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
Overview
- Phase
- Phase 1
- Intervention
- [68Ga]Ga-EVS459
- Conditions
- Ovarian Cancer
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 4
- Locations
- 1
- Primary Endpoint
- Number of participants with dose limiting toxicities of [177Lu]Lu-EVS459
- Status
- Terminated
- Last Updated
- 8 months ago
Overview
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.
Investigators
Eligibility Criteria
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
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.
Arms & Interventions
Arm1
Patients will receive \[68Ga\]Ga-EVS459 and, if eligible, \[177Lu\]Lu-EVS459
Intervention: [68Ga]Ga-EVS459
Arm1
Patients will receive \[68Ga\]Ga-EVS459 and, if eligible, \[177Lu\]Lu-EVS459
Intervention: [177Lu]Lu-EVS459
Outcomes
Primary Outcomes
Number of participants with dose limiting toxicities of [177Lu]Lu-EVS459
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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 Outcomes
- 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.)
- Overall response rate (ORR)(Up to approximately 42 months)
- 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.)
- 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.)
- 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.)
- 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.)
- Duration of Response (DOR)(Up to approximately 42 months)
- Disease control rate (DCR)(Up to approximately 42 months)
- 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.)
- 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.)
- 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)
- Progression free survival (PFS)(Up to approximately 42 months)
- 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.)
- 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.)
- 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)