Fotemustine

From discovery to approval

1. 1987 · Earliest report found

   A 1990 report says fotemustine was recently developed by the French company Servier, with an aminophosphonic acid grafted onto the chloronitrosourea radical. The earliest paper found is the 1987 phase I study of S 10036, which a 1989 title identifies as fotemustine; its synthesis was not traced.^[2][3][4][5]

2. No approval is recorded on this site.

How it works

A chloroethylating nitrosourea: this group alkylates DNA, first forming single-base adducts and then interstrand crosslinks that block replication and transcription. A review says the phosphonoalanine group makes fotemustine highly lipophilic, with better diffusion through cell membranes and the blood-brain barrier.^[1]

Where it came from and why

The phase I report says it was evaluated because of its activity in the National Cancer Institute panel screen and its rational chemical approach. Preclinical studies found lower mutagenicity and hepatotoxicity than BCNU.

Cancers

• Disseminated malignant melanoma

  Phase II studies from 1988 tested fotemustine in disseminated malignant melanoma, including cerebral metastases; the 1992 overview reports a response rate of 24.2% in 153 evaluable patients.^[6]

• Primary brain tumours and brain metastases

  A 1994 review reports an objective response rate of 26.3% among 38 evaluable patients with recurrent malignant glioma, and a 2012 review says fotemustine is registered for primary brain tumours.^[7]

Worth knowing

• In the 1987 phase I study of 22 evaluable patients, fotemustine was given as a 60-minute infusion weekly for four weeks, and thrombocytopenia was the only acute dose-limiting toxicity.^[3]
• An interim phase II report in 1988 recorded eight partial responses (response rate 26.67%) among 30 evaluable patients with disseminated melanoma, including two partial responses among seven patients with cerebral metastasis.^[8]
• A 2012 review says fotemustine has been registered for two indications, disseminated malignant melanoma including cerebral metastases and primary brain tumours, and reports objective response rates of 26% to 70% in recurrent glioma and a median survival of about 10 months.^[4]

References

1. Nikolova T, Roos WP, Krämer OH, Strik HM, Kaina B. Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling. Biochim Biophys Acta Rev Cancer. 2017;1868(1):29-39. PubMedDOI
2. Cour V, Langenbahn H. [Fotemustine, a new nitrosourea derivative. Current status of development]. Onkologie. 1990;13(1):7-11. PubMed
3. Khayat D, Lokiec F, Bizzari JP, Weil M, Meeus L, Sellami M, et al. Phase I clinical study of the new amino acid-linked nitrosourea, S 10036, administered on a weekly schedule. Cancer Res. 1987;47(24 Pt 1):6782-5. PubMed
4. Beauchesne P. Fotemustine: a third-generation nitrosourea for the treatment of recurrent malignant gliomas. Cancers (Basel). 2012;4(1):77-87. PubMedDOI
5. Deray G, Khayat D, Bizzari JP, Jacquillat C. Renal hemodynamic and tubular effects of S 10036 (fotemustine) in man. Clin Nephrol. 1989;32(3):150. PubMed
6. Khayat D, Avril MF, Gerard B, Bertrand P, Bizzari JP, Cour V. Fotemustine: an overview of its clinical activity in disseminated malignant melanoma. Melanoma Res. 1992;2(3):147-51. PubMed
7. Khayat D, Giroux B, Berille J, Cour V, Gerard B, Sarkany M, et al. Fotemustine in the treatment of brain primary tumors and metastases. Cancer Invest. 1994;12(4):414-20. PubMedDOI
8. Khayat D, Bizzari JP, Frenay M, Naman H, Weil M, Goupil A, et al. Interim report of phase II study of new nitrosourea S 10036 in disseminated malignant melanoma. J Natl Cancer Inst. 1988;80(17):1407-8. PubMedDOI