Altretamine

From discovery to approval

1. 1964 · Earliest report found

   A 1979 report describes hexamethylmelamine (NSC 13875) as a synthetic agent structurally related to triethylenemelamine. The earliest paper found is a 1964 report of it as a male housefly chemosterilant; the earliest anticancer record found is a 1965 phase I study (title only). Its synthesis was not traced.^{[2][3][4][5][6]}

2. 1990-12-26 · FDA regular · 26 years after first description

   Altretamine capsules (Hexalen), NDA 019926, original approval, classed as a new molecular entity with priority review and orphan status in the Drugs@FDA history. The label is not available there, so the indication at approval is not stated here. The type regular is an inference: no accelerated-approval wording was found.^[7]

How it works

It is extensively metabolised in animals and humans, and most evidence is consistent with the hypothesis that metabolic activation is needed for antitumour activity, although the reviewer notes this is not settled and that modest activity was seen in cells that did not metabolise it.^[1]

Where it came from and why

The sources read do not say why it was made or first tested. A 1986 review calls hexamethylmelamine the most widely used s-triazine in the clinic and says its low solubility and instability in solution largely restricted it to oral use.

Cancers

• Ovarian cancer

  A 2023 review says altretamine was first approved by the FDA in 1990 for refractory ovarian cancer. Studies in previously untreated stage III or IV, recurrent and platinum-resistant disease were published in 1979, 1997 and 2003.^[8]

Worth knowing

• In a 1979 study of 54 previously untreated women with stage III or IV ovarian carcinoma, 17 (31.8%) responded to single-agent HMM and three had no evidence of cancer at second-look operation; severe toxicity led to discontinuation in 10 patients.^[5]
• In a 1997 report of 52 patients with recurrent ovarian cancer given single-agent HMM, no patient with progressive disease on first-line cisplatin-based combination chemotherapy responded.^[9]
• In a phase II study of 31 women with platinum-resistant relapse, 3 had a partial response (9.7% intention to treat) and median time to progression was 10 weeks; the authors advised against altretamine as standard treatment in this setting.^[10]

References

1. Ames MM. Hexamethylmelamine: pharmacology and mechanism of action. Cancer Treat Rev. 1991;18 Suppl A:3-14. PubMedDOI
2. CHANG SC, TERRY PH, BORKOVEC AB. INSECT CHEMOSTERILANTS WITH LOW TOXICITY FOR MAMMALS. Science. 1964;144(3614):57-8. PubMedDOI
3. Wilson WL, De la Garza JG. Phase I study of hexamethylmelamine (NSC-13875). Cancer Chemother Rep. 1965;48:49-52. PubMed
4. Wilson WL, Schroeder JM, Bisel HF, Mrazek R, Hummel RP. Phase II study of hexamethylmelamine (NSC 13875). Cancer. 1969;23(1):132-6. PubMedDOI
5. Wharton JT, Rutledge F, Smith JP, Herson J, Hodge MP. Hexamethylmelamine: an evaluation of its role in the treatment of ovarian cancer. Am J Obstet Gynecol. 1979;133(7):833-44. PubMedDOI
6. Foster BJ, Clagett-Carr K, Hoth D, Leyland-Jones B. Pentamethylmelamine: review of an aqueous analog of hexamethylmelamine. Cancer Treat Rep. 1986;70(3):383-9. PubMed
7. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 019926 (altretamine; Hexalen). Page read 2026-10-26. Source
8. Dai Q, Sun Q, Ouyang X, Liu J, Jin L, Liu A, et al. Antitumor Activity of s-Triazine Derivatives: A Systematic Review. Molecules. 2023;28(11). PubMedDOI
9. Manetta A, Tewari K, Podczaski ES. Hexamethylmelamine as a single second-line agent in ovarian cancer: follow-up report and review of the literature. Gynecol Oncol. 1997;66(1):20-6. PubMedDOI
10. Keldsen N, Havsteen H, Vergote I, Bertelsen K, Jakobsen A. Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study. Gynecol Oncol. 2003;88(2):118-22. PubMedDOI