A Study of DB-1303/BNT323 vs Investigator's Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Metastatic Breast Cancer (DYNASTY-Breast02)

• ClinicalTrials.gov Identifier: NCT06018337
• Recruitment Status: Recruiting
• First Posted: August 30, 2023
• Last Update Posted: February 8, 2024
• Sponsor: DualityBio Inc.
• Collaborator: BioNTech SE
• Information provided by (Responsible Party): DualityBio Inc.

Tracking Information

• First Submitted Date: August 25, 2023
• First Posted Date: August 30, 2023
• Last Update Posted Date: February 8, 2024
• Actual Study Start Date: January 18, 2024
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2024)

Progression-free survival (PFS) in the HR+, HER2-low population [ Time Frame: Up to approximately 51 months ]

PFS by BICR according to RECIST 1.1 in the HR+, HER2-low population

Original Primary Outcome Measures (submitted: August 25, 2023)

To assess the efficacy of DB-1303 compared with chemotherapy in terms of progression-free survival (PFS) [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]

Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)

Current Secondary Outcome Measures (submitted: February 6, 2024)

• Overall survival (OS) in the HR+, HER2-low population [ Time Frame: Up to approximately 51 months ]
  OS in the HR+, HER2-low population
• Objective response rate (ORR) in the HR+, HER2-low population [ Time Frame: Up to approximately 51 months ]
  ORR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population
• PFS by Investigator assessment [ Time Frame: Up to approximately 51 months ]
  PFS by Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population
• Duration of response (DoR) in the HR+, HER2-low population [ Time Frame: Up to approximately 51 months ]
  DoR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population
• Treatment-emergent adverse events (TEAEs) [ Time Frame: from the time of the subject signing the informed consent form (ICF) until the follow-up period is completed (35 days after the last doseof study treatment ]
  TEAEs per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
• Serious adverse events (SAEs) [ Time Frame: from the time of the subject signing the ICF until the follow-up period is completed (35 days after the last doseof study treatment ]
  SAEs per NCI CTCAE v5.0
• Patient reported outcomes (PROs): European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) - C30 [ Time Frame: Up to approximately 51 months ]
  Change from baseline in the functioning/symptom/global quality of life (QoL) subscales of EORTC QLQ-C30. Scale scores range from 0-100. For functioning and global QoL scales, higher scores indicate better functioning or global health status. For symptom scales, higher scores indicate greater symptom burden.
• Patient reported outcomes (PROs): EORTC QLQ-BR45 [ Time Frame: Up to approximately 51 months ]
  Change from baseline in the functioning/symptom subscales of EORTC QLQ-BR45. Scale scores range from 0-100. For functioning scales, higher scores indicate better functioning. For symptom scales, higher scores indicate greater symptom burden.
• Patient reported outcomes (PROs): European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) [ Time Frame: Up to approximately 51 months ]
  Change from baseline in EQ-5D-5L health state utility index score and Visual Analogue Scale (VAS) score. VAS score range from 0-100, higher scores indicate better health status.
• European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) [ Time Frame: Up to approximately 51 months ]
  EQ-5D-5L health state utility index score and Visual Analogue Scale (VAS) score. The change from baseline value will be reported.

Original Secondary Outcome Measures (submitted: August 25, 2023)

• To assess the efficacy of DB-1303 compared with chemotherapy in terms of overall survival (OS) in the HR+, HER2-low populationchemotherapy in terms of overall survival (OS) [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]
  Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)
• To further assess the efficacy of DB-1303 in terms of PFS by Investigator assessment, objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and time to response (TTR) by BICR and Investigator assessment [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]
  Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)
• To assess the safety and tolerability profile of DB-1303 compared with investigator's choice chemotherapy. [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]
  Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)
• To assess the pharmacokinetics (PK) of DB-1303 (DB-1303 antibody-drug conjugate [ADC] and free payload P1003). [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]
  Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)
• To assess symptoms, functioning and health-related quality of life (HRQoL) in subjects treated with DB-1303 compared with investigator's choice single agent chemotherapy [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]
  Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)
• To assess the impact of treatment and disease state on health utility using the EQ-5D-5L [ Time Frame: From the date of randomization until objective (RECIST 1.1 defined) disease progression ]
  Tumor evaluation scans will be performed at screening (as baseline) with follow ups every 6 weeks (Q6W ± 1 week)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of DB-1303/BNT323 vs Investigator's Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Metastatic Breast Cancer (DYNASTY-Breast02)
• Official Title: A Phase 3, Randomized, Multi-center, Open-Label Study of DB-1303 Versus Investigator's Choice Chemotherapy in Human Epidermal Growth Factor Receptor 2 (HER2)-Low, Hormone Receptor Positive (HR+) Metastatic Breast Cancer Patients Whose Disease Has Progressed on Endocrine Therapy (ET) (DYNASTY-Breast02)
• Brief Summary: The goal of this clinical trial is to assess the efficacy of DB-1303/BNT323 compared with investigator's choice chemotherapy in terms of progression-free survival (PFS) by blinded independent central review (BICR) in the HR+, HER2-low (immunohistochemistry [IHC]2+/in situ hybridization [ISH]- and IHC 1+) population.
• Detailed Description: The study is a Phase III, Randomized, Multi-center, Open-label study in HER2-low, HR+ metastatic breast cancer subjects whose disease has progressed on at least 2 lines of prior ET or within 6 months of first line ET + Cyclin-dependent kinase (CDK) 4/6 inhibitor in the metastatic setting. The primary purpose of the study is to determine the efficacy and safety of DB-1303/BNT323 compared with investigator's choice single agent chemotherapy in the target population. Approximately 532 subjects with HER2 IHC 2+/ISH- and IHC 1+ (HER2-low] expression will be randomized 1:1 across approximately 230 centers globally to receive either DB-1303 or investigator's choice single agent chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) until Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression (PD), unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer

Intervention

• Drug: DB-1303/BNT323
  IV
• Drug: Capecitabine
  Oral
• Drug: Paclitaxel
  IV
• Drug: Nab-paclitaxel
  IV

Study Arms

• Experimental: DB-1303/BNT323
  Enrolled Subjects will be randomized to receive a 8 mg/kg IV dose of DB-1303/BNT323 on Day 1 of each cycle Q3W
  Intervention: Drug: DB-1303/BNT323
• Active Comparator: investigator's choice single agent chemotherapy
  Enrolled Subjects will be randomized to receive investigator's choice single agent chemotherapy (capecitabine:1000 or 1250 mg/m2, Oral, Twice daily orally for 2 weeks followed by a 1-week rest period in 3-week cycles; paclitaxel：80 mg/m2， IV, Every week (QW) in 3-week cycles; or nab-paclitaxel: 100 mg/m2, IV, Every week (QW) for 3 weeks followed by a one-week rest period in 4-week cycles) until RECIST 1.1 defined disease progression (PD), unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.
  Interventions:

  • Drug: Capecitabine
  • Drug: Paclitaxel
  • Drug: Nab-paclitaxel

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 13, 2023): 532
• Original Estimated Enrollment (submitted: August 25, 2023): 466
• Estimated Study Completion Date: May 2028
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female adults (defined as ≥ 18 years of age or acceptable age according to local regulations at the time of voluntarily signing of informed consent).
2. Pathologically documented breast cancer that:

1) Is advanced or metastatic 2) Has HER2-low expression (IHC 1+ or IHC 2+/ISH-) as determined by the central laboratory result.

3) Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.

4) Is documented as HR+ (either estrogen receptor [ER] and/or progesterone receptor [PgR] positive [ER or PgR ≥1%]) per ASCO/CAP guidelines (Allison et al 2020).

3. Must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory, preferably in formalin fixation and paraffin embedding (FFPE) blocks based on a mandatory FFPE tumor sample obtained at the time of metastatic disease or later;

4. Eastern Cooperative Oncology Group performance status of 0 or 1.

5. Must have had either:

1. Disease progression on endocrine therapy + CDK4/6 inhibitor within 6 months of starting first line treatment for metastatic disease and considered appropriate for chemotherapy as the next treatment by the investigator, OR
2. Disease progression on at least 2 previous lines of ET with or without a targeted therapy (such as CDK4/6, mammalian target of rapamycin [mTOR] or phosphoinositide 3-kinase [PI3-K] inhibitors) administered for the treatment of metastatic disease.

6. No prior chemotherapy for advanced or metastatic breast cancer. Subjects who have received chemotherapy in the neo-adjuvant or adjuvant setting are eligible, as long as they have had a disease-free interval (defined as completion of systemic chemotherapy to diagnosis of advanced or metastatic disease) of >12 months.

7. Life expectancy ≥12 weeks at screening.

8. Subjects must have at least one measurable lesion as defined per RECIST v1.1 or have non-measurable, bone-only disease that can be assessed by computer tomography (CT) or Magnetic Resonance Imaging (MRI) or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-Ray in the absence of measurable disease as defined above is acceptable; subjects with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.

9. Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 7 months after the last dose of study treatment.

10. Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening and throughout the duration of the study treatment and the washout period

Exclusion Criteria:

1. Ineligible for all options in the investigator's choice chemotherapy arm.
2. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events or compromise the ability of the subject to give written informed consent.
3. Clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to the randomization.
4. Uncontrolled or significant cardiovascular disease
5. Has as a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
6. Subjects with prior use of immunosuppressive medication within 14 days prior to first study dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses less than 10 mg/day of prednisone or equivalent.
7. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
8. Previous treatment with anti-HER2 therapy.
9. Prior treatment with antibody-drug conjugate that comprised an exatecan derivative that is a topoisomerase I inhibitor.
10. Prior randomization or treatment in a previous DB-1303/BNT323 study regardless of treatment assignment.
11. Has substance abuse or any other medical conditions such as psychological conditions, that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Helen Liu; 86-21-26018730; helen.liu@dualitybiologics.com

Contact: Michael Sun; michael.sun@dualitybiologics.com

• Listed Location Countries: Australia, China, United States

Administrative Information

• NCT Number: NCT06018337
• Other Study ID Numbers: DB-1303-O-3002; CTR20233708 ( Other Identifier: CENTER FOR DRUG EVALUATION, NMPA )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: DualityBio Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: DualityBio Inc.
• Original Study Sponsor: Same as current
• Collaborators: BioNTech SE

Investigators

• Study Director: Raymond Zhao; DualityBio Inc.

• PRS Account: DualityBio Inc.
• Verification Date: February 2024