A Study of DB-1311 in Advanced/Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a dose-escalation and dose-expansion Phase 1/2a trial to evaluate the safety and tolerability of DB-1311 in subjects with advanced solid tumors.

Detailed Description
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This is a multicenter, open-label, multiple-dose, FIH Phase 1/2a study. Phase 1 adopts an accelerated titration at first dose level followed with classic 3+3 design to identify the MTD and/or RP2D. Phase 2a is a dose expansion phase to confirm the safety, tolerability and explore efficacy in selected malignant solid tumors treated with DB-1311 as monotherapy.

Official Title
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A Phase 1/2a, Multicenter, Open-Label, First in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of DB-1311 in Subjects With Advanced/Metastatic Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: DB-1311


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Histologically or cytologically confirmed unresectable advanced/metastatic solid tumor that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment; or for which no standard treatment is available. At least one measurable lesion as assessed by the investigator according to response evaluation criteria in solid tumors (RECIST) version 1.1 criteria. Castrate-resistant prostate cancer (CRPC) participants with bone only disease may be eligible on a case-by- case basis after discussion with the Medical Monitor. 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 pre-existing resected tumor samples or undergo fresh tumor biopsy for the measurement of B7-H3 level and other biomarkers if no contraindication. Note: there is no minimum B7-H3 expression level mandatory for entry into the study. 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. 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. SCLC participants (Phase 2a Cohort 1 ONLY): Pathologically documented locally advanced, or metastatic SCLC not amenable to curative surgery or radiation. Relapsed/progressed on or after 2 cycles of platinum-based chemotherapy in combination with/without anti-PD-1/anti-PD-L1 monoclonal antibody or intolerant to completion of 2 cycles of platinum-based chemotherapy due to the toxicity for locally advanced or metastatic disease. NSCLC participants (Phase 2a Cohort 2 ONLY): Pathologically documented locally advanced, or metastatic NSCLC and is not amenable to curative surgery or radiation. Has received prior treatment with platinum-based chemotherapy regimen and/or anti-PD-1/PD-L1 antibody-based regimen in the advanced/unresectable, or metastatic setting unless unable or unwilling. Participants with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (e.g., ALK rearrangement, ROS1 rearrangement, KRAS G12C mutation, BRAF V600E mutation, NTRK1/2/3 Gene fusion, MET Exon 14 skipping, RET rearrangement etc.) for which treatment is available must have also received prior treatment with at least 1 genotype-directed therapy. ESCC participants (Phase 2a Cohort 3 ONLY): Pathologically documented locally advanced, or metastatic ESCC and is not amenable to curative surgery or radiation. Having received at least one prior therapy for unresectable disease. Patients with recurrence within 6 months of completion of neoadjuvant or adjuvant therapy will be considered as having received one prior therapy for unresectable disease. CRPC participants (Phase 2a Cohort 4 ONLY): Pathologically documented metastatic adenocarcinoma of the prostate cancer. Progressive metastatic CRPC as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND 2) progressive disease as defined by PCWG3 criteria. Having received prior docetaxel (before or after an AR-targeted therapy). Docetaxel rechallenge was allowed. Having received prior novel hormone therapy. Melanoma participants (Phase 2a Cohort 5 ONLY) • Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy, must have had either: Previously treated with a PD-1 or PD-L1 inhibitor. If participants with BRAF gene mutant melanoma, must have had a prior treatment regimen that included vemurafenib, dabrafenib, or another BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor. Participants with other solid tumors (Phase 2a Cohort 6 ONLY) Histologically or cytologically confirmed solid tumors. Progressed or relapsed after at least one prior standard therapeutic regimen (Patients who have not received all approved or standard treatments for their cancer must be informed that these alternatives to receiving DB-1311 are available prior to consenting to participate in this trial). Exclusion Criteria: Unless otherwise specified, the exclusion criteria are common to both Phase 1 and Phase 2a. Subjects who meet any of the following criteria will be excluded from the study: Prior treatment with B7-H3 targeted therapy. Prior treatment with antibody drug conjugate with topoisomerase inhibitor (e.g., trastuzumab deruxtecan). 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 within 6 months before enrollment. 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. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval. Has a medical history of interstitial lung diseases (e.g., non-infectious interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or current interstitial lung diseases or who are suspected to have these diseases by imaging at screening. Has a history of underlying pulmonary disorder including, but not limited to, pulmonary emboli within 3 months of the start of study treatment, severe asthma, severe COPD, restrictive lung disease, and other clinically significant pulmonary compromise or requirement for supplemental oxygen. Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjögren's, sarcoidosis) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Has an uncontrolled infection requiring intravenous injection of antibiotics, antivirals, or antifungals. Know human immunodeficiency virus (HIV) infection. Subjects have active viral (any etiology) hepatitis are excluded. However, subjects with serologic evidence of chronic hepatitis B virus (HBV) infection (defined by a positive hepatitis B surface antigen [HBsAg] test or a positive hepatitis B core antibody test) who have a viral load below the limit quantification (HBV DNA titer < 1000 cps/mL or 200 IU/mL) 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 a viral load below the limit of quantification are eligible for study entry. Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days prior to enrollment. 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 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. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DB-1311 Dose Level 1<br>Enrolled Subjects will receive a single-dose of DB-1311 at Dose Level 1 on Day 1 of each cycle Q3W | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Level 2<br>Enrolled Subjects will receive a single-dose of DB-1311 at Dose Level 2 on Day 1 of each cycle Q3W | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Level 3<br>Enrolled Subjects will receive a single-dose of DB-1311 at Dose Level 3 on Day 1 of each cycle Q3W | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Level 4<br>Enrolled Subjects will receive a single-dose of DB-1311 at Dose Level 4 on Day 1 of each cycle Q3W | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Level 5<br>Enrolled Subjects will receive a single-dose of DB-1311 at Dose Level 5 on Day 1 of each cycle Q3W | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Expansion 1<br>Subjects with advanced/unresectable, or metastatic SCLC who have progressed on or after standard systemic treatments, a 21-day treatment cycle (i.e., once every 3 weeks) via intravenous infusion will be used for DB-1311. | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Expansion 2<br>Subjects with advanced/unresectable, or metastatic NSCLC who have progressed on or after standard systemic treatments, a 21-day treatment cycle (i.e., once every 3 weeks) via intravenous infusion will be used for DB-1311. | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Expansion 3<br>Subjects with advanced/unresectable, or metastatic esophageal squamous cell carcinoma (ESCC) who have progressed on or after standard systemic treatments, a 21-day treatment cycle (i.e., once every 3 weeks) via intravenous infusion will be used for DB-1311. | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Expansion 4<br>Subjects with advanced/unresectable, or metastatic castration-resistant prostate cancer (CRPC) who have progressed on or after standard systemic treatments, a 21-day treatment cycle (i.e., once every 3 weeks) via intravenous infusion will be used for DB-1311. | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Expansion 5<br>Subjects with advanced/unresectable, or metastatic melanoma who have progressed on or after standard systemic treatments, a 21-day treatment cycle (i.e., once every 3 weeks) via intravenous infusion will be used for DB-1311. | Drug: DB-1311<br>* Administered I.V.<br>|
| Experimental: DB-1311 Dose Expansion 6<br>Subjects with other advanced or metastatic solid tumors who have progressed on or after standard systemic treatments, a 21-day treatment cycle (i.e., once every 3 weeks) via intravenous infusion will be used for DB-1311. | Drug: DB-1311<br>* Administered I.V.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Percentage of Participants with Dose-Limiting Toxicities (DLTs) as assessed by CTCAE v5.0. Percentage of participants in Part 1 with DLTs | Percentage of participants in Part 1 with DLTs | 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. | Percentage of participants with AEs in Part 1 graded according to NCI CTCAE v5.0 | 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. | Percentage of Participants with SAEs in Part 1 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 1 year post-treatment | 
| Maximum Tolerated Dose (MTD) of DB-1311 | MTD on the data collected during Part 1 | 12 months | 
| Phase 1: Recommended Phase 2 Dose (RP2D) of DB-1311 | RP2D of DB-1311 based on the data collected during Part 1 | 12 months | 
| Phase 2a: Percentage of Participants with Treatment Emergent adverse events (TEAEs) as assessed by CTCAE v5.0. | Percentage of participants with AEs in Part 2 graded according to NCI CTCAE v5.0 | 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. | Percentage of participants with SAEs in Part 2 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 1 year post-treatment | 
| Phase 2a: Percentage of Objective Response Rate (ORR) as assessed by RECIST 1.1. | The percentage of subjects who had a best response rating of CR and PR, for Part 2 only which was maintained ≥4 weeks | Up to follow-up period, approximately 1 year post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 & Phase 2a: Pharmacokinetic-AUC | Area under the concentration-time curve from time 0 to infinity of DB-1311 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-Cmax | Maximum observed plasma concentration (Cmax) of DB-1311 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-Tmax | Time to Cmax of DB-1311 | within 8 cycles (each cycle is 21 days) | 
| Phase 1 & Phase 2a: Pharmacokinetic-T1/2 | Terminal elimination half-life | within 8 cycles (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B7-H3, SCLC, NSCLC, ESCC, CRPC, Melanoma, small cell lung cancer, non-small cell lung cancer, esophageal squamous cell carcinoma, castration-resistant prostate cancer