Thiotepa

From discovery to approval

1. c. 1953 · Earliest report found

   Thiotepa was developed in the 1950s according to a 2000 review; a US government profile says it was introduced in 1953. Shay and colleagues' 1953 paper on leukaemia (title only) is the earliest found. A 1990 paper credits American Cyanamid with synthesis and places clinical trials in the 1960s, which conflicts with the 1950s papers; no synthesis date was found.^{[2][3][4][5][6]}

2. 1959-03-09 · FDA regular · 6 years after first description

   Thiotepa injection, NDA 011683, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history; the application is now listed as discontinued. No label or letter is available there, so the indication at approval is not stated here. The 2017 Tepadina label gives 1959 as the year of initial US approval. The type regular is an inference: no accelerated-approval wording was found. The EMA assessment report for Tepadina (dated 17 December 2009) also states that the indication was approved in the USA in March 1959.^[7]

3. 2010-03-15 · EMA regular · 57 years after first description

   Marketing authorisation date 15 March 2010 (CHMP positive opinion 17 December 2009). Indications on the EPAR page: conditioning treatment before allogeneic or autologous haematopoietic progenitor cell transplantation in haematological diseases in adults and children, and treatment of solid tumours when high-dose chemotherapy with transplant support is appropriate. The page does not describe the authorisation as conditional or exceptional, so regular is an inference.^[8]

4. 2017-01-26 · FDA regular · 64 years after first description

   To reduce the risk of graft rejection when used with high-dose busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic progenitor cell transplantation in pediatric patients with class 3 beta-thalassemia (approval letter, NDA 208264, submitted under section 505(b)(2); Drugs@FDA lists standard review, orphan). The letter has no accelerated-approval wording, so regular is an inference. The label also lists breast and ovarian adenocarcinoma, malignant effusions and superficial papillary bladder carcinoma.^[9]

How it works

A polyfunctional alkylating agent related to the nitrogen mustards. Its radiomimetic action is believed to come from release of ethyleneimine radicals, which disrupt DNA bonds, beginning with alkylation of guanine at the N-7 position.^[1]

Where it came from and why

No cited source states why it was made. The US profile reports that it was also tested as an intermediate for flame retardants and as an insect chemosterilant, uses that were not developed commercially.

Cancers

• Leukaemia (early clinical reports)

  Shay and colleagues reported preliminary results in experimental and clinical leukaemia in 1953 (title only; no abstract in PubMed).^[2]

• Breast and ovarian adenocarcinoma

  The 2017 US label lists treatment of adenocarcinoma of the breast or ovary.^[1]

• Superficial papillary bladder cancer and malignant effusions

  The 2017 US label lists superficial papillary carcinoma of the urinary bladder (instilled into the bladder) and control of intracavitary effusions from neoplastic disease of serosal cavities.^[1]

• Conditioning before haematopoietic cell transplantation

  The 2017 US approval covered use with high-dose busulfan and cyclophosphamide before allogeneic transplantation in paediatric class 3 beta-thalassemia; the 2010 EU authorisation covers conditioning before allogeneic or autologous transplantation in haematological diseases and, when high-dose therapy with transplant support is appropriate, solid tumours.^[9]

Worth knowing

• A US government profile says thiotepa was introduced in 1953 for cancer chemotherapy and was commonly used until the early 1970s (only 3 kg used in 1973), was largely replaced by the nitrogen mustards, and by the late 1980s was also used at high doses with autologous bone marrow transplantation.^[4]
• The EMA assessment says the clinical development of thiotepa started in the middle of the 1950s and lists chronic leukaemia, non-Hodgkin and Hodgkin lymphoma, breast and ovarian adenocarcinoma, melanoma, paediatric and germ-cell tumours among the diseases treated.^[6]
• A 1990 paper (about 217 patients given high-dose thiotepa with autologous bone marrow transplantation) reports a maximal tolerated dose of 900 to 1,125 mg/m2, central nervous system toxicity as dose-limiting, and an overall response rate of about 50%.^[5]
• The 2017 Tepadina label gives 1959 as the year of initial US approval, although the 1959 application (Immunex) is now listed as discontinued and the 2017 approval was under section 505(b)(2).^[1]
• A US government profile summarises nine case reports from 1970 to 1978 of non-lymphocytic leukemia after thiotepa alone and lists thiotepa as known to be a human carcinogen.^[4]

References

1. U.S. Food and Drug Administration. Tepadina (thiotepa) for injection: prescribing information (NDA 208264, original approval, January 2017). Source
2. SHAY H, ZARAFONETIS C, SMITH N, WOLDOW I, SUN DC. Treatment of leukemia with triethylene thiophosphoramide (thio-TEPA); preliminary results in experimental and clinical leukemia. AMA Arch Intern Med. 1953;92(5):628-45. PubMedDOI
3. Maanen MJ, Smeets CJ, Beijnen JH. Chemistry, pharmacology and pharmacokinetics of N,N',N" -triethylenethiophosphoramide (ThioTEPA). Cancer Treat Rev. 2000;26(4):257-68. PubMedDOI
4. National Toxicology Program, U.S. Department of Health and Human Services. Thiotepa. In: Report on Carcinogens, Fifteenth Edition (released 21 December 2021). Source
5. Wolff SN, Herzig RH, Fay JW, LeMaistre CF, Brown RA, Frei-Lahr D, et al. High-dose N,N',N"-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: phase I studies. Semin Oncol. 1990;17(1 Suppl 3):2-6. PubMed
6. European Medicines Agency. Tepadina: CHMP assessment report, London, 17 December 2009 (EMA/CHMP/55233/2010), procedure EMEA/H/C/001046. Source
7. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history for NDA 011683 (thiotepa, Immunex). Page read 2026-10-26. Source
8. European Medicines Agency. Tepadina (thiotepa): EPAR medicine page (authorisation details). Page read 2026-10-26. Source
9. U.S. Food and Drug Administration. Approval letter, NDA 208264, Tepadina (thiotepa) for injection, Adienne SA, 26 January 2017. Source
10. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history for NDA 208264 (Tepadina, thiotepa). Page read 2026-10-26. Source