Randomized, Open, Controlled, Multicenter Phase III Clinical Study of Fluzoparib in Combination With Apatinib Versus Investigator-Selected Chemotherapy for HRD-Positive/HER2-negative Advanced Breast Cancer

Breast Cancer Clinical Trial

Official title:

Randomized, Open, Controlled, Multicenter Phase III Clinical Study of Fluzoparib in Combination With Apatinib Versus Investigator-Selected Chemotherapy for HRD-Positive/HER2-negative Advanced Breast Cancer

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06255392
• Other study ID #: SYSKY-2023-1016-01
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: February 2024
• Est. completion date: March 2031

Study information

• Verified date: February 2024
• Source: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
• Contact: Zhao Jianli
• Phone: 86-20-34070870
• Email: zhaojli5[@]mail.sysu.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study develops a new therapeutic approach for HER2-negative advanced breast cancer patients without precise treatment targets. The trial aims at extending the combination target therapy involving PARP inhibitors and anti-angiogenesis from only BRCA mutation carriers to all patients with homologous recombination repair defects (HRD-positive). The phase III randomized clinical study will investigate the effectiveness of the combination therapy of PARP inhibitor "fludzoparib" and anti-angiogenic "apatinib" in treating HRD-positive/HER2-negative advanced breast cancers.

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. 80% of these patients have HER2-negative subtype breast cancer, which has not yet been found the similar target as HER2, with the median survival time of only 6-20 months. In the past, ovarian 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 ovarian cancer have successfully expanded the indications of PARP inhibitor-based combination targeted therapy from the small population of BRCA mutation(20%) to the large population of HRD-positive (Homologous recombination deficiency) (50%), which has significantly prolonged the survival time of patients. Because causes other than BRCA mutations can also cause tumor cells to be "HRD" and thus sensitive to PARP inhibitors, so that HRD-positive patients are likely to benefit. The HRD-positive profile of nearly 50% of the patients could be a potential beneficiary of PARP inhibitor-based targeted therapy. The synergistic effect of PARP inhibitor and anti-angiogenic combination therapy has already been confirmed in preliminary cellular experiments and clinical studies related to ovarian cancer. Further cell-based experiments and preclinical studies have also confirmed the feasibility of the combination targeted therapy in the HRD-positive/HER2-negative subtype of breast cancer. Therefore, we intend to further validate the efficacy and safety of the PARP inhibitor fluazoparib in combination with the antiangiogenic abatinib in a Phase III, randomized, controlled clinical study, in order to provide HRD-positive/HER2-negative breast cancer patients with a better choice of precision targeted therapy.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 200
• Est. completion date: March 2031
• Est. primary completion date: March 2031
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Adult female patients (age 18-70 years) with metastatic breast cancer confirmed by pathology or imaging;

2. Pathological diagnosis of HER-2 was negative (definition: immunohistochemical results were 0?+ or ++ and in situ hybridization results were negative);

3. Patient tested positive for HRD (defined by: BRCA 1 / 2 mutation, or HRD score is = 42);

4. HR+/HER2- patients were required to have received endocrine therapy during the metastatic phase;

5. ECOG physical status score = 2 and expected survival of not less than 3 months;

6. According to RECIST 1.1, patients with at least one target lesion or simple bone metastasis can be evaluated;

7. Prior treatment-related toxicity should be reduced to NCI CTCAE (version 5.0) = 1 degree (except for hair loss or other toxicity which is considered as no risk to patient's safety according to the investigator's judgment) 8)LVEF=50%;

8. Sufficient functional reserve of bone marrow

1. White blood cell count (WBC) = 3.0 × 10 ^ 9 / L,

2. Neutrophil count (ANC) = 1.5 × 10 ^ 9 / L,

3. Platelet count (PLT) = 100 × 10 ^ 9 / L

9. Previous treatment-related toxicity should be relieved as NCI CTCAE (version 5.0) = 1 degree, total bilirubin (TBIL) = 1.5 × upper limit of normal value (ULN), alanine aminotransferase (ALT / AST) = 2.5 × ULN (liver metastasis patients = 5xuln), serum creatinine = 1.5 × ULN or creatinine clearance rate (CCR) = 60 ml / min;

10. Left ventricular ejection fraction (LVEF) = 55%, QTcF(Fridericia correction) = 470 ms.

11. Be able to understand the research process, volunteer to participate in the study, and sign informed consent.

Exclusion Criteria:

1. HR+/HER2- MBC patients with no prior endocrine therapy;

2. No treatment for metastatic breast cancer was received;

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

4. They received radiotherapy, chemotherapy, endocrine therapy within 4 weeks before enrollment, or were participating in any clinical trials of intervention drugs;

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

6. Any other situation in which the researcher considers that the patient is not suitable for the study may interfere with the concomitant diseases or conditions involved in the study, or there are any serious medical barriers that may affect the safety of the subjects (e.g., uncontrollable heart disease, hypertension, active or uncontrollable infection, active hepatitis B virus infection)

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Fluzoparib
Fluzoparib capsules appropriate dose oral, each treatment cycle defined as 3 weeks (21 days).
• Apatinib Mesylate
Apatinib Mesylate oral; each treatment cycle defined as 3 weeks (21 days).
• Capecitabine tablets
Capecitabine tablets, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
• Vinorelbine Tartrate Oral
For the first three courses: reasonable dosage with reference to guidelines. After 3 courses of medication, it is recommended to increase the dose of vinorelbine tartrate once a week. Each treatment cycle defined as 3 weeks (21 days).
• Eribulin mesylate injection
Eribulin, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
• Gemcitabine Hydrochloride
Gemcitabine, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
• Paclitaxel-albumin
Paclitaxel-albumin, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).

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 (10)

Gonzalez-Martin A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, McCormick C, Lorusso D, Hoskins P, Freyer G, Baumann K, Jardon K, Redondo A, Moore RG, Vulsteke C, O'Cearbhaill RE, Lund B, Backes F, Barretina-Ginesta P, Haggerty AF, Rubio-Perez MJ, Shahin MS, Mangili G, Bradley WH, Bruchim I, Sun K, Malinowska IA, Li Y, Gupta D, Monk BJ; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2391-2402. doi: 10.1056/NEJMoa1910962. Epub 2019 Sep 28. — View Citation

Gruber JJ, Afghahi A, Timms K, DeWees A, Gross W, Aushev VN, Wu HT, Balcioglu M, Sethi H, Scott D, Foran J, McMillan A, Ford JM, Telli ML. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes. Nat Cancer. 2022 Oct;3(10):1181-1191. doi: 10.1038/s43018-022-00439-1. Epub 2022 Oct 17. — View Citation

Iglehart JD, Silver DP. Synthetic lethality--a new direction in cancer-drug development. N Engl J Med. 2009 Jul 9;361(2):189-91. doi: 10.1056/NEJMe0903044. Epub 2009 Jun 24. No abstract available. — View Citation

Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018 Aug 23;379(8):753-763. doi: 10.1056/NEJMoa1802905. Epub 2018 Aug 15. — View Citation

Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel B, Buss MK, Nattam S, Hurteau J, Luo W, Quy P, Whalen C, Obermayer L, Lee H, Winer EP, Kohn EC, Ivy SP, Matulonis UA. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014 Oct;15(11):1207-14. doi: 10.1016/S1470-2045(14)70391-2. Epub 2014 Sep 10. — View Citation

Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, Rimel BJ, Buss MK, Nattam SR, Hurteau J, Luo W, Curtis J, Whalen C, Kohn EC, Ivy SP, Matulonis UA. Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol. 2019 Apr 1;30(4):551-557. doi: 10.1093/annonc/mdz018. — View Citation

Ray-Coquard I, Pautier P, Pignata S, Perol D, Gonzalez-Martin A, Berger R, Fujiwara K, Vergote I, Colombo N, Maenpaa J, Selle F, Sehouli J, Lorusso D, Guerra Alia EM, Reinthaller A, Nagao S, Lefeuvre-Plesse C, Canzler U, Scambia G, Lortholary A, Marme F, Combe P, de Gregorio N, Rodrigues M, Buderath P, Dubot C, Burges A, You B, Pujade-Lauraine E, Harter P; PAOLA-1 Investigators. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2416-2428. doi: 10.1056/NEJMoa1911361. — View Citation

Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Aug 10;377(6):523-533. doi: 10.1056/NEJMoa1706450. Epub 2017 Jun 4. Erratum In: N Engl J Med. 2017 Oct 26;377(17 ):1700. — View Citation

Severson TM, Wolf DM, Yau C, Peeters J, Wehkam D, Schouten PC, Chin SF, Majewski IJ, Michaut M, Bosma A, Pereira B, Bismeijer T, Wessels L, Caldas C, Bernards R, Simon IM, Glas AM, Linn S, van 't Veer L. The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res. 2017 Aug 25;19(1):99. doi: 10.1186/s13058-017-0861-2. — View Citation

Sun C, Yin J, Fang Y, Chen J, Jeong KJ, Chen X, Vellano CP, Ju Z, Zhao W, Zhang D, Lu Y, Meric-Bernstam F, Yap TA, Hattersley M, O'Connor MJ, Chen H, Fawell S, Lin SY, Peng G, Mills GB. BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency. Cancer Cell. 2018 Mar 12;33(3):401-416.e8. doi: 10.1016/j.ccell.2018.01.019. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival,PFS(Independent Review Committee)	The time from the beginning of treatment to the progression or death of the patient	2 years
Secondary	Progression Free Survival,PFS(Investigator)	The time from the beginning of treatment to the progression or death of the patient	2 years
Secondary	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	Clinical Benefit Rate,CBR	Proportion of confirmed complete response, partial response, or stable disease = 24 weeks.	2 years
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	Overall survival time ,OS	The time from the start of randomization to death due to any cause.	2 years
Secondary	the rate of adverse events	The probability and severity of adverse reactions, and the extent and incidence of AEs were assessed according to CTCAE.	2 years
Secondary	Quality of life scale score,QoL	The function or quality of a patient's physical, psychological, and social adaptability is also known as quality, which is assessed according to the EROTC C30 scale.	2 years