A Phase 3 Study of DB-1303 vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dualitybio Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Apr 2024 → ongoing

Decision date (initial)

2024-03-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

BioNTech SE · DUALITYBIO INC.

External identifiers

EU CT number

2023-507333-17-00

ClinicalTrials.gov

NCT06018337

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the efficacy of DB-1303 compared with investigator’s choice chemotherapy in terms of a hazard ratio (HR) for progression-free survival (PFS) assessed by blinded independent central review (BICR) in the HR+, HER2-low (IHC 2+/ISH- and IHC 1+) population. The intercurrent event of initiation of subsequent anti-cancer therapy will follow a hypothetical strategy, and discontinuation of study treatment will follow a treatment policy strategy.

Secondary objectives 5

1. To assess the efficacy of DB-1303 followed by any other subsequent anti-cancer therapy compared with investigator’s choice chemotherapy followed by any other subsequent anticancer therapy in terms of a HR for overall Survival (OS) in the HR+, HER2-low (IHC 2+/ISH- and IHC 1+) population. Handling of intercurrent events will follow a treatment policy strategy.
2. To further assess the efficacy of DB-1303 compared with investigator’s choice chemotherapy in terms of PFS by Investigator assessment, objective response rate (ORR), and duration of response (DoR) by BICR and Investigator assessment in the HR+, HER2low population.
3. To assess the safety and tolerability profile of DB-1303 compared with investigator’s choice chemotherapy.
4. 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.
5. To assess the impact of treatment and disease state on health utility using the EQ-5D-5L

Conditions and MedDRA coding

HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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 HER2low expression (IHC 1+ or IHC 2+/ISH-) 3) Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per ASCO/CAP guidelines. 4) Is documented as HR+ (either ER and/or 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, in formalin fixation and paraffin embedding (FFPE) blocks based on a mandatory FFPE tumor sample preferably obtained at the time of metastatic disease or later.
4. ECOG 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, mTOR or 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, (For bone-only disease, subjects with lytic or mixed lytic bone lesions that can be measured by CT or MRI are eligible; subjects with sclerotic/osteoblastic bone lesions are not eligible).
9. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before randomization.
10. Adequate organ and bone marrow function within 14 days before randomization.
11. Has adequate treatment washout period before randomization, as defined in the protocol.
12. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner.
13. 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.
14. 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 (4 months after the last dose of DB-1303, 6 months after the last dose of paclitaxel or nab-paclitaxel, and 3 months after the last dose of capecitabine).

Exclusion criteria 22

1. Ineligible for all options in the investigator’s choice chemotherapy arm. Subjects with contraindications to capecitabine, paclitaxel, and nab-paclitaxel treatment, per local prescribing information, cannot be enrolled to the study.
2. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Subjects should be tested for HIV prior to randomization if required by local regulations or by the institutional review board (IRB)/independent ethics committee (IEC)
3. Receipt of live, attenuated vaccine (mRNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study treatment. Note: Subjects, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study treatment.
4. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline or Grade ≤ 2 anemia.
5. Pregnant or breastfeeding female subjects, or subjects who are planning to become pregnant.
6. Subjects with a known hypersensitivity to either the drug substances, inactive ingredients in the drug product or other monoclonal antibodies.
7. History of another primary malignancy within 3 years, except adequately resected non melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral breast cancer.
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 study regardless of treatment assignment
11. Participation in another clinical study with a study treatment administered recently (i.e. the washout period is less than five half-lives prior to the first dose of study treatment or 30 days prior to the first dose of study treatment if the half-life is unknown) or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow up period of an interventional study. Of note, tissue screening for this study while a subject is on follow-up in another clinical study is acceptable.
12. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent.
13. 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.
14. Clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring repeated drainage, peritoneal shunt or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to the randomization.
15. Uncontrolled or significant cardiovascular disease
16. Has a medical history of interstitial lung diseases (e.g., non-infectious interstitial pneumonia, pneumonitis /, pulmonary fibrosis, and radiation pneumonitis, which needs glucocorticoids and antibiotics) or current interstitial lung diseases or who are suspected have these diseases by imaging at screening.
17. 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.
18. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months prior to study randomization, severe asthma, severe chronic obstructive pulmonary disorder [COPD], restrictive lung disease, significant pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis etc.), and/or prior pneumonectomy (complete).
19. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals within 14 days prior to the first dose of study treatment.
20. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants within 7 days prior to first study dose may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study randomization.
21. Individuals who are dependent on the Sponsor, clinical site, or Investigator (e.g., is an employee of the Sponsor or the clinical trial site, a dependent of the Investigator, or any site staff member otherwise supervised by the Investigator).
22. Individuals who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities, in accordance with local regulations.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS by BICR according to response evaluation criteria in solid tumors (RECIST) 1.1 in the HR+, HER2-low population

Secondary endpoints 6

1. OS in the HR+, HER2-low population
2. ORR and DoR by BICR and Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population
3. PFS by Investigator assessment according to RECIST 1.1 in the HR+, HER2-low population
4. TEAEs and SAEs per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, physical examinations, changes from baseline in laboratory findings, electrocardiograms (ECGs), ECHO/MUGA and vital signs.
5. The patient reported outcomes (PROs) include: change from baseline in EORTC QLQC30 and EORTC QLQ-BR45 Scale scores, time to deterioration in EORTC QLQ-C30 scores
6. EQ-5D-5L health state utility index

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dualitybio Inc.

Sponsor organisation

Dualitybio Inc.

Address

3524 Silverside Road Suite 35b

City

Wilmington

Postcode

19810-4929

Country

United States

Scientific contact point

Organisation

Dualitybio Inc.

Contact name

Xiusong Qiu

Public contact point

Organisation

Dualitybio Inc.

Contact name

Helen Liu

Third parties 7

Locations

7 EU/EEA countries · 73 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 159 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

20 submissions — initial application plus substantial / non-substantial modifications