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This a phase 1 study to evaluate the safety and preliminary efficacy of cisplatin combined with bortezomib in patients with recurrent or metastatic breast cancer.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose level 1 | Experimental | In this dose level, all subjects will receive a dose of 1.3m/m2 bortezomib combined with a dose of 50mg/m2 cisplatin. |
|
| Dose level 2 | Experimental | In this dose level, all subjects will receive a dose of 1.5m/m2 bortezomib combined with a dose of 50mg/m2 cisplatin. |
|
| Dose level 3 | Experimental | In this dose level, all subjects will receive a dose of 1.7m/m2 bortezomib combined with a dose of 50mg/m2 cisplatin. |
|
| Dose level 4 | Experimental | In this dose level, all subjects will receive a dose of 1.3m/m2 bortezomib combined with a dose of 75mg/m2 cisplatin. |
|
| Dose level 5 | Experimental | In this dose level, all subjects will receive a dose of 1.5m/m2 bortezomib combined with a dose of 75mg/m2 cisplatin. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bortezomib (B) | Drug | 1.3mg/m2, IV, D1, D4, D8 and D11, every 3 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose-limiting toxicities (DLTs) | The DLT assessment period is from day 1 to day 21 of the subject's first dose plus 24 hours after the second dose, that is, 22 days. Each dose group must first enroll 3 subjects. If no DLT occurs in the first cycle (within 28 days after the first dose), the dose will be increased to the next cohort; if 1 subject develops DLT, 3 subjects will be added to the cohort, and if no DLT occurs in the last 3 subjects, the dose will be increased to the next dose. If 2 or more subjects in 3 or 6 subjects in a dose group develop DLT, the dose escalation will be stopped, and the previous dose of the dose will be the MTD. DLT is defined as a treatment-related adverse event of Grade 3 or higher, based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. | Within 28 days after the first dose. |
| Maximum Tolerated Dose (MTD) | If 2 or more subjects in 3 or 6 subjects in a dose group develop DLT, the dose escalation will be stopped , and the previous dose of the dose will be the MTD. If the MTD is not reached in this trial, the researchers will discuss whether to continue the subsequent escalation trial. | Within 28 days after the first dose. |
| Measure | Description | Time Frame |
|---|---|---|
| Progression- free survival ( PFS ) | PFS assessed by investigators according to RECIST version 1.1 criteria. | Within approximately 48 months. |
| Objective Response Rate (ORR) | ORR assessed by investigators according to RECIST version 1.1 criteria. |
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Inclusion Criteria:
1) The blood routine examination standards must meet: ANC ≥1.5×109/L, PLT ≥75×109/L, Hb ≥85g/L (no blood transfusion and blood products within 14 days, no use of G-CSF and other hematopoietic stimulating factors for correction) 2) Biochemical examinations must meet the following standards: TBIL <1.5×ULN, ALT, AST <2.5×ULN, ALT, AST <5×ULN for patients with liver metastasis, BUN and Cr ≤1×ULN or endogenous creatinine clearance ≥50ml/min (Cockcroft-Gault formula); 8. Women of childbearing age must have taken reliable contraceptive measures, or have undergone a pregnancy test (serum or urine) within 7 days before enrollment, with a negative result, and are willing to use appropriate contraceptive methods during the trial and 8 weeks after the last administration of the trial drug.
9. The subjects voluntarily join this study, have good compliance, and cooperate with follow-up.
Exclusion Criteria:
Any of the following will be considered as meeting the exclusion criteria of the study:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yanxia Shi, Doctor | Contact | 86-020-87343486 | shiyx@sysucc.org.cn |
| Name | Affiliation | Role |
|---|---|---|
| Yan-xia Shi, Doctor | Sun Yat-sen University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sun Yat-Sen University Cancer Center | Recruiting | Guangzhou | Guangdong | 510000 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33304752 | Background | Shao F, Lyu X, Miao K, Xie L, Wang H, Xiao H, Li J, Chen Q, Ding R, Chen P, Xing F, Zhang X, Luo GH, Zhu W, Cheng G, Lon NW, Martin SE, Wang G, Chen G, Dai Y, Deng CX. Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening. Adv Sci (Weinh). 2020 Oct 11;7(23):2001914. doi: 10.1002/advs.202001914. eCollection 2020 Dec. | |
| 28117417 |
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Individual participant data (IPD) will not be shared due to ethical and privacy concerns.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 18, 2024 | Mar 21, 2025 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D000069286 | Bortezomib |
| D002945 | Cisplatin |
| ID | Term |
|---|---|
| D001897 | Boronic Acids |
| D000148 | Acids, Noncarboxylic |
| D000143 | Acids |
| D007287 | Inorganic Chemicals |
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Single-center, non-randomized, open-label, phase I study
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| Dose level 6 | Experimental | In this dose level, all subjects will receive a dose of 1.7m/m2 bortezomib combined with a dose of 75mg/m2 cisplatin. |
|
| Cisplatin (CDDP) | Drug | 50mg/m2, IV, D1-3, every 3 weeks |
|
| Bortezomib (B) | Drug | 1.5mg/m2, IV, D1, D4, D8 and D11, every 3 weeks |
|
| Bortezomib (B) | Drug | 1.7mg/m2, IV, D1, D4, D8 and D11, every 3 weeks |
|
| Cisplatin (CDDP) | Drug | 70mg/m2, IV, D1-3, every 3 weeks |
|
| Within approximately 48 months |
| Disease Control Rate (DCR) | DCR assessed by investigators according to RECIST version 1.1 criteria. | Within approximately 48 months |
| Area Under the Curve (AUC) | The area under the plasma concentration-time curve (AUC) will be measured to evaluate the systemic exposure of bortezomib and cisplatin. Blood samples will be collected at specified time points to calculate AUC using non-compartmental analysis. | Blood samples for PK analysis were collected within 60 minutes before dosing, at 0.5, 2, 6, 24, 72 hours, and on days 8, 15, and 22 after the start of dosing. |
| Maximum Plasma Concentration (Cmax) | The maximum observed plasma concentration (Cmax) of bortezomib and cisplatin will be determined from the collected blood samples. Cmax reflects the peak concentration of the drug in plasma after administration. | Blood samples for PK analysis were collected within 60 minutes before dosing, at 0.5, 2, 6, 24, 72 hours, and on days 8, 15, and 22 after the start of dosing. |
| Time to Maximum Plasma Concentration (Tmax) | The time to reach the maximum plasma concentration (Tmax) will be assessed for bortezomib and cisplatin. Tmax will be determined directly from the plasma concentration-time data. | Blood samples for PK analysis were collected within 60 minutes before dosing, at 0.5, 2, 6, 24, 72 hours, and on days 8, 15, and 22 after the start of dosing. |
| Half-Life (T1/2) | The terminal elimination half-life (T1/2) of bortezomib and cisplatin will be calculated using non-compartmental analysis. T1/2 represents the time required for the plasma concentration of the drug to decrease by 50%. | Blood samples for PK analysis were collected within 60 minutes before dosing, at 0.5, 2, 6, 24, 72 hours, and on days 8, 15, and 22 after the start of dosing. |
| Background |
| Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017 Jul;14(7):417-433. doi: 10.1038/nrclinonc.2016.206. Epub 2017 Jan 24. |
| 21147690 | Background | Irvin WJ Jr, Orlowski RZ, Chiu WK, Carey LA, Collichio FA, Bernard PS, Stijleman IJ, Perou C, Ivanova A, Dees EC. Phase II study of bortezomib and pegylated liposomal doxorubicin in the treatment of metastatic breast cancer. Clin Breast Cancer. 2010 Dec 1;10(6):465-70. doi: 10.3816/CBC.2010.n.061. |
| 17952740 | Background | Engel RH, Brown JA, Von Roenn JH, O'Regan RM, Bergan R, Badve S, Rademaker A, Gradishar WJ. A phase II study of single agent bortezomib in patients with metastatic breast cancer: a single institution experience. Cancer Invest. 2007 Dec;25(8):733-7. doi: 10.1080/07357900701506573. Epub 2007 Oct 18. |
| 25530422 | Background | Thaler S, Thiede G, Hengstler JG, Schad A, Schmidt M, Sleeman JP. The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer. Int J Cancer. 2015 Aug 1;137(3):686-97. doi: 10.1002/ijc.29404. Epub 2015 Jan 8. |
| 12867067 | Background | Mack PC, Davies AM, Lara PN, Gumerlock PH, Gandara DR. Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. Lung Cancer. 2003 Aug;41 Suppl 1:S89-96. doi: 10.1016/s0169-5002(03)00149-1. |
| 15016328 | Background | Ikezoe T, Yang Y, Saito T, Koeffler HP, Taguchi H. Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells. Cancer Sci. 2004 Mar;95(3):271-5. doi: 10.1111/j.1349-7006.2004.tb02215.x. |
| 10363983 | Background | Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. |
| 10471047 | Background | Pharoah PD, Day NE, Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer. 1999 Aug;80(12):1968-73. doi: 10.1038/sj.bjc.6690628. |
| 11250681 | Background | Osin PP, Lakhani SR. The pathology of familial breast cancer: Immunohistochemistry and molecular analysis. Breast Cancer Res. 1999;1(1):36-40. doi: 10.1186/bcr11. Epub 1999 Oct 27. |
| 12559038 | Background | Orlowski RZ, Dees EC. The role of the ubiquitination-proteasome pathway in breast cancer: applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer. Breast Cancer Res. 2003;5(1):1-7. doi: 10.1186/bcr460. Epub 2002 Aug 14. |
| 15929791 | Background | Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy. Cancer Cell Int. 2005 Jun 1;5(1):18. doi: 10.1186/1475-2867-5-18. |
| 12738242 | Background | Lenz HJ. Clinical update: proteasome inhibitors in solid tumors. Cancer Treat Rev. 2003 May;29 Suppl 1:41-8. doi: 10.1016/s0305-7372(03)00082-3. |
| 12738240 | Background | Cusack JC. Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib. Cancer Treat Rev. 2003 May;29 Suppl 1:21-31. doi: 10.1016/s0305-7372(03)00079-3. |
| 11854543 | Background | Adams J. Development of the proteasome inhibitor PS-341. Oncologist. 2002;7(1):9-16. doi: 10.1634/theoncologist.7-1-9. |
| 16707588 | Background | Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res. 2006 May 15;12(10):2955-60. doi: 10.1158/1078-0432.CCR-06-0170. |
| 18454159 | Background | Awada A, Albanell J, Canney PA, Dirix LY, Gil T, Cardoso F, Gascon P, Piccart MJ, Baselga J. Bortezomib/docetaxel combination therapy in patients with anthracycline-pretreated advanced/metastatic breast cancer: a phase I/II dose-escalation study. Br J Cancer. 2008 May 6;98(9):1500-7. doi: 10.1038/sj.bjc.6604347. Epub 2008 Apr 29. |
| D017437 |
| Skin and Connective Tissue Diseases |
| D001896 |
| Boron Compounds |
| D009930 | Organic Chemicals |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D017606 | Chlorine Compounds |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |