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

Primary Purpose

Pancreatic Ductal Adenocarcinoma, Gastroesophageal Adenocarcinoma, Glioblastoma Multiforme

Status
Recruiting
Phase
Phase 1
Locations
Switzerland
Study Type
Interventional
Intervention
68Ga-FF58
177Lu-FF58
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pancreatic Ductal Adenocarcinoma focused on measuring pancreatic ductal adenocarcinoma, PDAC, pancreatic cancer, gastroesophageal adenocarcinoma, GEA, gastric cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, glioblastoma multiforme, GBM, 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative SiteRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm 1

Arm Description

Patients will receive 68Ga-FF58 and only patients with tumor uptake of 68Ga-FF58 will receive 177Lu-FF58.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
July 10, 2023
Last Updated
October 24, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT05977322
Brief Title
A Phase I Study of [177Lu]Lu-FF58 in Patients With Advanced Solid Tumors.
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 6, 2023 (Actual)
Primary Completion Date
July 14, 2026 (Anticipated)
Study Completion Date
July 15, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Ductal Adenocarcinoma, Gastroesophageal Adenocarcinoma, Glioblastoma Multiforme
Keywords
pancreatic ductal adenocarcinoma, PDAC, pancreatic cancer, gastroesophageal adenocarcinoma, GEA, gastric cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, glioblastoma multiforme, GBM, 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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
116 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1
Arm Type
Experimental
Arm Description
Patients will receive 68Ga-FF58 and only patients with tumor uptake of 68Ga-FF58 will receive 177Lu-FF58.
Intervention Type
Drug
Intervention Name(s)
68Ga-FF58
Intervention Description
Kit for radiopharmaceutical preparation of 68Ga- FF58 solution for injection
Intervention Type
Drug
Intervention Name(s)
177Lu-FF58
Intervention Description
Solution for injection/infusion
Primary Outcome Measure Information:
Title
Incidence and severity of dose limiting toxicities of 177Lu-FF58
Description
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.
Time Frame
From start of study treatment until 6 weeks after
Title
Incidence and severity of adverse events and serious adverse events of 177Lu-FF58
Description
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.
Time Frame
From start of study treatment until 180 days after the last dose of study treatment, assessed up to approximately 15 months
Title
Dose modifications for 177Lu-FF58
Description
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.
Time Frame
From start of study treatment until last dose of study treatment, assessed up to approximately 36 weeks
Title
Dose intensity for 177Lu-FF58
Description
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.
Time Frame
From start of study treatment until last dose of study treatment, assessed up to approximately 36 weeks
Secondary Outcome Measure Information:
Title
Overall response rate (ORR)
Description
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.
Time Frame
From start of study treatment until date of progression, assessed up to approximately 34 months
Title
Duration of Response (DOR)
Description
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.
Time Frame
From start of study treatment until date of progression, assessed up to approximately 34 months
Title
Disease control rate (DCR)
Description
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.
Time Frame
From start of study treatment until date of progression, assessed up to approximately 34 months
Title
Progression free survival (PFS)
Description
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.
Time Frame
From start of study treatment until date of progression, assessed up to approximately 34 months
Title
Area Under the Curve (AUC) from 177Lu-FF58 blood radioactivity data
Description
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.
Time Frame
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.
Title
Total body clearance from 177Lu-FF58 blood radioactivity data
Description
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.
Time Frame
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.
Title
Observed maximum plasma concentration (Cmax) from 177Lu-FF58 blood radioactivity data
Description
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.
Time Frame
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.
Title
Volume of distribution during the terminal phase following intravenous elimination (Vz) from 177Lu-FF58 blood radioactivity data
Description
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.
Time Frame
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.
Title
Terminal elimination half-life (T^1/2) from 177Lu-FF58 blood radioactivity data
Description
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.
Time Frame
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.
Title
Urinary excretion of radioactivity expressed as a percentage of injected activity (%IA)
Description
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.
Time Frame
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.
Title
Time-activity curves (TACs) related to 177Lu-FF58 uptake in organs and tumor lesions
Description
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.
Time Frame
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.
Title
Absorbed dose of 177Lu-FF58
Description
The absorbed dose in target organs will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.
Time Frame
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.
Title
Incidence and severity of adverse events and serious adverse events of 68Ga-FF58
Description
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.
Time Frame
From Imaging visit until 14 days after 68Ga-FF58 administration, or until first dose of study treatment
Title
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
Description
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.
Time Frame
From Imaging until 1 hour (hr), 2 hr and 3 hr after 68Ga-FF58 administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
1-888-669-6682
Email
novartis.email@novartis.com
First Name & Middle Initial & Last Name or Official Title & Degree
Novartis Pharmaceuticals
Phone
+41613241111
Email
novartis.email@novartis.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Geneve 14
ZIP/Postal Code
CH 1211
Country
Switzerland
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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