A Study of DB-1310 in Advanced/Metastatic Solid Tumors

Официальное название

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

Обзор

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.

Подробное описание

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, or in combination with capecitabine

Вмешательства

• Препарат DB-1310
  Administered I.V.
• Препарат Trastuzumab
  Administered I.V.
• Препарат Osimertinib
  Oral
• Препарат capecitabine
  Oral

Первичные конечные точки

• Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0. Percentage of participants in Part 1 with DLTs [Срок оценки: up to 21 days after Cycle 1 Day 1]
• Phase 1: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs) as assessed by CTCAE v5.0. [Срок оценки: Up to follow-up period, approximately 1 year post-treatment]
• Phase 1: Percentage of Participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. [Срок оценки: Up to follow-up period, approximately 1 year post-treatment]
• Maximum Tolerated Dose (MTD) of DB-1310 [Срок оценки: 12 months]
• Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1310 [Срок оценки: 12 months]
• Phase 2a: Percentage of Participants with Treatment Emergent adverse events (TEAEs) as assessed by CTCAE v5.0. [Срок оценки: Up to follow-up period, approximately 1 year post-treatment]
• Phase 2a: Percentage participants with Serious Adverse Events (SAEs) as assessed by CTCAE v5.0. [Срок оценки: Up to follow-up period, approximately 1 year post-treatment]
• Phase 2a: Percentage of Objective Response Rate (ORR) as assessed by RECIST 1.1. [Срок оценки: Up to follow-up period, approximately 1 year post-treatment]

Вторичные конечные точки (9)

• Phase 1 & Phase 2a: Pharmacokinetic-AUC [Срок оценки: within 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: Pharmacokinetic-Cmax [Срок оценки: within 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: Pharmacokinetic-Tmax [Срок оценки: within 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: Pharmacokinetic-T1/2 [Срок оценки: within 8 cycles (each cycle is 21 days)]
• Phase 1: ORR will be determined from tumor assessments by investigator per RECIST 1.1 [Срок оценки: with 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: duration of response (DoR) will be determined from tumor assessments by investigator per RECIST 1.1 [Срок оценки: with 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: disease-control rate (DCR) [Срок оценки: with 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: progression free survival (PFS) will be determined from tumor assessments by investigator per RECIST 1.1 [Срок оценки: with 8 cycles (each cycle is 21 days)]
• Phase 1 & Phase 2a: overall survival (OS) [Срок оценки: with 8 cycles (each cycle is 21 days)]

Критерии участия

Критерии включения

• 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).
• 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.
• At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria.
• Has a life expectancy of ≥ 3 months.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
• Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before enrollment.
• Is willing to provide archived tumor tissue or undergo fresh tumor biopsy for the retrospective measurement of human epidermal growth factor receptor 3 (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).
• 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.
• 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
• 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.
• 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.
• Phase 1 monotherapy subjects (Phase 1 monotherapy ONLY):

• Pathologically documented advanced/unresectable, or metastatic solid tumors that is refractory to or intolerable with standard treatment, or for which standard treatment is not available.

Критерии исключения

• Prior treatment with HER3 targeted therapy.
• Prior treatment with antibody drug conjugate with topoisomerase I inhibitor (except topoisomerase 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).
• Has a medical history of symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] classes II-IV) or serious cardiac arrhythmia requiring treatment.
• Has a medical history of myocardial infarction or unstable angina or cerebrovascular accident including transient ischemic attack (TIA) within 6 months before first dose. Or has uncontrolled hypertension (defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg).
• 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).
• Has an average of Fredericia's formula-QT corrected interval (QTcF) prolongation to > 470 millisecond (ms) based on a 12-lead electrocardiogram (ECG) in triplicate.
• 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.

• Has a history of (non-infectious) ILD/pneumonitis and/or radiation pneumonitis that required glucocorticoids, or 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.
• 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).
• Has an uncontrolled infection requiring intravenous injection of antibiotics, antivirals, or antifungals.
• Know human immunodeficiency virus (HIV) infection. Subjects should be tested for HIV prior to enrollment if required by local regulations or by the IRB/ EC.
• Subjects have active viral (any etiology) hepatitis are excluded.
• 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.
• Has clinically active central nervous system (CNS) metastases, defined as untreated, or symptomatic, or requiring therapy with glucocorticoids or anticonvulsants to control associated symptoms. However, subjects with asymptomatic CNS metastases who are radiologically and neurologically stable for at least 4 weeks following CNS-directed radiotherapy or surgery, and who are on stable or decreasing doses of glucocorticoids equivalent to ≤10 mg/day prednisone are eligible for study entry.
• 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.
• Has multiple primary malignancies within 5 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., < T1 urothelial carcinoma), or contralateral breast cancer.
• 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.
• Has known hypersensitivity to either the drug substances or inactive ingredients in the drug product.
• Patients with other reasons that, in the opinion of the Investigator, make them unsuitable to participate in this study.
• For Combo B of Phase 1 and Cohort 2g, 2k, 2m of Phase 2a, patients with refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of Osimertinib or capecitabine are ineligible.

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 15 центров

• University of California, Davis Comprehensive Cancer Center — Sacramento
• UCLA Hematology/Oncology - Santa Monica — Santa Monica
• Research Site 117 — Coral Gables
• D&H Cancer Research Center LLC — Margate
• Sarah Cannon Research Institute at Florida Cancer Specialists — Orlando
• BRCR global — Plantation
• Florida Cancer Specialists — Sarasota
• BRCR Medical Center Inc. — Tamarac
• … и ещё 7 центров

Китай · 9 центров

• Henan Cancer Hospital — Чжэнчжоу
• Hunan cancer hospital — Чанша
• Jiangsu Province hospital — Нанкин
• Affiliated Hospital of Jiangnan University — Wuxi
• The first hospital of Jilin University — Changchun
• The First Hospital of China Medical University — Шэньян
• Shanghai Chest Hospital — Шанхай
• Sichuan Provincial People's Hospital — Чэнду
• … и ещё 1 центр

Идентификаторы

NCT: NCT05785741 · DB-1310-O-1001 · CTR20231736

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)
• NMPA/CDE CTR20231736 (платформа chinadrugtrials.org.cn)

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