Copper Chelation

Advanced cancer as a whole

• Stable disease among 5 of the 6 people with metastatic cancer treated with tetrathiomolybdate and achieving copper deficiency at the target range for at least 90 days 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 design²Brewer 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.

Advanced solid tumors

• Stable disease of more than 6 months in 11% of people with advanced solid tumors treated with ATN-224 to deplete copper in a small uncontrolled trial³Lowndes 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.

Advanced esophageal cancer

• Better overall survival after neoadjuvant cisplatin, paclitaxel, and 45 Gy hyperfractionated radiotherapy for 3 weeks followed by transhiatal esophagectomy among people with resectable, locally advanced esophageal cancer treated with TM compared to historical controls in a small trial⁴Schneider 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.

Advanced kidney cancer

• Stable disease for at least 6 months among 31% of people with advanced kidney cancer treated with 40 mg TM 3 times a day with meals and 60 mg at bedtime in a small uncontrolled trial⁵Redman 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.

Advanced prostate cancer

• No apparent delay in disease progression among people with asymptomatic metastatic hormone-refractory prostate cancer achieving copper depletion with TM in a small uncontrolled trial⁶Henry 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.

• Better progression-free survival during a median follow-up of 6.9 years among people with breast cancer including triple-negative breast cancer, at high risk of recurrence treated with tetrathiomolybdate for copper depletion compared to historical controls 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 trial⁷Sahota 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.
• 81% progression-free survival (PFS) at a median follow up of 5.6 yrs―including 94% PFS among 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 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 design⁸Nackos 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.
• 91% event-free survival (EFS) of 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 uncontrolled trial;⁹Chan 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. these survival rates are better than average for triple-negative breast cancer¹⁰Triple-negative Breast Cancer. American Cancer Society. March 1, 2023. Viewed August 7, 2024.
• 85% relapse-free survival at 12 months among women with breast cancer, mostly among those with triple-negative breast cancer, treated with TM for copper depletion in a small uncontrolled trial¹¹Jain 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.

• Longer time to progression (20 months) after cytoreduction of malignant pleural mesothelioma among people with stage 1 or 2 disease but no evidence of an effect with stage 3 disease treated with TM for copper depletion  compared to 10 months among controls 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 trial¹²Pass 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 PSA progression among  people with biochemically recurrent hormone-naïve prostate cancer and prostate specific antigen doubling times (PSADT) less than 12 months treated with 30 mg choline tetrathiomolybdate (ATN-224) a day compared to baseline, and slower than people treated with 300 mg ATN-224, 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 design¹³Lin 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.

Irinotecan, 5-fluorouracil, and leucovorin (IFL) plus tetrathiomolybdate (TM)

• 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;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. 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.”

Trientine, a copper-lowering agent, combined with carboplatin

• Stable disease for 6 months or longer in 8 patients and 1 partial response (16% total) among people with advanced cancer, most of whom had failed platinum, treated with carboplatin and trientine in a small uncontrolled trial, with substantially longer survival among people who maintained their ceruloplasmin (major copper-carrying protein) levels at 5-15 mg/dL compared to those with higher levels¹⁵Fu S, Hou MM et al. Exploratory study of carboplatin plus the copper-lowering agent trientine in patients with advanced malignancies. Investigational New Drugs. 2014 Jun;32(3):465-72.
• Partial remission in 1 patient (10+ months), stable disease in 3 patients (2, 3.5+, and 5 months, respectively), and 1 patient had progressive disease among 5 people with platinum-resistant high-grade advanced epithelial ovarian cancer treated with carboplatin once every 4 weeks combined with 500 mg oral trientine 4 times a day with dose adjustment to maintain serum ceruloplasmin levels at 5–15 mg/dL in a case series¹⁶Fu S, Naing A, Fu C, Kuo MT, Kurzrock R. Overcoming platinum resistance through the use of a copper-lowering agent. Molecular Cancer Therapies. 2012 Jun;11(6):1221-5.

Trientine combined with carboplatin and pegylated liposomal doxorubicin

• 33.3% clinical benefit rate (complete or partial response or stable disease for 4 months or longer) among platinum-resistant patients and 50% benefit rate among partially platinum-sensitive patients among people with epithelial ovarian, tubal, or peritoneal cancer who experienced disease progression during platinum-based chemotherapy or showed relapse less than 12 months after completing first-line chemotherapy treated with fixed doses of carboplatin and pegylated liposomal doxorubicin on 4-week cycles and escalated daily trientine doses in a small uncontrolled trial¹⁷Huang YF, Kuo MT et al. A dose escalation study of trientine plus carboplatin and pegylated liposomal doxorubicin in women with a first relapse of epithelial ovarian, tubal, and peritoneal cancer within 12 months after platinum-based chemotherapy. Frontiers in Oncology. 2019 May 24;9:437.

• Fewer bone marrow-derived endothelial progenitor cells (EPCs, critical for metastatic progression) and lower levels of lysyl oxidase (LOX) and other components of the tumor microenvironment among women with stage 2-4 triple negative breast cancer using tetrathiomolybdate (TM) and achieving  copper depletion in small uncontrolled trialsa 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 design¹⁸Jain 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.

• No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on markers of inflammation (IL-6 and IL-8) among people with asymptomatic metastatic hormone-refractory prostate cancer treated with tetrathiomolybdate and achieving copper depletion 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 design¹⁹Henry 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.

• Lower vascular endothelial growth factor levels after surgery among people with stage 1 or 2 disease but no evidence of an effect with stage 3 malignant pleural mesothelioma treated with tetrathiomolybdate for copper depletion for 10 months compared to among controls 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 trial²⁰Pass 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.
• No evidence of an effect on VEGF levels among people with asymptomatic metastatic hormone-refractory prostate cancer treated with tetrathiomolybdate and achieving copper depletion 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 design²¹Henry 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.