Evofosfamide

Last updated
Evofosfamide
Evofosfamide.svg
Names
Preferred IUPAC name
(1-Methyl-2-nitro-1H-imidazol-5-yl)methyl N,N′-bis(2-bromoethyl)phosphorodiamidate
Other names
TH-302; HAP-302
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
  • 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) Yes check.svgY
    Key: UGJWRPJDTDGERK-UHFFFAOYSA-N Yes check.svgY
  • CN1C(=CN=C1[N+](=O)[O-])COP(=O)(NCCBr)NCCBr
Properties
C9H16Br2N5O4P
Molar mass 449.040 g·mol−1
6 to 7 g/L
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Evofosfamide (INN, [1] USAN; [2] formerly known as TH-302) is a compound being evaluated in clinical trials for the treatment of multiple tumor types as a monotherapy and in combination with chemotherapeutic agents and other targeted cancer drugs.

Contents

This compound has been evaluated in the treatment of solid tumors, as a hypoxia-activated prodrug (HAPs), such chemical agents in low oxygen conditions undergo bio-reduction to yield cancer fighting cytotoxic breakdown products.

Many such agents have been developed, though this compound has been extensively studied, in preclinical and clinical studies. [3] [4]

Collaboration

Evofosfamide was developed by Threshold Pharmaceuticals Inc. In 2012, Threshold signed a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany (EMD Serono Inc. in the US and Canada), which includes an option for Threshold to co-commercialize evofosfamide in the United States. Threshold is 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 are developing evofosfamide together. [5] From 2012 to 2013, Merck KGaA paid 110 million US$ for upfront payment and milestone payments to Threshold. Additionally, Merck KGaA covers 70% of all evofosfamide development expenses. [6]

Mechanism of prodrug activation and Mechanism of action (MOA) of the released drug

Evofosfamide is a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). 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 essentially 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. [8]

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). [9]

Synthesis

Evofosfamide can be synthesized in 7 steps. [10] [11]

Formulation

The evofosfamide drug product formulation used until 2011 was a lyophilized powder. The current drug product formulation is a sterile liquid containing ethanol, dimethylacetamide and polysorbate 80. For intravenous infusion, the evofosfamide drug product is diluted in 5% dextrose in WFI. [12]

Diluted evofosfamide formulation (100 mg/mL evofosfamide, 70% ethanol, 25% dimethylacetamide and 5% polysorbate 80; diluted to 4% v/v in 5% dextrose or 0.9% NaCl) can cause leaching of DEHP from infusion bags containing PVC plastic. [13]

Clinical trials

Overview and results

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

Evofosfamide clinical trials (as of 21 November 2014) [14] sorted by (Estimated) Primary Completion Date: [15]

Soft tissue sarcoma

Both, evofosfamide and ifosfamide have been investigated in combination with doxorubicin in patients with advanced soft tissue sarcoma. The study TH-CR-403 is a single arm trial investigating evofosfamide in combination with doxorubicin. [36] The study EORTC 62012 compares doxorubicin with doxorubicin plus ifosfamide. [37] Doxorubicin and ifosfamide are generic products sold by many manufacturers.

The indirect comparison of both studies shows comparable hematologic toxicity and efficacy profiles of evofosfamide and ifosfamide in combination with doxorubicin. However, a longer overall survival of patients treated with evofosfamide/doxorubicin (TH-CR-403) trial was observed. The reason for this increase is probably the increased number of patients with certain sarcoma subtypes in the evofosfamide/doxorubicin TH-CR-403 trial, see table below.

However, in the Phase 3 TH-CR-406/SARC021 study (conducted in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC)), patients with locally advanced unresectable or metastatic soft tissue sarcoma treated with evofosfamide in combination with doxorubicin did not demonstrate a statistically significant improvement in OS compared with doxorubicin alone (HR: 1.06; 95% CI: 0.88 - 1.29).[ citation needed ]

Metastatic pancreatic cancer

Both, evofosfamide and protein-bound paclitaxel (nab-paclitaxel) have been investigated in combination with gemcitabine in patients with metastatic pancreatic cancer. The study TH-CR-404 compares gemcitabine with gemcitabine plus evofosfamide. [40] The study CA046 compares gemcitabine with gemcitabine plus nab-paclitaxel. [41] Gemcitabine is a generic product sold by many manufacturers.

The indirect comparison of both studies shows comparable efficacy profiles of evofosfamide and nab-paclitaxel in combination with gemcitabine. However, the hematologic toxicity is increased in patients treated with evofosfamide/gemcitabine (TH-CR-404 trial), see table below.

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 (OS) compared with gemcitabine plus placebo (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.71 - 1.01; p=0.0589).[ citation needed ]

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. [44] Hypoxia-activated prodrugs (HAPs) function in hypoxic conditions and inhibit the growth of tumor cells. [45] Evofosfamide is a HAP that targets tumor progression in nasopharyngeal carcinoma (NPC) tissues by inhibitng the overexpression of hypoxia-inducible factor-1α (HIF-1α). [46]

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". [47] 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.

Drug development risks

Risks published in the quarterly/annual reports of Threshold and Merck KGaA that could affect the further development of evofosfamide (TH-302):

The evofosfamide formulation that Threshold and Merck KGaA are using in the clinical trials was changed in 2011 [48] to address issues with storage and handling requirements that were not suitable for a commercial product. Additional testing is ongoing to verify if the new formulation is suitable for a commercial product. If this new formulation is also not suitable for a commercial product another formulation has to be developed and some or all respective clinical phase 3 trials may be required to be repeated which could delay the regulatory approvals. [49]

Even if Threshold/Merck KGaA succeed in obtaining regulatory approvals and bringing evofosfamide to the market, the amount reimbursed for evofosfamide may be insufficient and could adversely affect the profitability of both companies. Obtaining reimbursement for evofosfamide from third-party and governmental payors depend upon a number of factors, e.g. effectiveness of the drug, suitable storage and handling requirements of the drug and advantages over alternative treatments.

There could be the case that the data generated in the clinical trials are sufficient to obtain regulatory approvals for evofosfamide but the use of evofosfamide has a limited benefit for the third-party and governmental payors. In this case Threshold/Merck KGaA could be forced to provide supporting scientific, clinical and cost effectiveness data for the use of evofosfamide to each payor. Threshold/Merck KGaA may not be able to provide data sufficient to obtain reimbursement. [50]

Each cancer indication has a number of established medical therapies with which evofosfamide will compete, for example:

Threshold relies on third-party contract manufacturers for the manufacture of evofosfamide to meet its and Merck KGaA's clinical supply needs. Any inability of the third-party contract manufacturers to produce adequate quantities could adversely affect the clinical development and commercialization of evofosfamide. Furthermore, Threshold has no long-term supply agreements with any of these contract manufacturers and additional agreements for more supplies of evofosfamide will be needed to complete the clinical development and/or commercialize it. In this regard, Merck KGaA has to enter into agreements for additional supplies or develop such capability itself. The clinical programs and the potential commercialization of evofosfamide could be delayed if Merck KGaA is unable to secure the supply. [52]

History

DateEvent
Jun 2005Threshold files evofosfamide (TH-302) patent applications in the U.S. [53]
Jun 2006Threshold files an evofosfamide (TH-302) patent application in the EU and in Japan [54]
Sep 2011Threshold starts a Phase 3 trial (TH-CR-406) of evofosfamide in combination with doxorubicin in patients with soft tissue sarcoma
Feb 2012Threshold signs an agreement with Merck KGaA to co-develop evofosfamide
Apr 2012A Phase 2b trial (TH-CR-404) of evofosfamide in combination with gemcitabine in patients with pancreatic cancer meets primary endpoint
Jan 2013Merck KGaA starts a global Phase 3 trial (MAESTRO) of evofosfamide in combination with gemcitabine in patients with pancreatic cancer
Dec 2015two Phase 3 trials fail, Merck will not apply for a license[ citation needed ]

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References

  1. ↑ WHO Drug Information; Recommended INN: List 73
  2. ↑ Adopted Names of the United States Adopted Names Council
  3. ↑ Li, Yue; Zhao, Long; Li, Xiao-Feng (2021). "The Hypoxia-Activated Prodrug TH-302: Exploiting Hypoxia in Cancer Therapy". Frontiers in Pharmacology. 12. doi: 10.3389/fphar.2021.636892 . ISSN   1663-9812. PMC   8091515 . PMID   33953675.
  4. ↑ "Evofosfamide". go.drugbank.com. Retrieved 2023-11-03.
  5. ↑ "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.
  6. ↑ "Threshold Pharmaceuticals Form 8-K from 3 Nov 2014". Archived from the original on 6 November 2014. Retrieved 5 November 2014.
  7. ↑ Weiss, G. J.; Infante, J. R.; Chiorean, E. G.; Borad, M. J.; Bendell, J. C.; Molina, J. R.; Tibes, R.; Ramanathan, R. K.; Lewandowski, K.; Jones, S. F.; Lacouture, M. E.; Langmuir, V. K.; Lee, H.; Kroll, S.; Burris, H. A. (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.
  8. ↑ J. Thomas Pento (2011). "TH-302". Drugs of the Future. 36 (9): 663–667. doi:10.1358/dof.2011.036.09.1678337. S2CID   258469551.
  9. ↑ Duan J; Jiao, H; Kaizerman, J; Stanton, T; Evans, JW; Lan, L; Lorente, G; Banica, M; et al. (2008). "Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs". J. Med. Chem. 51 (8): 2412–20. doi:10.1021/jm701028q. PMID   18257544.
  10. ↑ "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.
  11. ↑ Synthetic route Reference: International patent application WO2007002931A2
  12. ↑ FDA Advisory Committee Briefing Materials Available for Public Release, TH-302: Pediatric oncology subcommittee of the oncologic drugs advisory committee (ODAC) meeting, December 4, 2012
  13. ↑ "AAPS 2014 – Measurement of Diethylhexyl Phthalate (DEHP) Leached from Polyvinyl Chloride (PVC) Containing Plastics by Infusion Solutions Containing an Organic Parenteral Formulation – Poster W4210, Nov 5, 2014" (PDF). Archived from the original (PDF) on April 3, 2015. Retrieved March 11, 2015.
  14. ↑ ClinicalTrials.gov
  15. ↑ The Primary Completion Date is defined as the date when the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome.
  16. ↑ "Detailed Results From Positive Phase 2b Trial of TH-302 in Pancreatic Cancer at AACR Annual Meeting - Press release from 30 March 2012". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  17. ↑ "TH-302 Plus Gemcitabine vs. Gemcitabine in Patients with Untreated Advanced Pancreatic Adenocarcinoma. Borad et al. Presentation at the European Society for Medical Oncology (ESMO) 2012 Congress, September 2012. (Abstract 6660)" (PDF). Archived from the original (PDF) on 2014-08-31. Retrieved 2014-10-29.
  18. ↑ Stifel 2014 Healthcare Conference; Speaker: Harold Selick - 18 November 2014
  19. ↑ "Updated Phase 2 Results Including Analyses of Maintenance Therapy With TH-302 Following Induction Therapy With TH-302 Plus Doxorubicin in Soft Tissue Sarcoma - Press release from 15 November 2012". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  20. ↑ "TH-302 Maintenance Following TH-302 Plus Doxorubicin Induction: The Results of a Phase 2 Study of TH-302 in Combination with Doxorubicin in Soft Tissue Sarcoma. Ganjoo et al. Connective Tissue Oncology Society (CTOS) 2012 Meeting, November 2012" (PDF). Archived from the original (PDF) on 2014-08-31. Retrieved 2014-10-29.
  21. ↑ Chawla, Sant P.; Cranmer, Lee D.; Van Tine, Brian A.; Reed, Damon R.; Okuno, Scott H.; Butrynski, James E.; Adkins, Douglas R.; Hendifar, Andrew E.; Kroll, Stew; Ganjoo, Kristen N. (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.
  22. ↑ "Follow-Up Data From a Phase 1/2 Clinical Trial of TH-302 in Solid Tumors - Press release from 12 October 2010". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  23. ↑ "TH-302 Continues to Demonstrate Promising Activity in Pancreatic Cancer Phase 1/2 Clinical Trial - Press release from 24 January 2011". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  24. ↑ "TH-302, a tumor selective hypoxia-activated prodrug, complements the clinical benefits of gemcitabine in first line pancreatic cancer. Borad et al. ASCO Gastrointestinal Cancers Symposium, January 2011" (PDF). Archived from the original (PDF) on 2014-09-01. Retrieved 2014-10-29.
  25. ↑ Stifel 2014 Healthcare Conference; Speaker: Harold Selick - 18 November 2014
  26. ↑ Borad et al., ESMO Annual Meeting, October 2010
  27. ↑ Video interview of Stefan Oschmann, CEO Pharma at Merck - Merck Serono Investor & Analyst Day 2014 - 18 Sept 2014 - 2:46 min - Youtube
  28. ↑ "The Phase 3 Trial of TH-302 in Patients With Advanced Soft Tissue Sarcoma Will Continue as Planned Following Protocol-Specified Interim Analysis - Press release from 22 September 2014". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  29. ↑ "Threshold Pharmaceuticals' Partner Merck KGaA, Darmstadt, Germany, Completes Target Enrollment in the TH-302 Phase 3 MAESTRO Study in Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma - Press release from 3 November 2014". Archived from the original on 10 November 2014. Retrieved 9 November 2014.
  30. ↑ "Data From Ongoing Phase 1/2 Trial of TH-302 Plus Bevacizumab (Avastin(R)) in Patients With Recurrent Glioblastoma - Press release from 30 May 2014". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
  31. ↑ "Phase 1/2 Study of Investigational Hypoxia-Targeted Drug, TH-302, and Bevacizumab in Recurrent Glioblastoma Following Bevacizumab Failure. Brenner, et al. 2014 ASCO, 7 – 30 May 2014" (PDF). Archived from the original (PDF) on 31 August 2014. Retrieved 29 October 2014.
  32. ↑ "Phase 1/2 Interim Data Signaling Activity of TH-302 Plus Bevacizumab (Avastin(R)) in Patients With Glioblastoma - Press release from 17 November 2014". Archived from the original on 29 November 2014. Retrieved 17 November 2014.
  33. ↑ "Threshold Pharmaceuticals' Partner Merck KGaA, Darmstadt, Germany, Completes Target Enrollment in the TH-302 Phase 3 MAESTRO Study in Patients With Locally Advanced or Metastatic Pancreatic Adenocarcinoma - Press release from 3 November 2014". Archived from the original on 10 November 2014. Retrieved 9 November 2014.
  34. ↑ Stifel 2014 Healthcare Conference; Speaker: Harold Selick - 18 November 2014
  35. ↑ Stifel 2014 Healthcare Conference; Speaker: Harold Selick - 18 November 2014
  36. ↑ Chawla, Sant P.; Cranmer, Lee D.; Van Tine, Brian A.; Reed, Damon R.; Okuno, Scott H.; Butrynski, James E.; Adkins, Douglas R.; Hendifar, Andrew E.; Kroll, Stew; Ganjoo, Kristen N. (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.
  37. ↑ Judson, Ian; Verweij, Jaap; Gelderblom, Hans; Hartmann, Jörg T.; Schöffski, Patrick; Blay, Jean-Yves; Kerst, J Martijn; Sufliarsky, Josef; Whelan, Jeremy; Hohenberger, Peter; Krarup-Hansen, Anders; Alcindor, Thierry; Marreaud, Sandrine; Litière, Saskia; Hermans, Catherine; Fisher, Cyril; Hogendoorn, Pancras C W.; Dei Tos, A Paolo; Van Der Graaf, Winette T A.; European Organisation Treatment of Cancer Soft Tissue Bone Sarcoma Group (2014). "Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled phase 3 trial". The Lancet Oncology. 15 (4): 415–423. doi:10.1016/S1470-2045(14)70063-4. hdl: 1887/104639 . PMID   24618336.
  38. ↑ Judson, Ian; Verweij, Jaap; Gelderblom, Hans; Hartmann, Jörg T.; Schöffski, Patrick; Blay, Jean-Yves; Kerst, J Martijn; Sufliarsky, Josef; Whelan, Jeremy; Hohenberger, Peter; Krarup-Hansen, Anders; Alcindor, Thierry; Marreaud, Sandrine; Litière, Saskia; Hermans, Catherine; Fisher, Cyril; Hogendoorn, Pancras C W.; Dei Tos, A Paolo; Van Der Graaf, Winette T A.; European Organisation Treatment of Cancer Soft Tissue Bone Sarcoma Group (2014). "Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled phase 3 trial". The Lancet Oncology. 15 (4): 415–423. doi:10.1016/S1470-2045(14)70063-4. hdl: 1887/104639 . PMID   24618336.
  39. ↑ Chawla, Sant P.; Cranmer, Lee D.; Van Tine, Brian A.; Reed, Damon R.; Okuno, Scott H.; Butrynski, James E.; Adkins, Douglas R.; Hendifar, Andrew E.; Kroll, Stew; Ganjoo, Kristen N. (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.
  40. ↑ Borad, Mitesh J.; Reddy, Shantan G.; Bahary, Nathan; Uronis, Hope E.; Sigal, Darren; Cohn, Allen L.; Schelman, William R.; Stephenson, Joe; Chiorean, E. Gabriela; Rosen, Peter J.; Ulrich, Brian; Dragovich, Tomislav; Del Prete, Salvatore A.; Rarick, Mark; Eng, Clarence; Kroll, Stew; Ryan, David P. (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.
  41. ↑ von Hoff, Daniel D.; Ervin, Thomas; Arena, Francis P.; Chiorean, E. Gabriela; Infante, Jeffrey; Moore, Malcolm; Seay, Thomas; Tjulandin, Sergei A.; Ma, Wen Wee; Saleh, Mansoor N.; Harris, Marion; Reni, Michele; Dowden, Scot; Laheru, Daniel; Bahary, Nathan; Ramanathan, Ramesh K.; Tabernero, Josep; Hidalgo, Manuel; Goldstein, David; Van Cutsem, Eric; Wei, Xinyu; Iglesias, Jose; Renschler, Markus F. (2013). "Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine". New England Journal of Medicine. 369 (18): 1691–1703. doi:10.1056/NEJMoa1304369. PMC   4631139 . PMID   24131140.
  42. ↑ von Hoff, Daniel D.; Ervin, Thomas; Arena, Francis P.; Chiorean, E. Gabriela; Infante, Jeffrey; Moore, Malcolm; Seay, Thomas; Tjulandin, Sergei A.; Ma, Wen Wee; Saleh, Mansoor N.; Harris, Marion; Reni, Michele; Dowden, Scot; Laheru, Daniel; Bahary, Nathan; Ramanathan, Ramesh K.; Tabernero, Josep; Hidalgo, Manuel; Goldstein, David; Van Cutsem, Eric; Wei, Xinyu; Iglesias, Jose; Renschler, Markus F. (2013). "Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine". New England Journal of Medicine. 369 (18): 1691–1703. doi:10.1056/NEJMoa1304369. PMC   4631139 . PMID   24131140.
  43. ↑ Borad, Mitesh J.; Reddy, Shantan G.; Bahary, Nathan; Uronis, Hope E.; Sigal, Darren; Cohn, Allen L.; Schelman, William R.; Stephenson, Joe; Chiorean, E. Gabriela; Rosen, Peter J.; Ulrich, Brian; Dragovich, Tomislav; Del Prete, Salvatore A.; Rarick, Mark; Eng, Clarence; Kroll, Stew; Ryan, David P. (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.
  44. ↑ Li, Yue; Zhao, Long; Li, Xiao-Feng (2021-07-29). "Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy". Frontiers in Oncology. 11: 700407. doi: 10.3389/fonc.2021.700407 . ISSN   2234-943X. PMC   8358929 . PMID   34395270.
  45. ↑ Li, Yue; Zhao, Long; Li, Xiao-Feng (2021-07-29). "Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy". Frontiers in Oncology. 11: 700407. doi: 10.3389/fonc.2021.700407 . ISSN   2234-943X. PMC   8358929 . PMID   34395270.
  46. ↑ Huang, Yan; Tian, Ying; Zhao, Yuanyuan; Xue, Cong; Zhan, Jianhua; Liu, Lin; He, Xiaobo; Zhang, Li (December 2018). "Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo". Cancer Communications. 38 (1): 15. doi: 10.1186/s40880-018-0285-0 . PMC   5993153 . PMID   29764490.
  47. ↑ Huang, Yan; Tian, Ying; Zhao, Yuanyuan; Xue, Cong; Zhan, Jianhua; Liu, Lin; He, Xiaobo; Zhang, Li (December 2018). "Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo". Cancer Communications. 38 (1): 15. doi: 10.1186/s40880-018-0285-0 . PMC   5993153 . PMID   29764490.
  48. ↑ Threshold Pharmaceuticals 10-K Annual report 2011 from 15 Mar 2012
  49. ↑ "Threshold Pharmaceuticals 10-Q Quarterly report Q3/2014 from 3 Nov 14". Archived from the original on 2014-11-06. Retrieved 2014-11-05.
  50. ↑ "Threshold Pharmaceuticals Form 8-K from 9 Oct 14". Archived from the original on 2014-10-25. Retrieved 2015-01-05.
  51. ↑ "Threshold Pharmaceuticals Form 8-K from 9 Oct 14". Archived from the original on 2014-10-25. Retrieved 2015-01-05.
  52. ↑ "Threshold Pharmaceuticals Form 8-K from 9 Oct 14". Archived from the original on 2014-10-25. Retrieved 2015-01-05.
  53. ↑ Phosphoramidate alkylator prodrugs US8003625B2, US8507464B2, US8664204B2
  54. ↑ Phosphoramidate alkylator prodrugs EP1896040B1 and JP5180824B2
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