Clinical trial NCT05785741: A Study of DB-1310 in Advanced/Metastatic Solid Tumors
Official title: A Phase 1/2a, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1310 in Subjects With Advanced/Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumor
Keywords: HER3
NSCLC
CRPC
HNSCC
BC
non-small cell lung cancer
castration-resistant prostate cancer
head and neck squamous cell carcinoma
breast cancer
ESCC
BTC
Lead sponsor: DualityBio Inc.
Sponsor class: INDUSTRY
First posted: 2023-03-27
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a dose-escalation and dose-expansion Phase 1/2a trial to evaluate the safety and tolerability of DB-1310 in subjects with advanced solid tumors.

Detailed description: This is a multicenter, open-label, multiple-dose, FIH Phase 1/2a study. Phase 1 adopts the standard "3+3" design to identify: the MTD and/or RP2D of DB-1310 as monotherapy, the RCD_A of DB-1310 in combination with trastuzumab or approved trastuzumab biosimilar and the RCD_B of DB-1310 in combination with Osimertinib; Phase 2a is a dose expansion phase to confirm the safety, tolerability and explore efficacy in selected malignant solid tumors treated with DB-1310 as monotherapy or in combination with trastuzumab or approved trastuzumab biosimilar or in combination with Osimertinib.

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. Have relapsed or progressed on or after standard systemic treatments, or intolerable with standard treatment, or for which no standard treatment is available. Documented radiological disease progression during/after most recent treatment regimen for advanced/unresectable, or metastatic disease.
3. At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria.
4. Has a life expectancy of ≥ 3 months.
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
6. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before enrollment.
7. Has adequate organ functions within 7 days prior to Day 1 of Cycle 1.
8. Has adequate treatment washout period prior to Day 1 of Cycle 1.
9. Is willing to provide pre-existing resected tumor samples or undergo fresh tumor biopsy for the measurement of HER3 level and other biomarkers if no contraindication. For HER2 IHC 0 breast cancer subjects, it is highly recommended to collect additional tumor sample (Refer to Lab Manual).
10. Is capable of comprehending study procedures and risks outlined in the informed consent and able to provide written consent and agree to comply with the requirements of the study and the schedule of assessments.
11. Male and female subjects of reproductive/childbearing potential must agree to use adequate contraceptive methods (e.g., double barrier or intrauterine contraceptive) during the study and for at least 4 months and 7 months after the last dose of study drug, respectively.

    Females must be using highly effective contraceptive measures during the study and for at least 7 months after the last dosing of study drug, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
    * Post-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
    * Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution
    * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
12. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration.
13. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration.

Exclusion Criteria:

1. Prior treatment with HER3 targeted therapy.
2. Prior treatment with antibody drug conjugate with topoisomerase I inhibitor (except trastuzumab deruxtecantopoisomerase I inhibitor HER2 ADC for backfilled subjects in Combo A of Phase 1 and subjects in Cohort 2e of Phase 2a, and not applicable for subjects enrolled for DLT observation in Phase 1).
3. Has a medical history of symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] classes II-IV) or serious cardiac arrhythmia requiring treatment.
4. Has a medical history of myocardial infarction or unstable angina within 6 months before enrollment.
5. Has any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval \> 250 milliseconds (ms).
6. Has an average of Fredericia's formula-QT corrected interval (QTcF) prolongation to \> 470 millisecond (ms) in males and females based on a 12-lead electrocardiogram (ECG) in triplicate.
7. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval.

   For Combo B of Phase 1 and Cohort 2g, 2k of Phase 2a, patients currently receiving (or unable to stop use prior to receiving the first dose of Osimertinib) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3-week prior) (refer to Section 6.9.1) are ineligible, and all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
8. Has a history of (non-infectious) ILD/pneumonitis and/or radiation pneumonitis that required steroids, has current ILD/pneumonitis and/or radiation pneumonitis, or where suspected ILD/pneumonitis and/or radiation pneumonitis cannot be ruled out by imaging at screening.
9. Have a lung-specific intercurrent clinically significant illness including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months prior to Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disorder, restrictive lung disease, significant pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), and/or prior pneumonectomy (complete).
10. Has an uncontrolled infection requiring intravenous injection of antibiotics, antivirals, or antifungals.
11. Has clinically significant corneal disease.
12. Know human immunodeficiency virus (HIV) infection.
13. Subjects have active viral (any etiology) hepatitis are excluded. However, subjects with positive hepatitis B surface antigen (HBsAg) who have the HBV DNA (viral load) below the lower limit quantification or HBV DNA titer \< 1000 cps/mL or 100 IU/mL per local testing and are not currently on viral suppressive therapy may be eligible and should be discussed with the Sponsor's Medical Monitor. However, subjects with a history of hepatitis C virus (HCV) infection who have completed curative antiviral treatment and have the HCV RNA below the lower limit of quantification per local testing are eligible for study entry.
14. Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will also be excluded), or pregnant as confirmed by serum pregnancy tests performed within 7 days prior to Cycle 1 Day 1.
15. Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. However, subjects with asymptomatic central nervous system (CNS) metastases who are radiologically and neurologically stable for at least 4 weeks following CNS-directed therapy, and who are on stable or decreasing doses of corticosteroids equivalent to ≤10 mg/day prednisone are eligible for study entry.
16. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE version 5.0, grade ≤ 1 or baseline. Subjects with chronic Grade 2 toxicities (e.g., Grade 2 neuropathy) may be eligible based on the discussion and agreement between Investigator and Sponsor.
17. Has multiple primary malignancies within 3 years before enrollment, except adequately resected non-melanoma skin cancer (e.g., resected basal or squamous cell skin cancer), curatively treated in-situ disease (e.g., carcinoma in situ of the cervix or breast), other solid tumors curatively treated (e.g., superficial bladder cancer), or contralateral breast cancer.
18. Has substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation or evaluation of the clinical study in the opinion of the investigator.
19. Has known hypersensitivity to either the drug substances or inactive ingredients in the drug product.
20. Patients with other reasons that, in the opinion of the Investigator, make them unsuitable to participate in this study.

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

Primary outcomes:
measure: Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0. Percentage of participants in Part 1 with DLTs
timeFrame: up to 21 days after Cycle 1 Day 1
measure: Phase 1: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v5.0.
timeFrame: Up to follow-up period, approximately 1 year post-treatment
measure: Phase 1: Percentage of Participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0.
timeFrame: Up to follow-up period, approximately 1 year post-treatment
measure: Maximum Tolerated Dose (MTD) of DB-1310
timeFrame: 12 months
measure: Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1310
timeFrame: 12 months
measure: Phase 2a: Percentage of Participants with Treatment Emergent adverse events (TEAEs) as assessed by CTCAE v5.0.
timeFrame: Up to follow-up period, approximately 1 year post-treatment
measure: Phase 2a: Percentage participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0.
timeFrame: Up to follow-up period, approximately 1 year post-treatment
measure: Phase 2a: Percentage of Objective Response Rate (ORR) as assessed by RECIST 1.1.
timeFrame: Up to follow-up period, approximately 1 year post-treatment
Secondary outcomes:
measure: Phase 1 & Phase 2a: Pharmacokinetic-AUC
timeFrame: within 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: Pharmacokinetic-Cmax
timeFrame: within 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: Pharmacokinetic-Tmax
timeFrame: within 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: Pharmacokinetic-T1/2
timeFrame: within 8 cycles (each cycle is 21 days)
measure: Phase 1: ORR will be determined from tumor assessments by investigator per RECIST 1.1
timeFrame: with 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: duration of response (DoR) will be determined from tumor assessments by investigator per RECIST 1.1
timeFrame: with 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: disease-control rate (DCR)
timeFrame: with 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: progression free survival (PFS) will be determined from tumor assessments by investigator per RECIST 1.1
timeFrame: with 8 cycles (each cycle is 21 days)
measure: Phase 1 & Phase 2a: overall survival (OS)
timeFrame: with 8 cycles (each cycle is 21 days)
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology - Santa Monica
state: California
city: Margate
country: United States
facility: D&H Cancer Research Center LLC
state: Florida
city: Orlando
country: United States
facility: Sarah Cannon Research Institute at Florida Cancer Specialists
state: Florida
city: Plantation
country: United States
facility: BRCR global
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tamarac
country: United States
facility: BRCR Medical Center Inc.
state: Florida
city: Atlanta
country: United States
facility: Research Site 111
state: Georgia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Cincinnati
country: United States
facility: Carl & Edyth Lindner Center for Research & Education at The Christ Hospital and The Christ Hospital Cancer Center
state: Ohio
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Fairfax
country: United States
facility: NEXT Virginia
state: Virginia
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Changsha
country: China
facility: Hunan cancer hospital
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Province hospital
state: Jiangsu
city: Wuxi
country: China
facility: Affiliated Hospital of Jiangnan University
state: Jiangsu
city: Changchun
country: China
facility: The first hospital of Jilin University
state: Jilin
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Liaoning
city: Shanghai
country: China
facility: Shanghai Chest Hospital
state: Shanghai
city: Chendu
country: China
facility: Sichuan Provincial People's Hospital
state: Sichuan
Study officials:
affiliation: DualityBio Inc.
name: Lily Hu
role: STUDY_DIRECTOR
References: