Bladder Cancer, Breast Cancer, Gastric/Gastroesophageal Junction (GEJ) Cancer, Non-small Cell Lung Cancer (NSCLC)
Conditions
Keywords
Breast cancer, Non-small cell lung cancer (NSCLC), Bladder cancer, Gastric/gastroesophageal junction (GEJ), Radioligand therapy (RLT), [177Lu]Lu-DWJ155, [68Ga]Ga-DWJ155, Human Epidermal Growth Factor Receptor 2 (HER2), FML539, FKL480
Brief summary
The purpose of this phase I study is to evaluate the safety, tolerability, dosimetry, and preliminary anti-tumor activity of \[177Lu\]Lu-DWJ155 and the safety and imaging properties of \[68Ga\]Ga-DWJ155 in patients with histologically or cytologically confirmed advanced HER2+, HR+/HER2-negative, or triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), HER2-3+ or 2+ (ISH positive or negative) gastric/gastroesophageal junction (GEJ) cancer, and bladder cancer.
Detailed description
The study will be done in two parts. The first part is called "escalation" and the second part is called "expansion". In both parts of the study, patients will initially be imaged with a \[68Ga\]Ga-DWJ155 positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI) scan. In the escalation part, different doses of \[177Lu\]Lu-DWJ155 will then be tested to identify recommended dose(s) (RD(s)) for further evaluation. The expansion part of the study will examine the safety and preliminary efficacy of \[177Lu\]Lu-DWJ155 at the RD(s) determined during the escalation part. In both parts, there will be a safety follow-up period after the last \[177Lu\]Lu-DWJ155 administration.
Interventions
DIAGNOSTIC_TEST[68Ga]Ga-DWJ155
Radioligand imaging agent
DRUG[177Lu]Lu-DWJ155
Radioligand therapy
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients age ≥ 18 years. * Patients with one of the following histologically or cytologically confirmed and documented malignancies who have progressed on or been intolerant to standard of care therapy, and are not considered appropriate for any standard therapy with proven benefit, in the investigator's judgment: * Dose Escalation: * Advanced HER2+ breast cancer with disease progression after at least two prior lines of systemic therapy in the advanced setting * Advanced HR+/HER2-low breast cancer with disease progression after prior therapy in the advanced setting * Advanced NSCLC without actionable genetic alterations (AGAs) with disease progression after prior therapy in the advanced setting * Advanced NSCLC with AGAs who have received prior treatment * Measurable disease as determined by RECIST version 1.1. * Dose Expansion: * Advanced HER2+ breast cancer with disease progression after at least two prior lines of systemic therapy in the advanced setting * Advanced HR+/HER2-low breast cancer with disease progression after prior therapy in the advanced setting * Advanced HR+/HER2 0 breast cancer with disease progression after prior therapy in the advanced setting * Advanced HR-/HER2-low breast cancer with disease progression after prior therapy in the advanced setting * Advanced HR-/HER2 0 breast cancer with disease progression after prior therapy in the advanced setting * Advanced NSCLC with AGAs, who have received prior treatment * Advanced NSCLC without known AGAs who have received prior treatment. * Advanced gastric/GEJ cancer with HER2 IHC 3+ or 2+ (ISH + or -), following disease progression after prior therapy in the advanced setting * Advanced bladder cancer following disease progression after prior therapy in the advanced setting * Measurable disease as determined by RECIST version 1.1.
Exclusion criteria
* Out-of-range laboratory values defined as: * Creatinine clearance \< 60 mL/min (calculated using CKD-EPI 2021 formula, or measured) * Total bilirubin \> 1.5 x ULN (except for patients with Gilbert's syndrome who are excluded if total bilirubin \>3.0 x ULN) or direct bilirubin \> 1.5 x ULN * Alanine aminotransferase (ALT) \> 3 x ULN, except for patients with tumor involvement of the liver who are excluded if ALT \> 5 x ULN * Aspartate aminotransferase (AST) \> 3 x ULN, except for patients with tumor involvement of the liver who are excluded if AST \> 5 x ULN * Lipase \> 1.5 x ULN * Absolute neutrophil count (ANC) \< 1.5 x 109/L * Hemoglobin \< 9 g/dL * Platelet count \< 100 x 109/L * Initiation of hematopoietic colony stimulating factors, thrombopoietin mimetics, or erythroid stimulating agents initiated ≤ 2 weeks prior to imaging agent administration. * Use of transfusion support ≤4 weeks prior to imaging agent administration. * Impaired cardiac function or clinically significant cardiac disease. * Unmanageable urinary tract obstruction or urinary incontinence. * Any serious uncontrolled infection (acute or chronic). * Pregnant or breastfeeding women. * Treatment with any of the following anti-cancer therapies prior to imaging agent administration within the stated timeframes: * Prior treatment with any therapeutic radiopharmaceutical * \< 10 half-lives for any imaging radiopharmaceutical * ≤ 4 weeks for external beam radiation therapy (EBRT) or brachytherapy * ≤ 6 months for lung-directed external beam radiotherapy * Patients with non-tumor uptake of \[68Ga\]Ga-DWJ155 in tissues or organs that, in the opinion of the investigator, increases the risk associated with \[177Lu\]Lu-DWJ155 treatment. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) of [177Lu]Lu-DWJ155 | Up to 6 weeks | A DLT is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness/injury or concomitant medications that occurs within the first treatment cycle. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. |
| Frequency of dose interruptions and reductions [177Lu]Lu-DWJ155 | 11 months | Number of participants with dose interruptions and/or reductions to assess the tolerability. |
| Dose intensity [177Lu]Lu-DWJ155 | 11 months | Dose intensity defined as the ratio of actual cumulative dose received and actual duration of exposure |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) of [177Lu]Lu-DWJ155 | Up to approximately 53 months | Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, echocardiograms (ECGs), and imaging assessments qualifying and reported as AEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) per RECIST v1.1 | Up to approximately 53 months | PFS is defined as the time from the date of start of treatment to the date of the first documented progression as per local review and according to RECIST v1.1 or death due to any cause. |
| Area under the concentration-time curve (AUC) of [177Lu]Lu-DWJ155 | From pre-dose up to 168 hours after the end of the infusion on Day 1 | The pharmacokinetic (PK) analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. AUC will be determined by non-compartmental methods. |
| Systemic clearance (CL) of [177Lu]Lu-DWJ155 | From pre-dose up to 168 hours after the end of the infusion on Day 1 | The PK analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. CL will be determined by non-compartmental methods. |
| Maximum observed concentration (Cmax) of [177Lu]Lu-DWJ155 | From pre-dose up to 168 hours after the end of the infusion on Day 1 | The PK analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Cmax will be determined by non-compartmental methods. |
| Volume of distribution during the terminal phase (Vz) of [177Lu]Lu-DWJ155 | From pre-dose up to 168 hours after the end of the infusion on Day 1 | The PK analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Vz will be determined by non-compartmental methods. |
| Terminal half-life (T1/2) of [177Lu]Lu-DWJ155 | From pre-dose up to 168 hours after the end of the infusion on Day 1 | The PK analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. T1/2 will be determined by non-compartmental methods. |
| Urinary excretion of [177Lu]Lu-DWJ155 | From pre-dose up to 72 hours after the end of the infusion on Day 1 | The PK analysis will be performed based on decay-corrected urine radioactivity concentration data converted to mass units. Urinary excretion will be derived based on the percentage of injected dose excreted in urine in each collection interval and overall. |
| Renal clearance (CLr) of [177Lu]Lu-DWJ155 | From pre-dose up to 72 hours after the end of the infusion on Day 1 | The PK analysis will be performed based on decay-corrected blood and urine radioactivity concentration data converted to mass units. CLr will be determined by non-compartmental methods. |
| Absorbed radiation dose in selected organs, tumor lesions and total body of [177Lu]Lu-DWJ155 | Up to 168 hours after the end of the infusion on Day 1 | Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) images will be acquired to assess total body, organ and tumor lesion dosimetry. |
| Standard uptake values (SUVs) in normal tissues and selected tumor lesions of [68Ga]Ga-DWJ155 | Up to approximately 1.5 hours after the end of infusion | 68Ga-DWJ155 positron emission tomography/computed tomography (PET/CT) or positron emission tomography/magnetic resonance imaging (PET/MRI) imaging assessments will be performed to derive SUVs in normal tissues and selected tumor lesions. |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) of [68Ga]Ga-DWJ155: | Up to 3 days | Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, echocardiograms (ECGs), and cardiac imaging qualifying and reported as AEs. |
| Overall Response Rate (ORR) per RECIST v1.1 | Up to approximately 53 months | ORR is defined as the proportion of patients with a best overall response (BOR) of complete response (CR) or partial response (PR) as per local review and according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). |
| Disease Control Rate (DCR) per RECIST v1.1 | Up to approximately 53 months | DCR is defined as the proportion of patients with a BOR of CR, PR, or stable disease (SD) as per local review and according to RECIST v1.1. |
| Duration of Response (DOR) per RECIST v1.1 | Up to approximately 53 months | DOR is the time between the first documented response (CR or PR) and the date of progression as per local review and according to RECIST v1.1, or death due to any cause. |
Countries
Australia, Canada, Japan, United States
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed