A Phase I Study of [177Lu]Lu-EVS459 in Patients With Ovarian and Lung Cancers

A Phase I, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Dosimetry, and Preliminary Activity of [177Lu]Lu-EVS459 in Patients With Ovarian and Lung Cancers

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).

Study Overview

• Status: Terminated
• Conditions: Ovarian Cancer; Lung Cancer
• Intervention / Treatment: Drug: [68Ga]Ga-EVS459; Drug: [177Lu]Lu-EVS459

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• Israel
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• 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 Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm1; Patients will receive [68Ga]Ga-EVS459 and, if eligible, [177Lu]Lu-EVS459	Drug: [68Ga]Ga-EVS459; Radioligand imaging agent; Drug: [177Lu]Lu-EVS459; Radioligand therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with dose limiting toxicities of [177Lu]Lu-EVS459	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.	From start of study treatment until 6 weeks after
Incidence and severity of adverse events and serious adverse events of [177Lu]Lu- EVS459	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.	From start of study treatment until completion of the 36 month follow up , assessed up to approximately 42 months
Dose modifications for [177Lu]Lu- EVS459	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.	From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks
Dose intensity for [177Lu]Lu- EVS459	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.	From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	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.	Up to approximately 42 months
Duration of Response (DOR)	DOR is the time between the first documented response (CR or PR) and the date of progression according to RECIST v1.1 guidelines.	Up to approximately 42 months
Disease control rate (DCR)	DCR is defined as the proportion of patients with a BOR of CR, PR, or stable disease according to RECIST v1.1 guidelines.	Up to approximately 42 months
Progression free survival (PFS)	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.	Up to approximately 42 months
Area Under the Curve (AUC) of [177Lu]Lu-EVS459	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.	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.
Total body clearance of [177Lu[Lu-EVS459	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.	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.
Observed maximum plasma concentration (Cmax) of [177Lu]Lu-EVS459	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.	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.
Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-EVS459	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.	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.
Terminal elimination half-life (T1/2) of [177Lu]Lu-EVS459	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.	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.
Urinary excretion of radioactivity expressed as a percentage of injected activity (%IA)	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).	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.
Renal clearance of [177Lu]Lu- EVS459	Urine samples will be collected over specified time intervals and analysed for radioactivity. Renal clearance of 177Lu-EVS459 will be summarized using descriptive statistics.	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.
Absorbed dose of [177Lu]Lu- EVS459	The absorbed dose in normal tissues and tumor lesions will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.	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) related to [177Lu]Lu-EVS459 uptake in organs and tumor lesions	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.	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.
Incidence and severity of adverse events and serious adverse events of [68Ga]Ga-EVS459	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.	From Imaging visit until 14 days after 68Ga-EVS459 administration or until first dose of study treatment, assessed up to approximately 14 days
Visual and quantitative assessment of [68Ga]Ga-EVS459 uptake in normal tissues and tumor lesions over time	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.	From 0 up to approximately 3 hours after [68Ga]Ga-EVS459 dosing

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2024
• Primary Completion (Actual): July 10, 2025
• Study Completion (Actual): July 10, 2025

Study Registration Dates

• First Submitted: April 2, 2024
• First Submitted That Met QC Criteria: April 16, 2024
• First Posted (Actual): April 19, 2024

Study Record Updates

• Last Update Posted (Actual): August 7, 2025
• Last Update Submitted That Met QC Criteria: August 4, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: ovarian cancer; advanced solid tumors; non-squamous non-small cell lung cancer (non sq. NSCLC); radioligand therapy (RLT); [177Lu]Lu-EVS459; [68Ga]Ga-EVS459; folate receptor (FR)
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Respiratory Tract Diseases; Genital Diseases, Female; Lung Diseases; Endocrine Gland Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Lung Neoplasms; Ovarian Neoplasms
• Other Study ID Numbers: CGIZ943A12101; 2023-507674-41-00 (Other Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No