HCQ+ADC vs ADC in the Treatment of Advanced Breast Cancer

NCT06328387 | Recruiting Phase 1

• 1 other identifier: SYSKY-2024-064-03
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Advanced breast cancer is a special subtype of human breast cancer. Conventional guidelines recommend chemotherapy combined with other adjuvant therapies for this subtype of patients. However, the choice of treatment for these patients after treatment progress is a research hotspot in this field. Trastuzumab Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG) are new ADC drugs targeting HER2 or TROP-2 with high efficacy and low toxicity after the progress of first-line treatment. The autophagy agents hydroxychloroquine or chloroquine has become the only FDA (Food and Drug Administration) approved autophagy inhibitor, and hydroxychloroquine and antibody-drug conjugate(ADC) may have synergistic effects based on the previous work results of our research group. Therefore,we envisage that Trastuzumab Deruxtecan(T-DXd) or Sacituzumab Govitecan (SG) combined with hydroxychloroquine(HCQ) in the treatment of advanced breast cancer in clinical practice has the advantages of improving efficacy and survival. To this end, we intend to conduct a prospective,multi-center, phase I/II clinical trial to evaluate the efficacy and safety of T-DXd or SG in combination with HCQ in patients with advacned breast cancer.

Conditions

Advanced Breast Cancer; Metastatic Breast Cancer

Keywords

Antibody-drug Conjugate; Hydroxychloroquine; Advanced Breast Cancer; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (3)

• Dose Limiting Toxicity, DLT

  A dose limiting toxicity（DLT）is defined as any of the following-related adverse event(AE) that occurs during the DLT period, graded according to the NCI Common Terminology Criteria for Adverse Events(CTCAE), Version 5.0

  3 weeks

• Adverse event, AE

  Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

  2 years

• Objective Response Rate, ORR

  the proportion of patients with a tumor volume reduction of ≥30% and a minimum timeframe according to accepted response evaluation criteria (e.g., RECIST version 1.1 in solid tumors), including cases of complete response (CR) and partial response (PR).

  2 years

Secondary Outcomes (7)

• Progression-Free Survival, PFS

  2 years

• Overall Survival, OS

  4 years

• Clinical Benefit Rate, CBR

  24 weeks after enrollment

• Disease Control Rate, DCR

  2 years

• The rate of adverse events

  up to 24 weeks after enrollment

Study Arms (4)

Sacituzumab Govitecan

OTHER

Sacituzumab Govitecan (SG) is given by intervenous route, 10 mg/kg on day 1 and day 8 of 21-day treatment cycles. Patient will receive treatment until disease progression, unacceptable toxicity, or decision to withdraw its participation.

Drug: Sacituzumab Govitecan

Hydroxychloroquine Combined With Sacituzumab Govitecan

EXPERIMENTAL

The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result. Sacituzumab Govitecan (SG) is given by intervenous route, 10 mg/kg on day 1 and day 8 of 21-day treatment cycles. Patient will receive treatment until disease progression, unacceptable toxicity, or decision to withdraw its participation.

Drug: Hydroxychloroquine; Drug: Sacituzumab Govitecan

Trastuzumab Deruxtecan

OTHER

Patients will receive T-DXd at 5.4 mg/kg administered as an intravenous (IV) infusion every three-weeks (Q3W) until disease progression, unacceptable toxicity, death, or discontinuation from the study.

Drug: Trastuzumab Deruxtecan

Hydroxychloroquine Combined With Trastuzumab Deruxtecan

EXPERIMENTAL

The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result. Patients will receive T-DXd at 5.4 mg/kg administered as an intravenous (IV) infusion every three-weeks (Q3W) until disease progression, unacceptable toxicity, death, or discontinuation from the study.

Drug: Hydroxychloroquine; Drug: Trastuzumab Deruxtecan

Interventions

Hydroxychloroquine DRUG

The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result.

Also known as: Plaquenil

Hydroxychloroquine Combined With Sacituzumab Govitecan; Hydroxychloroquine Combined With Trastuzumab Deruxtecan

Sacituzumab Govitecan DRUG

Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a chemotherapy drug, called govitecan. Sacituzumab is a form of targeted therapy because it attaches to specific molecules on the surface of cancer cells, known as Trop-2 receptors, and delivers govitecan to kill them.

Also known as: IMMU-132, Trodelvy™, GS-0132

Hydroxychloroquine Combined With Sacituzumab Govitecan; Sacituzumab Govitecan

Trastuzumab Deruxtecan DRUG

Trastuzumab-deruxtecan is a human HER2-directed antibody-drug conjugate (ADC) composed of humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, covalently linked to the membrane-permeable topoisomerase I inhibitor payload, DXd, an exatecan derivative, via a stable tetrapeptide-based linker, selectively cleaved within tumor cells.

Also known as: DS-8201, Enhertu

Hydroxychloroquine Combined With Trastuzumab Deruxtecan; Trastuzumab Deruxtecan

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of advanced breast cancer (female, 18 to 70 years old).
• Pathological confirmed advanced breast cancer.
• The patient is willing to receive SG or T-DXd treatment.
• Failure of first-line treatment.
• Have received no more than 3 chemotherapy schemes for metastatic breast cancer in the past.
• ECOG physical condition score ≤ 2 points, estimated survival time of no less than 3 months.
• At least one measurable lesion should be present in the imaging examination within 2 weeks prior to enrollment; Or simple bone metastasis lesions.
• LVEF≥50%.
• Previous treatment related toxicity must be relieved to NCI CTCAE (version 5.0) ≤ 1 degree, AST and ALT ≤ 2.5 times the upper limit of normal value, and total bilirubin ≤ 1.5 times the upper limit of normal value.
• Adequate reserve of bone marrow function: white blood cell count ≥ 3.0 × 10\^9/L, neutrophil count ≥ 1.5 × 10\^9/L; Platelet count ≥ 100 × 10\^9/L; Hemoglobin ≥ 90g/L; Serum creatinine ≤ 1.5 times the upper limit of normal value.

You may not qualify if:

• Patients suffer from various factors such as difficulty swallowing and chronic diarrhea, which affect medication intake and absorption.
• Individuals with severe heart disease or discomfort, expected inability to tolerate chemotherapy, including but not limited to: fatal arrhythmias or higher-level atrioventricular block, unstable angina, clinically significant valvular heart disease, electrocardiogram showing transmural myocardial infarction, and uncontrolled hypertension.
• Patients who are known to be allergic to the active ingredients or other components of the investigational drug.
• Received radiotherapy, chemotherapy, endocrine therapy within 4 weeks prior to enrollment, or is currently participating in any intervention drug clinical trials.
• Pregnant or lactating women, women of childbearing age who refuse to take effective contraceptive measures during the study period.
• The researchers believe that patients are not suitable to participate in any other circumstances of this study, which may interfere with the accompanying diseases or conditions of the study, or have any serious medical obstacles that may affect the safety of the subjects.

Sponsors & Collaborators

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: lead

Study Sites (1)

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Guangzhou, Guangdong, 510120, China

RECRUITING

Related Publications (11)

• Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022 Mar 22;7(1):93. doi: 10.1038/s41392-022-00947-7.

  PMID: 35318309 BACKGROUND

• Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, Chiu JWY, Xu B, Hamilton E, Madhusudan S, Iwata H, Altintas S, Henning JW, Curigliano G, Perez-Garcia JM, Kim SB, Petry V, Huang CS, Li W, Frenel JS, Antolin S, Yeo W, Bianchini G, Loi S, Tsurutani J, Egorov A, Liu Y, Cathcart J, Ashfaque S, Cortes J. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023 Jan 14;401(10371):105-117. doi: 10.1016/S0140-6736(22)02420-5. Epub 2022 Dec 7.

  PMID: 36495879 BACKGROUND

• Chen YF, Xu YY, Shao ZM, Yu KD. Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions. Cancer Commun (Lond). 2023 Mar;43(3):297-337. doi: 10.1002/cac2.12387. Epub 2022 Nov 10.

  PMID: 36357174 BACKGROUND

• Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O'Shaughnessy JA. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011 Feb 1;29(4):398-405. doi: 10.1200/JCO.2010.29.5865. Epub 2010 Dec 20.

  PMID: 21172893 BACKGROUND

• Loganzo F, Tan X, Sung M, Jin G, Myers JS, Melamud E, Wang F, Diesl V, Follettie MT, Musto S, Lam MH, Hu W, Charati MB, Khandke K, Kim KS, Cinque M, Lucas J, Graziani E, Maderna A, O'Donnell CJ, Arndt KT, Gerber HP. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther. 2015 Apr;14(4):952-63. doi: 10.1158/1535-7163.MCT-14-0862. Epub 2015 Feb 2.

  PMID: 25646013 BACKGROUND

• Rios-Luci C, Garcia-Alonso S, Diaz-Rodriguez E, Nadal-Serrano M, Arribas J, Ocana A, Pandiella A. Resistance to the Antibody-Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity. Cancer Res. 2017 Sep 1;77(17):4639-4651. doi: 10.1158/0008-5472.CAN-16-3127. Epub 2017 Jul 7.

  PMID: 28687619 BACKGROUND

• Yu SF, Zheng B, Go M, Lau J, Spencer S, Raab H, Soriano R, Jhunjhunwala S, Cohen R, Caruso M, Polakis P, Flygare J, Polson AG. A Novel Anti-CD22 Anthracycline-Based Antibody-Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs. Clin Cancer Res. 2015 Jul 15;21(14):3298-306. doi: 10.1158/1078-0432.CCR-14-2035. Epub 2015 Apr 3.

  PMID: 25840969 BACKGROUND

• Le Joncour V, Martins A, Puhka M, Isola J, Salmikangas M, Laakkonen P, Joensuu H, Barok M. A Novel Anti-HER2 Antibody-Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine. Mol Cancer Ther. 2019 Oct;18(10):1721-1730. doi: 10.1158/1535-7163.MCT-19-0207. Epub 2019 Jul 10.

  PMID: 31292166 BACKGROUND

• Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020 Jan 22;19(1):12. doi: 10.1186/s12943-020-1138-4.

  PMID: 31969156 BACKGROUND

• Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, Coppes RP, Engedal N, Mari M, Reggiori F. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435-1455. doi: 10.1080/15548627.2018.1474314. Epub 2018 Jul 20.

  PMID: 29940786 BACKGROUND

• Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, Sohn ASW, Mukhopadhyay S, Lin EY, Parker SJ, Banh RS, Paulo JA, Wen KW, Debnath J, Kim GE, Mancias JD, Fearon DT, Perera RM, Kimmelman AC. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020 May;581(7806):100-105. doi: 10.1038/s41586-020-2229-5. Epub 2020 Apr 22.

  PMID: 32376951 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Hydroxychloroquine; sacituzumab govitecan; trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Jianli J Zhao, doctorate

  Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jianli J Zhao, doctorate

CONTACT

15920589334; zhaojli5@mail.sysu.edu.cn

Erwei E Song, doctorate

CONTACT

13926477694; songew@mail.sysu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Model Details: The research model consists of four arms： 1. arm A: SG. 2. arm B: HCQ+SG. 3. arm C: T-DXd . 4. arm D: HCQ+T-DXd.

Study Record Dates

• First Submitted: March 17, 2024
• First Posted: March 25, 2024
• Study Start: January 29, 2024
• Primary Completion: February 1, 2026
• Study Completion: March 1, 2026
• Last Updated: March 25, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)