinical Trials With Satraplatinmentioning

confidence: 99%

Satraplatin: leading the new generation of oral platinum agents

Bhargava

Vaishampayan

2009

Expert Opinion on Investigational Drugs

127

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Background In recent years, JM-216/satraplatin (GPC Biotech, Inc.) has emerged as a novel oral platinum analogue with a better toxicity profile than cisplatin. Since satraplatin is more hydrophobic than cisplatin or oxaliplatin, it appears to demonstrate efficacy in cisplatin-resistant cell lines. The preclinical and clinical evaluation of satraplatin stimulated this review of the pharmacology and clinical trial data of this agent. Methods A literature review was conducted in the MEDLINE database from 1985 to present using the keywords ‘satraplatin’ or ‘JM-216’. The abstracts regarding satraplatin reported at the 2007 – 2009 American Society of Clinical Oncology meetings were also reviewed. Results/conclusion Satraplatin has a favorable toxicity profile, and appears to have clinical activity against a variety of malignancies such as breast, prostate and lung cancer. The oral route of administration and the intermittent schedule makes it very convenient for clinical use. Despite this, a FDA-approved indication has not yet been achieved. The only Phase III trial with satraplatin was conducted in pretreated metastatic castrate-resistant prostate cancer (CRPC), revealing an improvement in progression-free survival but no overall survival benefit. Future development would have to include designing trials in docetaxel-refractory metastatic CRPC, or in other malignancies where cisplatin is of benefit.

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Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients

Abstract: We conclude that oral JM216 shows no nephrotoxicity.

Cited by 20 publications

References 21 publications

Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study

Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study

A Better Platinum-Based Anticancer Drug Yet to Come?

Satraplatin: leading the new generation of oral platinum agents

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