Ammonium Tetrathiomolybdate (ATTM) - Phase 1b/2 clinical program (Dartmouth)

Copper Chelator for Breast Cancer

cGMP API - Type II DMF

Oral Capsule - Phase 1 & 2 clinical studies

Tetrathiomolybdate (TM) lowers copper levels in the body. Tetrathiomolybdate has been tested in 22 clinical studies as ammonium tetrathiomolybdate and bis-choline tetrathiomolybdate. The pharmacological class for TM is that of an oral drug which lowers copper levels in the body. TM forms a tripartite complex with copper and protein, eventually cleared primarily by the liver with excretion into the bile. The target indication for usage of TM in this study is in cancer as an anti-metastasis agent. Robust pre-clinical and clinical data in breast cancer suggest that reprogramming of the tumor microenvironment leading to a non-permissive environment for metastases occurs.

Ammonium tetrathiomolybdate (ATTM), a type of chelating and antiangiogenesis agent, is currently in clinical development for the treatment of many types of cancer. Known for its ability to remove extra copper from the body, ATTM may prevent the growth of new blood vessels that tumors need to grow and may also possess the ability to kill cancer cells. Nanopharmaceutics announced the initiation of a Phase 1b / 2 clinical study with Dartmouth Health’s Dartmouth Hitchcock Medical "Novel Targeting of the Microenvironment to Decrease Metastatic Recurrence of High-Risk TNBC: A Randomized Phase II Study of Tetrathiomolybdate (TM) plus capecitabine in patients with breast cancer at high risk of recurrence" (ClinicalTrials.gov Identifier: NCT06134375). The primary objective of the phase 1b study is to establish the safety of the combination of adjuvant tetrathiomolybdate with capecitabine and pembrolizumab administered to patients with triple negative breast cancer (TNBC) after completion of neoadjuvant chemotherapy and with a non-pCR (RCB 2, 3) after standard surgery. The primary objective of the phase 2 study will be relapse-free survival (DRFS) between ATTM and capecitabine versus capecitabine +/- pembrolizumab. The Principal Investigator is Linda Vahdat, MD MBA, Chief of Medical Oncology and interim Chief of Hematology an Deputy Cancer Center Director at Dartmouth Cancer Center and the study will recruit 204 patients.

Clinical Studies

  • NCT06134375 A Study of Tetrathiomolybdate (TM) Plus Capecitabine

  • NCT00195091 Phase II Study of Tetrathiomolybdate (TM) in Patients With Breast Cancer

References (over 500 total)

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Copper metabolism in cell death and autophagy, Qian Xue, Rui Kang, Daniel J Klionsky, Daolin Tang, Jinbao Liu, Xin Chen. Autophagy. 2023 Aug;19(8):2175-2195. doi: 10.1080/15548627.2023.2200554. Epub 2023 Apr 16. PMID: 37055935.

Ammonium tetrathiomolybdate relieves oxidative stress in cisplatin-induced acute kidney injury via NRF2 signaling pathway. Hao Qi, et.al. Cell Death Discov. 2023 Jul 25;9(1):259. doi: 10.1038/s41420-023-01564-1. PMID: 37491360.

The copper chelator ammonium tetrathiomolybdate inhibits the progression of experimental endometriosis in TNFR1-deficient mice. Rocío Ayelem Conforti, María Belén Delsouc, Ana Sofia Zabala, Sandra Silvina Vallcaneras, Marilina Casais. Sci Rep. 2023 Jun 26;13(1):10354. doi: 10.1038/s41598-023-37031-1. PMID: 37365216

Tetrathiomolybdate as an old drug in a new use: As a chemotherapeutic sensitizer for non-small cell lung cancer. Li Y, Fang M, Xu Z, Li X. J Inorg Biochem. 2022 Aug;233:111865. doi: 10.1016/j.jinorgbio.2022.111865. Epub 2022 May 19. PMID: 35623139.

Investigation and management of Wilson's disease: a practical guide from the British Association for the Study of the Liver. Shribman S, Marjot T, Sharif A, Vimalesvaran S, Ala A, Alexander G, Dhawan A, Dooley J, Gillett GT, Kelly D, McNeill A, Warner TT, Wheater V, Griffiths W, Bandmann O; British Association for the Study of the Liver Rare Diseases Special Interest Group. Lancet Gastroenterol Hepatol. 2022 Jun;7(6):560-575. doi: 10.1016/S2468-1253(22)00004-8. Epub 2022 Apr 13. PMID: 35429442.

Copper chelation therapy inhibits renal fibrosis by modulating copper transport proteins. Saifi MA, Godugu C. Biofactors. 2022 Mar 24. doi: 10.1002/biof.1837. PMID: 35322483.