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Bending the Curve Trial by Trial
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Topoisomerase inhibitorsIn useDerivative of an earlier drug

Irinotecan

Also known as CPT-11, Camptosar

A semisynthetic, water-soluble derivative of camptothecin given by injection. The US label lists first-line therapy with fluorouracil and leucovorin, and use after initial fluorouracil-based therapy, for metastatic colorectal cancer.

From discovery to approval

  1. 1987 · Earliest report found

    Kunimoto and colleagues reported CPT-11 in 1987 as a novel water-soluble camptothecin derivative with activity against a broad range of mouse tumours. A second 1987 paper (in Japanese, with an English abstract) describes making many camptothecin derivatives; two active ones, 7-ethyl-camptothecin and SN-38, were insoluble, and CPT-11 was made as a soluble derivative.[2][3][4][5][1]

  2. 1996-06-14 · FDA accelerated

    Treatment of patients with metastatic carcinoma of the colon or rectum whose disease has progressed following 5-FU-based therapy. The approval letter says the application was reviewed according to the regulations for accelerated approval and approved under 21 CFR 314.510, with a requirement to verify clinical benefit in a controlled trial. The letter's date stamp reads JUN 14 1996 (degraded in the scan); Drugs@FDA lists 06/14/1996 and the 22 October 1998 letter refers to the approval letter dated June 14, 1996.[6]

  3. 1998-10-22 · FDA converted

    Metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following 5-FU-based therapy. The letter states the NDA was approved under the accelerated approval regulations (21 CFR 314.510) and that approval of this supplement fulfils those commitments; it does not use the word 'converted'. The letter carries the date stamp 22 October 1998 (also the user-fee goal date it states, and the date the April 2000 letter gives for this approval letter).[7]

  4. 2000-04-20 · FDA regular

    As a component of first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum (the letter contains no accelerated-approval wording, so the type is an inference).[8]

How it works

The label says irinotecan and its active metabolite SN-38 bind the topoisomerase I-DNA complex and prevent re-ligation of single-strand breaks; cytotoxicity is thought to come from double-strand damage during DNA synthesis, which cells cannot efficiently repair.[1]

Where it came from and why

The stated aim was water-soluble camptothecin analogues with higher activity and less toxicity. A 2006 review says the water-soluble sodium salt of camptothecin, introduced in early trials in the 1960s, was highly toxic in animals, and that irinotecan and topotecan did not cause haemorrhagic cystitis.

Cancers

  • Colorectal cancer

    The 2022 US label lists first-line therapy with fluorouracil and leucovorin for metastatic carcinoma of the colon or rectum, and use after recurrence or progression on initial fluorouracil-based therapy.[1]

  • Small cell lung cancer

    In a multicentre phase 3 study of extensive small cell lung cancer, irinotecan plus cisplatin gave a median survival of 12.8 months against 9.4 months with etoposide plus cisplatin (P=0.002); enrolment stopped early at 154 patients after an interim analysis.[9]

  • Non-small-cell lung cancer

    In the 1991 phase I study of weekly CPT-11 in 17 patients with advanced non-small-cell lung cancer, two previously untreated patients had partial responses.[10]

Family and partners

Derived from: Camptothecin

Worth knowing

  • A 2006 review calls irinotecan a prodrug that must be converted to SN-38, and says patients with Gilbert's syndrome and other forms of glucuronidation deficiency are at higher risk of neutropenia and diarrhoea.[5]
  • A 2025 review says irinotecan was first approved in Japan in 1994 and then in the United States in 1996; no Japanese regulatory document was read.[11]
  • In a randomised trial after fluorouracil failure, one-year survival was 36.2% with irinotecan and supportive care against 13.8% with supportive care alone.[12]
  • In a randomised trial against continuous-infusion fluorouracil after fluorouracil failure, median survival was 10.8 months with irinotecan and 8.5 months with fluorouracil (P=0.035).[13]

On this site

References

  1. U.S. Food and Drug Administration. Camptosar (irinotecan hydrochloride injection), prescribing information, NDA 020571 supplement 053 (action date 27 January 2022; Initial U.S. Approval 1996). Source
  2. Kunimoto T, Nitta K, Tanaka T, Uehara N, Baba H, Takeuchi M, et al. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res. 1987;47(22):5944-7. PubMed
  3. Nitta K, Yokokura T, Sawada S, Kunimoto T, Tanaka T, Uehara N, et al. [Antitumor activity of new derivatives of camptothecin]. Gan To Kagaku Ryoho. 1987;14(3 Pt 2):850-7. PubMed
  4. Sawada S, Okajima S, Aiyama R, Nokata K, Furuta T, Yokokura T, et al. Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem Pharm Bull (Tokyo). 1991;39(6):1446-50. PubMedDOI
  5. Hartmann JT, Lipp HP. Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 2006;29(3):209-30. PubMedDOI
  6. U.S. Food and Drug Administration. Approval letter, NDA 20-571, Camptosar (irinotecan hydrochloride) Injection, The Upjohn Company, date stamp JUN 14 1996 (page 6 of FDA's historical file for the application; the stamp is degraded in the scan but readable, and the 22 October 1998 supplement letter refers to the approval letter dated June 14, 1996). Source
  7. US Food and Drug Administration. Supplement approval letter, Camptosar (irinotecan hydrochloride injection), NDA 20-571/S-008, Pharmacia & Upjohn; letter dated 22 October 1998 (date stamp on the scanned letter; the letter also gives 22 October 1998 as the user-fee goal date). Source
  8. US Food and Drug Administration. Supplement approval letter, Camptosar (irinotecan hydrochloride injection), NDA 20-571/S-009, Pharmacia & Upjohn; letter dated 20 April 2000. Source
  9. Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, Yokoyama A, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346(2):85-91. PubMedDOI
  10. Negoro S, Fukuoka M, Masuda N, Takada M, Kusunoki Y, Matsui K, et al. Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst. 1991;83(16):1164-8. PubMedDOI
  11. Gong J, Zhang W, Balthasar JP. Camptothein-Based Anti-Cancer Therapies and Strategies to Improve Their Therapeutic Index. Cancers (Basel). 2025;17(6). PubMedDOI
  12. Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352(9138):1413-8. PubMedDOI
  13. Rougier P, Van Cutsem E, Bajetta E, Niederle N, Possinger K, Labianca R, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998;352(9138):1407-12. PubMedDOI
  14. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 020571 (Camptosar, irinotecan hydrochloride). Page read 2026-10-29. Source