A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473)

Our plain-English summary of A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473), by P. Beale, I. Judson, A. O'Donnell, et al (British Journal of Cancer, 2003).

The study

• Authors: P. Beale, I. Judson, A. O'Donnell, J. Trigo, C. Rees, F. Raynaud, A. Turner, L. Simmons, L. Etterley
• Journal: British Journal of Cancer
• Published: 2003;88(7):1128-34
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1-8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m(-2). Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m(-2). Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m(-2) every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

In plain English

This article reported an early-stage (Phase I) trial of AMD473, an experimental platinum-based cancer drug, at the Royal Marsden Hospital. Between November 1997 and December 1999, 42 patients with advanced solid tumours, 7 of them with mesothelioma, received 147 treatment cycles by intravenous infusion. Doses rose from 12 to 150 mg per square metre of body surface. Almost all patients had had earlier chemotherapy, 37 of them platinum drugs. The article does not discuss asbestos. Low platelet and neutrophil blood counts limited the dose, and 30 patients (71%) had low platelets. No drug-related kidney damage was seen. One patient with ovarian cancer had a confirmed partial tumour shrinkage. A second ovarian response was not confirmed by a repeat scan. Five other patients, with mesothelioma, ovarian, non-small cell lung cancer or melanoma, had stable disease. One further mesothelioma patient, whose disease was described as not evaluable, had less pain and returned to work. The authors set the maximum tolerated dose at 150 mg per square metre and recommended 120 mg per square metre every 21 days for further study.

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: Open-label, dose-escalating, single-centre Phase I drug trial
• Who was studied: 42 patients with advanced solid tumours treated at the Royal Marsden Hospital between 10 November 1997 and 14 December 1999. By tumour type: ovary 10, non-small cell lung 9, mesothelioma 7, head and neck 6, colon 3, other 7. 41 (98%) had prior chemotherapy and 37 (88%) had prior platinum.
• Exposure: The experimental platinum drug AMD473, given as an intravenous infusion at doses of 12, 24, 48, 96, 110, 120, 130 and 150 mg per square metre, every 21 or 28 days. Asbestos exposure is not addressed.
• Main results:
  • Low platelet count (thrombocytopenia) was the most common toxicity, seen in 30 of 42 patients (71%). There were 103 episodes, of which 24% were grade 3 or higher.
  • At 150 mg per square metre, given every 4 weeks to six less heavily pretreated patients with good performance status, three of the six had dose-limiting toxicity.
  • No drug-related kidney toxicity was observed.
  • Free (ultrafiltrable) platinum exposure in the blood increased linearly with dose (r2 = 0.79).
  • Best response among all 42 patients: partial response 1 (2.4%), stable disease 6 (14.3%), early progression 3 (7.1%), progressive disease 12 (28.6%), not evaluable 19 (45.2%), not assessed 1 (2.4%).
  • A second ovarian cancer patient had a partial response after two cycles, but this was not confirmed by a second CT scan.
  • Five other patients had stable disease after multiple cycles. They had mesothelioma, ovarian carcinoma, non-small cell lung cancer or melanoma.
  • One further mesothelioma patient, whose disease was not evaluable, had reduced pain and improved breathing and effort capacity, and returned to work.
  • One patient with ovarian cancer died of rectal bleeding while having a low platelet count. The authors felt the death was due to disease progression rather than drug toxicity.
• The authors' conclusion: The authors concluded that the maximum tolerated dose was 150 mg per square metre, with myelosuppression (mainly low platelets) being dose-limiting. They recommended 120 mg per square metre every 21 days for Phase II study. They saw evidence of activity in ovarian cancer despite prior platinum therapy.
• Limitations the authors state:
  • Formal nerve conduction studies were not performed.
  • Serial 51Cr EDTA kidney function evaluations were not performed.
  • The sensitivity of the drug-level assay was stretched at the lower dose levels.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Neutropenia, Ovarian Cancer, Mesothelioma, Performance Status.

Related studies

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• Phase II trial of ZD0473 as second-line therapy in mesothelioma — G. Giaccone, M.E. O'Brien, et al. (2002)
• EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells — H.I. Onen, A. Yilmaz, et al. (2015)
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• Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion — I. Rassmann, R. Thödtmann, et al. (1998)
• 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)

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