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

Metastatic Breast Cancer Clinical Trial

Official title:

Open, Controlled, Multicenter Phase I/II Clinical Study of Hydroxychloroquine in Combination With Antibody-drug Conjugate Versus Antibody-drug Conjugate for Advanced Breast Cancer.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06328387
• Other study ID #: SYSKY-2024-064-03
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 29, 2024
• Est. completion date: March 1, 2026

Study information

• Verified date: March 2024
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Contact: Jianli J Zhao, doctorate
• Phone: 15920589334
• Email: zhaojli5[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Breast cancer is the most prevalent malignant tumor in the world, and 30% of breast cancer patients will enter the advanced stage due to treatment failure. Most patients with advanced breast cancer have had distant organ metastasis, and the median progression free survival period is only 1-2 years. In the past, advanced breast cancer patients faced the dilemma of poor survival due to the lack of precise targeted therapy. However, through a series of clinical studies, experts in the field of advanced breast cancer have successfully expanded the indications of ADC-based combination targeted therapy from the emergence of first generation ADC to the third generation ADC with "bystander effect", which has significantly prolonged the survival time of patients. 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. Because both ADC and autophagy involve lysosomes, and the relationship between ADC and autophagy microenvironment has not been elucidated, the combination of autophagy regulators and ADC may be a treatment option that can benefit some patients more.The autophagy agents hydroxychloroquine or chloroquine has become the only FDA (Food and Drug Administration) approved autophagy inhibitor. And the synergistic effect of hydroxychloroquine and antibody-drug conjugate (ADC) has already been confirmed based on preliminary experiments of our research group. 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. Therefore, we intend to further validate the efficacy and safety of the Autophagy inhibitor hydroxychloroquine(HCQ) in combination with the latest ADC drugs (T-DXd or SG) in a Phase I/II, randomized, controlled clinical study, in order to provide advanced breast cancer patients with a better choice of precision targeted therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: March 1, 2026
• Est. primary completion date: February 1, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of advanced breast cancer (female, 18 to 70 years old).

2. Pathological confirmed advanced breast cancer.

3. The patient is willing to receive SG or T-DXd treatment.

4. Failure of first-line treatment.

5. Have received no more than 3 chemotherapy schemes for metastatic breast cancer in the past.

6. ECOG physical condition score = 2 points, estimated survival time of no less than 3 months.

7. At least one measurable lesion should be present in the imaging examination within 2 weeks prior to enrollment; Or simple bone metastasis lesions.

8. LVEF=50%.

9. 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.

10. 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.

Exclusion Criteria:

1. Patients suffer from various factors such as difficulty swallowing and chronic diarrhea, which affect medication intake and absorption.

2. 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.

3. Patients who are known to be allergic to the active ingredients or other components of the investigational drug.

4. Received radiotherapy, chemotherapy, endocrine therapy within 4 weeks prior to enrollment, or is currently participating in any intervention drug clinical trials.

5. Pregnant or lactating women, women of childbearing age who refuse to take effective contraceptive measures during the study period.

6. 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.

Related Conditions & MeSH terms

• Advanced Breast Cancer
• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Hydroxychloroquine
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
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.
• Trastuzumab Deruxtecan
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.

Locations

Country	Name	City	State
China	Sun Yat-sen Memorial Hospital, Sun Yat-sen University	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Country where clinical trial is conducted

China, 

References & Publications (11)

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: Lancet. 2023 Feb 18;401(10376):556. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Progression-Free Survival, PFS	The time from the beginning of treatment to the progression or death of the patient	2 years
Secondary	Overall Survival, OS	The time from the start of randomization to death due to any cause.	4 years
Secondary	Clinical Benefit Rate, CBR	Proportion of confirmed complete response, partial response, or stable disease = 24 weeks.	24 weeks after enrollment
Secondary	Disease Control Rate, DCR	Proportion of patients with stable or shrinking tumor size--sum of the proportions of complete remission (CR), partial remission (PR) and stable disease (SD).	2 years
Secondary	The rate of adverse events	The probability and severity of adverse reactions were analyzed up to 24 weeks after enrollment	up to 24 weeks after enrollment
Secondary	Quality of life scale score, QoL	The quality of life score of patients during treatment was analyzed(FACT-B). Performance Status Rating (PSR) was demonstrated for the FACT-B total score, which is the result of the following subscale scores: SWB (the Social / family Well-Being subscale) , EWB (the Emotional Well-Being subscale), AC (Additional Concerns subscale), PWB (the Physical Well-Being subscale), FWB (the Functional Well-Being subscale)	1 year
Secondary	Exploration of biomarkers	Objective to explore the correlation between biomarkers and the ORR. The biomarkers will be test by nest-generation sequence, which include 520 genes and tumor mutation burden, like ERBB2/TP53/PIK3CA/ERBB4/CCND1 and so on.	the first week after the enrollment