A Phase I Study of [177Lu]Lu-EVS459 in Patients With Ovarian and Lung Cancers
- Conditions
- Lung CancerOvarian Cancer
- Interventions
- Registration Number
- NCT06376253
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of \[177Lu\]Lu-EVS459 and the safety and imaging properties of \[68Ga\]Ga-EVS459 in patients aged ≥ 18 years with advanced high-grade serous ovarian cancer (OC) or locally advanced unresectable or metastatic non-squamous non-small cell lung carcinoma (non-sq. NSCLC).
- 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 EVS459 positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI) scan. In the escalation part, different doses of \[177Lu\]Lu-EVS459 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-EVS459 at the RD(s) determined during the escalation part. The end of study will occur when at least 80% of the patients in the expansion part have completed the follow-up for disease progression or discontinued from the study for any reason, and all patients have completed treatment and the 36-month long-term follow-up period.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 4
- Age >= 18 years old
- Patients with advanced high-grade serous ovarian cancer (OC) or locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (non sq. NSCLC) with disease progression following, or intolerance to, at least 1 line of therapy
Key
- Absolute neutrophil count (ANC) < 1.5 x 10^9/L, hemoglobin < 10 g/dL, or platelet count < 100 x 10^9/L
- QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
- Creatinine clearance < 60 mL/min
- Unmanageable urinary tract obstruction or urinary incontinence
- Radiation therapy within 4 weeks prior to the first dose of [177Lu]Lu-EVS459
Other protocol-defined inclusion/exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm1 [177Lu]Lu-EVS459 Patients will receive \[68Ga\]Ga-EVS459 and, if eligible, \[177Lu\]Lu-EVS459 Arm1 [68Ga]Ga-EVS459 Patients will receive \[68Ga\]Ga-EVS459 and, if eligible, \[177Lu\]Lu-EVS459
- Primary Outcome Measures
Name Time Method Number of participants with dose limiting toxicities of [177Lu]Lu-EVS459 From start of study treatment until 6 weeks after A dose limiting toxicity (DLT) is defined as any adverse event or abnormal laboratory value of CTCAE (version 5.0) Grade 3 or higher that occurs within the DLT evaluation period and that is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications with a few exceptions defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Incidence and severity of adverse events and serious adverse events of [177Lu]Lu- EVS459 From start of study treatment until completion of the 36 month follow up , assessed up to approximately 42 months The distribution of adverse events will be done via the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) and through the monitoring of relevant clinical and laboratory safety parameters.
Dose intensity for [177Lu]Lu- EVS459 From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks Dose intensity for \[177Lu\]Lu- EVS459 will be assessed and summarized using descriptive statistics. Dose intensity is computed as the ratio of actual cumulative dose received and actual duration of exposure.
Dose modifications for [177Lu]Lu- EVS459 From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks Dose modifications (dose interruptions and reductions) for \[177Lu\]Lu-EVS459 will be assessed and summarized using descriptive statistics. The number of patients with dose modification will be summarized by treatment groups.
- Secondary Outcome Measures
Name Time Method Area Under the Curve (AUC) of [177Lu]Lu-EVS459 Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes and 30 minutes, 1, 2, 4, 6 and 12 hours), Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. The \[177Lu\]Lu-EVS459 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. AUC will be determined by non-compartmental methods.
Overall response rate (ORR) Up to approximately 42 months ORR is defined as the proportion of patients with a BOR of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines.
Total body clearance of [177Lu[Lu-EVS459 Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes and 30 minutes, 1, 2, 4, 6 and 12 hours), Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. The \[177Lu\]Lu-EVS459 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Total body clearance will be determined by non-compartmental methods.
Observed maximum plasma concentration (Cmax) of [177Lu]Lu-EVS459 Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes and 30 minutes, 1, 2, 4, 6 and 12 hours), Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. The \[177Lu\]Lu-EVS459 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Cmax will be determined by non-compartmental methods.
Urinary excretion of radioactivity expressed as a percentage of injected activity (%IA) Cycle 1: Pre-infusion, beginning of infusion to first SPECT/CT image acquisition, first SPECT/CT image acquisition and 6 hours post-end-of infusion(EOI), 6-24 hours post-EOI, 24-48 hours post-EOI, 48-72 hours post-EOI. The duration of a cycle is 6 weeks. Urine elimination data for \[177Lu\]Lu-EVS459 will be assessed based on decay-corrected urine radioactivity concentration data. Urine elimination data will be expressed as percentage of injected activity (%IA).
Renal clearance of [177Lu]Lu- EVS459 Cycle 1: Pre-infusion, beginning of infusion to first SPECT/CT image acquisition, first SPECT/CT image acquisition and 6 hours post-end-of infusion(EOI), 6-24 hours post-EOI, 24-48 hours post-EOI, 48-72 hours post-EOI. The duration of a cycle is 6 weeks. Urine samples will be collected over specified time intervals and analysed for radioactivity. Renal clearance of 177Lu-EVS459 will be summarized using descriptive statistics.
Duration of Response (DOR) Up to approximately 42 months DOR is the time between the first documented response (CR or PR) and the date of progression according to RECIST v1.1 guidelines.
Disease control rate (DCR) Up to approximately 42 months DCR is defined as the proportion of patients with a BOR of CR, PR, or stable disease according to RECIST v1.1 guidelines.
Terminal elimination half-life (T1/2) of [177Lu]Lu-EVS459 Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes and 30 minutes, 1, 2, 4, 6 and 12 hours), Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. The \[177Lu\]Lu-EVS459 pharmacokinetic 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.
Absorbed dose of [177Lu]Lu- EVS459 Cycle 1 Day 1, Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. The absorbed dose in normal tissues and tumor lesions will be summarized with descriptive statistics.
Lesion number will be assigned by dosimetry expert.Visual and quantitative assessment of [68Ga]Ga-EVS459 uptake in normal tissues and tumor lesions over time From 0 up to approximately 3 hours after [68Ga]Ga-EVS459 dosing After \[68Ga\]Ga-EVS459 administration, \[68Ga\]Ga-EVS459 PET/CT or PET/MRI will be performed. Standardized uptake values (SUVs) of \[68Ga\]Ga-EVS459 in normal tissues and tumor lesions over time will be summarized.
Progression free survival (PFS) Up to approximately 42 months PFS is defined as the time from the date of start of treatment to the date of the first documented progression according to RECIST v1.1 guidelines or death due to any cause.
Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-EVS459 Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes and 30 minutes, 1, 2, 4, 6 and 12 hours), Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. The \[177Lu\]Lu-EVS459 pharmacokinetic analysis will be performed based on decay-corrected blood radioactivity concentration data converted to mass units. Vz will be determined by non-compartmental methods.
Time-activity curves (TACs) related to [177Lu]Lu-EVS459 uptake in organs and tumor lesions Cycle 1 Day 1, Cycle 1 Day 2 (24 hours), Cycle 1 Day 3 (48 hours), Cycle 1 Day 4 (72 hours), Cycle 1 Day 8 (168 hours). The duration of a cycle is 6 weeks. Time-activity curves (TACs) for the various organs and tumor lesions will be produced as fraction of injected activity per gram of tissue (%IA/g) as a function of time.
Incidence and severity of adverse events and serious adverse events of [68Ga]Ga-EVS459 From Imaging visit until 14 days after 68Ga-EVS459 administration or until first dose of study treatment, assessed up to approximately 14 days The distribution of adverse events will be done via the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) and through the monitoring of relevant clinical and laboratory safety parameters.
Trial Locations
- Locations (1)
Novartis Investigative Site
🇮🇱Tel Aviv, Israel