Copper Chelation

Preliminary evidence of better overall survival among people with advanced esophageal cancer treated with conventional therapies and TM to reduce copper

• Better overall survival among people with resectable, locally advanced esophageal cancer treated with TM in addition to neoadjuvant cisplatin, paclitaxel, and 45 Gy hyperfractionated radiotherapy for 3 weeks followed by transhiatal esophagectomy compared to historical controls in a small trial³Schneider BJ, Lee JS et al. Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer. Investigational New Drugs. 2013 Apr;31(2):435-42.

Weak evidence of a higher-than-expected stable disease rate among people with advanced cancer achieving copper deficiency

• Stable disease among 5 of the 6 people with metastatic cancer who achieved copper deficiency at the target range for at least 90 days through TM use in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁴Brewer GJ, Dick RD et al. Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clinical Cancer Research. 2000 Jan;6(1):1-10.
• Stable disease of greater than 6 months in 2 people of 18 total in the study with advanced solid tumors using ATN-224 to deplete copper in a small uncontrolled trial⁵Lowndes SA, Adams A et al. Phase I study of copper-binding agent ATN-224 in patients with advanced solid tumors. Clinical Cancer Research. 2008 Nov 15;14(22):7526-34.
• Stable disease for at least 6 months among 4 of 15 people (31%) with advanced kidney cancer in an uncontrolled trial⁶Redman BG, Esper P et al. Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer. Clinical Cancer Research. 2003 May;9(5):1666-72.

Preliminary evidence of better progression-free survival compared to historical controls and better markers of decreased microenvironment support for tumors among women with breast cancer, mostly triple-negative breast cancer, using TM

• Lower levels of endothelial progenitor cells and lysyl oxidase, critical components of the tumor microenvironment to foster tumor growth and spread, among people with breast cancer at high risk for recurrence achieving copper depletion compared to those not achieving depletion in small comparison trials⁷Nackos E, Kornhauser N et al. Altering the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence. Journal of Clinical Oncology. 2015 May 20;33(15_suppl):11008-11008
• Lower levels of endothelial progenitor cells and lysyl oxidase, critical components of the tumor microenvironment to foster tumor growth and spread, among people with stage 2-4 breast cancer with no evidence of disease achieving copper depletion compared to those not achieving depletion in small comparison trials⁸Chan N, Willis A et al. Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research. 2017 Feb 1;23(3):666-676.
• Progression-free survival (PFS) of 81% at a median follow up of 5.6 yrs―including PFS of 94% for people with stage 2/3 triple-negative breast cancer―among people with breast cancer at high risk for recurrence treated with TM to deplete copper in a small comparison study⁹Nackos E, Kornhauser N et al. Altering the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence. Journal of Clinical Oncology. 2015 May 20;33(15_suppl):11008-11008.
• Cancer eventlocal/regional recurrence, distant metastasis, new primary cancer, or death from the cancer under investigation-free survival (EFS) of 91% at a median follow up of 6.3 years among people with stage 2 triple-negative breast cancer or stage 3 breast cancer with no evidence of disease, and 69% among people with stage 4 breast cancer with no evidence of disease, treated with TM to deplete copper in a small comparison study¹⁰Chan N, Willis A et al. Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research. 2017 Feb 1;23(3):666-676.
• Better progression-free survival during a median follow-up of 6.9 years among people with breast cancer at high risk of recurrence, including triple-negative breast cancer, treated with tetrathiomolybdate for copper depletion compared to historical controls in a small trial¹¹Sahota S, Kornhauser N et al. A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence: updated results. Journal of Clinical Oncology. 2017 May 20:35(15_suppl):2557-2557.
• Longer progression-free survival than expected, with low toxicity, mostly among women with stage 2-4 triple-negative breast cancer achieving copper chelation with tetrathiomolybdate in small trials¹²Jain S, Cohen J et al. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Annals of Oncology. 2013 Jul;24(6):1491–1498.

Preliminary evidence of a lower rate of relapse than expected among people with triple-negative breast cancer treated with TM

• Lower rate of relapse among women with breast cancer, mostly among those with triple-negative breast cancer, achieving copper depletion with TM compared to those not achieving depletion in a small comparison study¹³Jain S, Cohen J et al. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Annals of Oncology. 2013 Jul;24(6):1491–1498.

• Partial response in 6 of 24 people with advanced metastatic colorectal cancer and stable disease in a further 9 treated with IFL and TM to reduce copper for up to 6 months in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design; all who responded to treatment had not been treated previously for metastatic disease, and once IFL treatment ended, treatment with TM alone led to progression in an average of 2.4 months. Time to progression (TTP) correlated with inflammatory markers VEGF, IL-8, and IL-6, and the authors conclude that “this result is similar to prior studies and is likely due to TM and chemotherapy having lowered tumor VEGF levels.”¹⁴Gartner EM, Griffith KA et al. A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer. Investigational New Drugs. 2009 Apr;27(2):159-65.

• Longer time to progression (20 months), with decreased vascular endothelial growth factor levels, among people with malignant pleural mesothelioma following surgery compared to those not receiving TM (10 months) in a small controlled triala study design in which people are assigned to either an experimental group or a control group to compare the outcomes from different treatment; assignment is not random, and so this is not as strong a study design as a randomized controlled trial, but still stronger than an uncontrolled trial¹⁵Pass HI, Brewer GJ, Dick R, Carbone M, Merajver S. A phase II trial of tetrathiomolybdate after surgery for malignant mesothelioma: final results. Annals of Thoracic Surgery. 2008 Aug;86(2):383-9; discussion 390.

• Slower than expected PSA progression in a small clinical trial of TM with people with biochemically recurrent hormone-naïve prostate cancer, but with uncertain clinical significance in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design¹⁶Lin J, Zahurak M et al. A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer. Urologic Oncology. 2013 Jul;31(5):581-8.
• No apparent delay in disease progression in a small clinical trial of people with asymptomatic metastatic hormone-refractory prostate cancer achieving copper depletion with TM in a small uncontrolled trial¹⁷Henry NL, Dunn R et al. Phase II trial of copper depletion with tetrathiomolybdate as an antiangiogenesis strategy in patients with hormone-refractory prostate cancer. Oncology. 2006;71(3-4):168-75.

• Ceruloplasmin levels: Depleted copper and lower ceruloplasmin levels among people with glioblastoma using penicillamine in a small uncontrolled trial¹⁸Brem S, Grossman SA, Carson KA et al, New Approaches to Brain Tumor Therapy CNS Consortium. Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma. Neuro-Oncology. 2005 Jul;7(3):246-53.
• EPCs and LOX: Fewer bone marrow-derived endothelial progenitor cells (EPCs, critical for metastatic progression), lower levels of lysyl oxidase (LOX) and other components of the tumor microenvironment, and low toxicity among women with stage 2-4 triple negative breast cancer using tetrathiomolybdate (TM) to deplete copper in small uncontrolled studies¹⁹Jain S, Cohen J et al. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Annals of Oncology. 2013 Jul;24(6):1491–1498; Nackos E, Kornhauser N et al. Altering the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence. Journal of Clinical Oncology. 2015 May 20;33(15_suppl):11008-11008; Chan N, Willis A et al. Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research. 2017 Feb 1;23(3):666-676.