Evofosfamide

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Evofosfamide
Evofosfamide.svg
Clinical data
Other namesTH-302; HAP-302
Identifiers
  • 2-bromo-N-[(2-bromoethylamino)-[(3-methyl-2-nitroimidazol-4-yl)methoxy]phosphoryl]ethanamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C9H16Br2N5O4P
Molar mass 449.040 g·mol−1
3D model (JSmol)
  • CN1C(=CN=C1[N+](=O)[O-])COP(=O)(NCCBr)NCCBr
  • InChI=InChI=1S/C9H16Br2N5O4P/c1-15-8(6-12-9(15)16(17)18)7-20-21(19,13-4-2-10)14-5-3-11/h6H,2-5,7H2,1H3,(H2,13,14,19)
  • Key:UGJWRPJDTDGERK-UHFFFAOYSA-N

Evofosfamide, formerly known as TH-302 is an investigational new drug that is being evaluated for the treatment of multiple tumor types, including pancreatic cancer, [1] soft tissue sarcoma, and multiple myeloma, often in combination with other therapies. It is a hypoxia-activated prodrug designed to target and kill hypoxic cells within tumors. It functions by releasing the DNA crosslinking agent bromo-isophosphoramide mustard under low oxygen conditions, making it potentially effective against tumor regions where standard chemotherapy and radiation therapies are less effective due to hypoxia. [2] [3] [4]

Contents

Commercialization has not been pursued due to the failure of several clinical trials. [5]

Pharmacology

Evofosfamide is a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). [2] Evofosfamide is activated by a process that involves a 1-electron (1 e−) reduction mediated by ubiquitous cellular reductases, such as the NADPH cytochrome P450, to generate a radical anion prodrug:

Evofosfamide is largely inactive under normal oxygen levels. In areas of hypoxia, evofosfamide becomes activated and converts to an alkylating cytotoxic agent resulting in DNA cross-linking. This renders cells unable to replicable their DNA and divide, leading to apoptosis. This investigational therapeutic approach of targeting the cytotoxin to hypoxic zones in tumors may cause less broad systemic toxicity that is seen with untargeted cytotoxic chemotherapies. [7]

The activation of evofosfamide to the active drug Br-IPM and the mechanism of action (MOA) via cross-linking of DNA is shown schematically below:

TH-302 Activation and Mechanism of action.png

Drug development history

Phosphorodiamidate-based, DNA-crosslinking, bis-alkylator mustards have long been used successfully in cancer chemotherapy and include e.g. the prodrugs ifosfamide and cyclophosphamide. To demonstrate that known drugs of proven efficacy could serve as the basis of efficacious hypoxia-activated prodrugs, the 2-nitroimidizole HAP of the active phosphoramidate bis-alkylator derived from ifosfamide was synthesized. The resulting compound, TH-281, had a high HCR (hypoxia cytotoxicity ratio), a quantitative assessment of its hypoxia selectivity. Subsequent structure-activity relationship (SAR) studies showed that replacement of the chlorines in the alkylator portion of the prodrug with bromines improved potency about 10-fold. The resulting, final compound is evofosfamide (TH-302) which was developed by Threshold Pharmaceuticals Inc. . [8] Threshold Pharmaceuticals Inc. applied for a patent on evofosfamide in 2006 which was granted in 2011. [9]

In 2012, Threshold signed a global license and co-development agreement for evofosfamide with Merck KGaA. Threshold was responsible for the development of evofosfamide in the soft tissue sarcoma indication in the United States. In all other cancer indications, Threshold and Merck KGaA developed evofosfamide together. [10] After evofosfamide failed to improve longevity in patients in phase three clinical trials, Merck abandoned attempts to commercialize evofosfamide in 2015. [5]

Chemistry

Synthesis

Evofosfamide synthesis involves several steps, starting with the preparation of 2-nitroimidazole derivatives:

  1. Preparation of 2-nitroimidazole: This is the key bioreductive group used in the synthesis.
  2. Formation of the prodrug: The 2-nitroimidazole is linked to a brominated derivative of isophosphoramide mustard.
  3. Activation under hypoxic conditions: In low oxygen environments, typical of solid tumors, the prodrug is activated to release the cytotoxic agent.

The activation under hypoxic conditions allows evofosfamide to target hypoxic tumor cells selectively, making it a candidate in for cancer treatment. [11] [12] [13]

Clinical trials

Overview and results

Evofosfamide (TH-302) was evaluated in clinical studies as a monotherapy and in combination with chemotherapy agents and other targeted cancer drugs. The indications were a broad spectrum of solid tumor types and blood cancers.

Evofosfamide clinical trials (as of 16 March 2025): [14]

Clinical Trials of TH-302 (Evofosfamide)
NCT IDTitlePhaseStudy Status
Clinical trial number NCT0074337 at ClinicalTrials.gov Dose-Escalation Study of TH-302PHASE1COMPLETED
Clinical trial number NCT0114445 at ClinicalTrials.gov Study of the Safety and Efficacy of TH-302PHASE2COMPLETED
Clinical trial number NCT0114991 at ClinicalTrials.gov Study of Hypoxia-Activated Prodrug TH-302 to Treat Advanced LeukemiasPHASE1COMPLETED
Clinical trial number NCT0138182 at ClinicalTrials.gov Dose-Escalation Study of TH-302 in Combination With SunitinibPHASE1UNKNOWN
Clinical trial number NCT0140361 at ClinicalTrials.gov Safety and Efficacy Study of TH-302 CNS Penetration in Recurrent High Grade AstrocytomaPHASE2COMPLETED
Clinical trial number NCT0144008 at ClinicalTrials.gov A Trial of TH-302 in Combination With DoxorubicinPHASE2COMPLETED
Clinical trial number NCT0148504 at ClinicalTrials.gov Dose Escalation Study of Pazopanib Plus TH-302PHASE1COMPLETED
Clinical trial number NCT0149744 at ClinicalTrials.gov Sorafenib Tosylate and Hypoxia-Activated Prodrug TH-302 in Treating Advanced Kidney or Liver CancerPHASE1COMPLETED
Clinical trial number NCT0152287 at ClinicalTrials.gov Open-label Study of TH-302 and DexamethasonePHASE1UNKNOWN
Clinical trial number NCT0172194 at ClinicalTrials.gov TH-302 Plus Doxorubicin Delivered by Trans-Arterial Chemoembolization (TACE)PHASE1UNKNOWN
Clinical trial number NCT0174697 at ClinicalTrials.gov Clinical Trial Testing TH-302 in Combination With GemcitabinePHASE3COMPLETED
Clinical trial number NCT0183354 at ClinicalTrials.gov A Japanese Phase 1 Trial of TH-302PHASE1COMPLETED
Clinical trial number NCT0186459 at ClinicalTrials.gov A Phase 2 Biomarker-Enriched Study of TH-302 in Advanced MelanomaPHASE2TERMINATED
Clinical trial number NCT0202022 at ClinicalTrials.gov A Cardiac Safety Study of TH-302PHASE1UNKNOWN
Clinical trial number NCT0204750 at ClinicalTrials.gov Phase I TH-302 Plus Gemcitabine Plus Nab-PaclitaxelPHASE1TERMINATED
Clinical trial number NCT0207629 at ClinicalTrials.gov A Phase 1 TH-302 Mass Balance TrialPHASE1COMPLETED
Clinical trial number NCT0209396 at ClinicalTrials.gov Study of TH-302 or Placebo in Combination With PemetrexedPHASE2TERMINATED
Clinical trial number NCT0225511 at ClinicalTrials.gov A Japanese Trial of TH-302 in Soft Tissue SarcomaPHASE2TERMINATED
Clinical trial number NCT0234237 at ClinicalTrials.gov TH-302 in Combination With Bevacizumab for GlioblastomaPHASE2COMPLETED
Clinical trial number NCT0240206 at ClinicalTrials.gov A Study to Assess the Safety and Efficacy of TH-302 and Sunitinib in Neuroendocrine Pancreatic TumoursPHASE1COMPLETED
Clinical trial number NCT0243369 at ClinicalTrials.gov Study of TH-302 Monotherapy as Second-line Treatment in Biliary Tract CancerPHASE2COMPLETED
Clinical trial number NCT0249689 at ClinicalTrials.gov A Study of Hypoxia Imaging in Pancreatic Cancer Patients Being Treated With Gemcitabine and TH-302NAWITHDRAWN
Clinical trial number NCT0259868 at ClinicalTrials.gov Testing TH-302, in Combination With Preoperative Chemoradiotherapy, in Esophageal CancerPHASE1WITHDRAWN
Clinical trial number NCT0271256 at ClinicalTrials.gov SARC021C: A Continuation Study of TH-CR-406/SARC021NANO_LONGER_AVAILABLE
Clinical trial number NCT0309816 at ClinicalTrials.gov Immunotherapy Study of Evofosfamide in Combination With IpilimumabPHASE1UNKNOWN
Clinical trial number NCT0678255 at ClinicalTrials.gov A Study of Evofosfamide in Combination with Zalifrelimab and BalstilimabPHASE1RECRUITING
Clinical trial number NCT0683672 at ClinicalTrials.gov Clinical Trial to Test Efficacy of Targeting Hypoxia Combined With ARSI After First-line ARSI Therapy for Castrate Resistant Prostate CancerPHASE2NOT_YET_RECR

Soft tissue sarcoma

Evofosfamide was tested in combination with doxorubicin in patients with advanced soft tissue sarcoma. The study TH-CR-403 was a single arm trial investigating evofosfamide in combination with doxorubicin. [15] Evofosfamide was further tested in the Phase 3 clinical trial TH-CR-406/SARC021 with results published in 2017 indicating no improvement in patient mortality rates. [16]

Metastatic pancreatic cancer

Evofosfamide was studied in combination with gemcitabine in patients with metastatic pancreatic cancer. The study TH-CR-404 compared gemcitabine with gemcitabine plus evofosfamide. [17] The study showed comparable efficacy profiles for evofosfamide and nab-paclitaxel when combined with gemcitabine; [18] however, the hematologic toxicity was higher for patients given evofosfamide vs. nab-paclitaxel.

In the Phase 3 MAESTRO study, patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with evofosfamide in combination with gemcitabine did not demonstrate a statistically significant improvement in overall survival. [19]

Nasopharyngeal Carcinoma

Oxygen deficient conditions are linked to tumor progression throughout the body and poses an issue in cancer treatments such as chemotherapy and radiation. [20] Hypoxia-activated prodrugs (HAPs) function in hypoxic conditions and inhibit the growth of tumor cells. [20] Evofosfamide is a HAP that targets tumor progression in nasopharyngeal carcinoma (NPC) tissues by inhibiting the overexpression of hypoxia-inducible factor-1α (HIF-1α). [21]

In this study , the efficacy of Evofosfamide along with cisplastin (DDP) in blocking cell progression was measured. "The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF-1α expression suppressed after evofosfamide treatment under hypoxic conditions". [21] These findings allow for evidence for Evofosfamide to be pushed towards clinical trials to further investigate the potential to be developed as an FDA approved anticancer drug.

See also

Hypoxia-activated prodrugs

Hypoxia

PR-104

CP-506

References

  1. ↑ Pourmorteza M, Rahman ZU, Young M (September 2016). "Evofosfamide, a new horizon in the treatment of pancreatic cancer". Anti-cancer Drugs. 27 (8): 723–5. doi:10.1097/CAD.0000000000000386. PMID   27232101.
  2. 1 2 Hong CR, Dickson BD, Jaiswal JK, Pruijn FB, Hunter FW, Hay MP, et al. (October 2018). "Cellular pharmacology of evofosfamide (TH-302): A critical re-evaluation of its bystander effects". Biochemical Pharmacology. 156: 265–280. doi:10.1016/j.bcp.2018.08.027. PMID   30134191.
  3. ↑ Li Y, Zhao L, Li XF (2021). "The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy". Frontiers in Pharmacology. 12: 636892. doi: 10.3389/fphar.2021.636892 . PMC   8091515 . PMID   33953675.
  4. ↑ "Evofosfamide". go.drugbank.com. Retrieved 2023-11-03.
  5. 1 2 "Merck abandons evofosfamide as two trials fail - PMLiVE". pmlive.com. 2015-12-09. Retrieved 2025-03-09.
  6. ↑ Weiss GJ, Infante JR, Chiorean EG, Borad MJ, Bendell JC, Molina JR, et al. (May 2011). "Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies". Clinical Cancer Research. 17 (9): 2997–3004. doi: 10.1158/1078-0432.CCR-10-3425 . PMID   21415214.
  7. ↑ Pento JT (2011). "TH-302". Drugs of the Future. 36 (9): 663–667. doi:10.1358/dof.2011.036.09.1678337. S2CID   258469551.
  8. ↑ Duan JX, Jiao H, Kaizerman J, Stanton T, Evans JW, Lan L, et al. (April 2008). "Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs". Journal of Medicinal Chemistry. 51 (8): 2412–2420. doi:10.1021/jm701028q. PMID   18257544.
  9. ↑ US 8003625,Matteucci M, Duan JX, Jiao H, Kaizerman J,"Phosphoramidate alkylator prodrugs",issued 2011-08-23, assigned to Immunogenesis Inc.
  10. ↑ "Threshold Pharmaceuticals and Merck KGaA Announce Global Agreement to Co-Develop and Commercialize Phase 3 Hypoxia-Targeted Drug TH-302 - Press release from 3 February 2012". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  11. ↑ "CPhI.cn: Synthetic routes to explore anti-pancreatic cancer drug Evofosfamide, 22 Jan 2015". Archived from the original on 14 February 2015. Retrieved 14 February 2015.
  12. ↑ O'Connor LJ, Cazares-Körner C, Saha J, Evans CN, Stratford MR, Hammond EM, et al. (2015-08-13). "Efficient synthesis of 2-nitroimidazole derivatives and the bioreductive clinical candidate Evofosfamide (TH-302)". Organic Chemistry Frontiers. 2 (9): 1026–1029. doi:10.1039/C5QO00211G. ISSN   2052-4129.
  13. ↑ "Evofosfamide". go.drugbank.com. Retrieved 2024-09-14.
  14. ↑ "Search results for: Evofosfamide". ClinicalTrials.gov.
  15. ↑ Chawla SP, Cranmer LD, Van Tine BA, Reed DR, Okuno SH, Butrynski JE, et al. (October 2014). "Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma". Journal of Clinical Oncology. 32 (29): 3299–3306. doi:10.1200/JCO.2013.54.3660. PMC   4588714 . PMID   25185097.
  16. ↑ Tap WD, Papai Z, Van Tine BA, Attia S, Ganjoo KN, Jones RL, et al. (August 2017). "Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial". The Lancet. Oncology. 18 (8): 1089–1103. doi:10.1016/S1470-2045(17)30381-9. PMC   7771354 . PMID   28651927.
  17. ↑ Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, et al. (May 2015). "Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer". Journal of Clinical Oncology. 33 (13): 1475–1481. doi:10.1200/JCO.2014.55.7504. PMC   4881365 . PMID   25512461.
  18. ↑ Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. (October 2013). "Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine". The New England Journal of Medicine. 369 (18): 1691–1703. doi:10.1056/NEJMoa1304369. PMC   4631139 . PMID   24131140.
  19. ↑ Van Cutsem E, Lenz HJ, Furuse J, Tabernero J, Heinemann V, Ioka T, et al. (2016-05-20). "MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC)". Journal of Clinical Oncology. 34 (15_suppl): 4007. doi:10.1200/JCO.2016.34.15_suppl.4007. ISSN   0732-183X.
  20. 1 2 Li Y, Zhao L, Li XF (2021-07-29). "Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy". Frontiers in Oncology. 11: 700407. doi: 10.3389/fonc.2021.700407 . PMC   8358929 . PMID   34395270.
  21. 1 2 Huang Y, Tian Y, Zhao Y, Xue C, Zhan J, Liu L, et al. (May 2018). "Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo". Cancer Communications. 38 (1): 1–9. doi: 10.1186/s40880-018-0285-0 . PMC   5993153 . PMID   29764490.
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