A Phase I Study of [177Lu]Lu-FF58 in Patients With Advanced Solid Tumors.

Study Overview
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Brief Summary
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The purpose of the study is to test the safety and dosing of [177Lu]Lu-FF58, a radioligand therapy for patients with advanced or metastatic tumors that express proteins known as integrins: alpha-v beta-3 integrin (αvβ3) and alpha-v beta-5 integrin (αvβ5). The study will also further characterize the radioligand imaging agent [68Ga]Ga-FF58 including its ability to identify tumor lesions and its safety profile.

Detailed Description
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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 be screened with a [68Ga]Ga-FF58 positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI) scan to assess eligibility for treatment with [177Lu]Lu-FF58. In the escalation part, different doses of [177Lu]Lu-FF58 will be tested to identify the recommended dose. The expansion part of the study will examine the safety and preliminary efficacy of [177Lu]Lu-FF58 at the recommended dose 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, or the study is terminated early in which case all patients would also be followed up for safety.

Official Title
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A Phase I, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Dosimetry and Preliminary Activity of [177Lu]Lu-FF58 in Patients With Selected Advanced Solid Tumors.

Conditions
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Pancreatic Ductal Adenocarcinoma, Gastroesophageal Adenocarcinoma, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: 68Ga-FF58
* Drug: 177Lu-FF58


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria Age >= 18 years old Patients with locally advanced unresectable or metastatic PDAC, locally advanced unresectable or metastatic GEA, or recurrent GBM To be treated with [177Lu]Lu-FF58, patients must have at least one measurable lesion that shows [68Ga]Ga-FF58 uptake on PET/CT or PET/MRI Key Exclusion criteria Absolute neutrophil count (ANC) < 1.5 x 109/L, hemoglobin < 10 g/dL, or platelet count < 100 x 109/L Prior external beam radiation therapy (EBRT) to > 25% of the bone marrow Creatinine clearance < 60 mL/min Unmanageable bladder outflow obstruction or urinary incontinence Non-GBM patients: Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids within 1 week before [177Lu]Lu-FF58 administration Other protocol-defined inclusion/exclusion criteria may apply

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Patients will receive 68Ga-FF58 and only patients with tumor uptake of 68Ga-FF58 will receive 177Lu-FF58. | Drug: 68Ga-FF58<br>* Kit for radiopharmaceutical preparation of 68Ga- FF58 solution for injection<br>Drug: 177Lu-FF58<br>* Solution for injection/infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of dose limiting toxicities of 177Lu-FF58 | A dose limiting toxicity (DLT) is defined as any AE or abnormal laboratory value of CTCAE (v5.0) Grade 3 or higher that occurs within the DLT evaluation period (i.e., 6 weeks starting from the first administration of 177Lu-FF58) and that is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications. | From start of study treatment until 6 weeks after | 
| Incidence and severity of adverse events and serious adverse events of 177Lu-FF58 | The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs) due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. | From start of study treatment until 180 days after the last dose of study treatment, assessed up to approximately 15 months | 
| Dose modifications for 177Lu-FF58 | Dose modifications (dose interruptions and reductions) for 177Lu-FF58 will be assessed and summarized using descriptive statistics. The number of patients with dose modification and the reasons will be summarized by treatment groups. | From start of study treatment until last dose of study treatment, assessed up to approximately 36 weeks | 
| Dose intensity for 177Lu-FF58 | Dose intensity for 177Lu-FF58 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 36 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) as per local review and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines (non-GBM patients) or modified Response Assessment in Neuro- Oncology (mRANO) (GBM patients). It will be summarized along with the corresponding 90% exact CI using FAS. | From start of study treatment until date of progression, assessed up to approximately 34 months | 
| Duration of Response (DOR) | DOR is the time between the first documented response (CR or PR) and the date of progression as per local review and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines (non-GBM patients) or modified Response Assessment in Neuro- Oncology (mRANO) (GBM patients), or death due to any cause. Here, death due to any cause is considered as an event to be conservative and align with PFS event definition. DOR may be presented graphically if enough events are available for analysis, using Kaplan Meier plots for all patients who achieved a CR/PR in the study. The median DOR and corresponding 90% CI will be presented. Analysis will include responders with confirmed responses. | From start of study treatment until date of progression, assessed up to approximately 34 months | 
| Disease control rate (DCR) | DCR is defined as the proportion of patients with a BOR of CR, PR, or stable disease as per local review and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines (non-GBM patients) or modified Response Assessment in Neuro- Oncology (mRANO) (GBM patients). It will be summarized along with the corresponding 90% exact CI, using FAS. | From start of study treatment until date of progression, assessed up to approximately 34 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 as per local review and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines (non-GBM patients) or modified Response Assessment in Neuro- Oncology (mRANO) (GBM patients), or death due to any cause. | From start of study treatment until date of progression, assessed up to approximately 34 months | 
| Area Under the Curve (AUC) from 177Lu-FF58 blood radioactivity data | Venous whole blood samples will be collected and analysed for radioactivity. Radioactivity-based concentration units will be converted to mass-based concentration units using the specific activity of the dose at the time of manufacture (MBq/µg). Pharmacokinetics characterization will be performed on mass-based concentrations. AUC from time zero to specified time point (mass x time x volume-1) will be listed and summarized using descriptive statistics. | Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes(min), 30 min, 1 hours(hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). Cycle=6 weeks or 3 weeks depending on schedule. | 
| Total body clearance from 177Lu-FF58 blood radioactivity data | Venous whole blood samples will be collected and analysed for radioactivity. Radioactivity based concentration units will be converted to mass-based concentration units using the specific activity of the dose at the time of manufacture (MBq/µg). Pharmacokinetics characterization will be performed on mass-based concentrations. The total body clearance of drug from the plasma (volume x time-1) will be listed and summarized using descriptive statistics. | Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes(min), 30 min, 1 hours(hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). Cycle=6 weeks or 3 weeks depending on schedule. | 
| Observed maximum plasma concentration (Cmax) from 177Lu-FF58 blood radioactivity data | Venous whole blood samples will be collected and analysed for radioactivity. Radioactivity based concentration units will be converted to mass-based concentration units using the specific activity of the dose at the time of manufacture (MBq/µg). Pharmacokinetics characterization will be performed on mass-based concentrations. Cmax will be listed and summarized using descriptive statistics. | Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes(min), 30 min, 1 hours(hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). Cycle=6 weeks or 3 weeks depending on schedule. | 
| Volume of distribution during the terminal phase following intravenous elimination (Vz) from 177Lu-FF58 blood radioactivity data | Venous whole blood samples will be collected and analysed for radioactivity. Radioactivity based concentration units will be converted to mass-based concentration units using the specific activity of the dose at the time of manufacture (MBq/µg). Pharmacokinetics characterization will be performed on mass-based concentrations. Vz will be listed and summarized using descriptive statistics. | Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes(min), 30 min, 1 hours(hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). Cycle=6 weeks or 3 weeks depending on schedule. | 
| Terminal elimination half-life (T^1/2) from 177Lu-FF58 blood radioactivity data | Venous whole blood samples will be collected and analysed for radioactivity. Radioactivity based concentration units will be converted to mass-based concentration units using the specific activity of the dose at the time of manufacture (MBq/µg). Pharmacokinetics characterization will be performed on mass-based concentrations. The half-life will be listed and summarized using descriptive statistics. | Cycle 1 Day 1 (Pre-infusion, end of infusion, Post-dose (10 minutes(min), 30 min, 1 hours(hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). Cycle=6 weeks or 3 weeks depending on schedule. | 
| Urinary excretion of radioactivity expressed as a percentage of injected activity (%IA) | Urine samples will be collected over specified time intervals and analysed for radioactivity. The radioactivity excreted in each interval as a percentage of injected activity (%IA) will be listed and 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(hr) post-end-of infusion(EOI),6-24hr post-EOI,24-48hr post-EOI,48-72hr post-EOI. Cycle= 6 weeks or 3 weeks depending on schedule. | 
| Time-activity curves (TACs) related to 177Lu-FF58 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 (hr)), Cycle 1 Day 3 (48 hr), Cycle 1 Day 4 (72 hr), Cycle 1 Day 8 (168 hr). Cycle = 6 weeks or 3 weeks depending on schedule. | 
| Absorbed dose of 177Lu-FF58 | The absorbed dose in target organs will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert. | Cycle 1 Day 1, Cycle 1 Day 2 (24 hours (hr)), Cycle 1 Day 3 (48 hr), Cycle 1 Day 4 (72 hr), Cycle 1 Day 8 (168 hr). Cycle = 6 weeks or 3 weeks depending on schedule. | 
| Incidence and severity of adverse events and serious adverse events of 68Ga-FF58 | The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs) and Serious Adverse Event (TESAEs) due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. | From Imaging visit until 14 days after 68Ga-FF58 administration, or until first dose of study treatment | 
| Imaging properties: Visual and quantitative assessment (expressed as SUV) and tumor-to-background ratio (TBR) of 68Ga-FF58 uptake in organs and tumor lesions over time | After 68Ga-FF58 administration, 68Ga-FF58 PET/CT or PET/MRI will be performed. The statistical analyses of imaging properties of 68Ga-FF58 will be descriptive in nature and will include summaries and graphical presentations of data. No formal testing will be performed. | From Imaging until 1 hour (hr), 2 hr and 3 hr after 68Ga-FF58 administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GBM, pancreatic ductal adenocarcinoma, PDAC, pancreatic cancer, gastroesophageal adenocarcinoma, GEA, gastric cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, glioblastoma multiforme, advanced solid tumors, radioligand therapy, RLT, [177Lu]Lu-FF58, [68Ga]Ga-FF58, integrins, alpha-v beta-3 integrin, αvβ3, alpha-v beta-5 integrin, αvβ5