First in Human (FIH) study to characterize the safety, tolerability, pharmacokinetics (PK), distribution, radiation dosimetry, and anti-tumor activity of \[177Lu\]-NeoB in patients with advanced solid tumors known to overexpress GRPR and with \[68Ga\]-NeoB lesion uptake.
This study was designed to establish whether the ligand NeoB, a high affinity antagonist for GRPR, could be used in a theragnostic approach for selection and therapy of GRPRexpressing malignancies: radiolabeled with (1) Gallium 68 (68Ga) to identify lesions and with (2) Lutetium-177 (177Lu) for the treatment of these lesions.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
35
\[177Lu\]-NeoB: peptide receptor radionuclide therapy
\[68Ga\]-NeoB radioactive diagnostic agent
dose strength 49/51 mg, film-coated tablets for oral use
City of Hope
Duarte, California, United States
Stanford University
Stanford, California, United States
John Hopkins University
Baltimore, Maryland, United States
Phase I: Incidence of dose limiting toxicities (DLTs) of [177Lu]-NeoB
A dose-limiting toxicity (DLT) is defined as a clinically relevant adverse event or abnormal laboratory value not attributable to the disease or disease-related processes under investigation, considered possibly related to \[177Lu\]-NeoB that occurs within 42 days following the first administration of \[177Lu\]-NeoB (cycle 1) and meets any of the criteria listed in Table 6-4 (Criteria for defining dose-limiting toxicities).
Time frame: Within 42 days following the first administration of [177Lu]-NeoB
Phase I: Determination of Maximum Tolerated Dose (MTD)/ Recommended phase two dose (RP2D) of [177Lu]-NeoB
The maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of \[177Lu\]-NeoB will be identified: 1. MTD is defined as the lowest single dose at which 25% or more of the patients experienced a DLT during the first cycle (6 weeks). 2. RP2D is defined as the single dose level below the MTD. The number of cycles recommended for Phase II will be defined based on the cumulative dose toxicities reported during Phase I.
Time frame: Within 42 days following the first administration of [177Lu]-NeoB
Phase IIa (Cohorts A, B and C): Individual clinical responses assessed by Response Evaluation Criteria In Solid Tumors (RECIST v1.1)
To assess the anti-tumor activity of \[177Lu\]-NeoB at the RP2D across different solid tumors
Time frame: 25 months
Phase IIa (Cohort E): Absorbed radiation doses of [177Lu]-NeoB in organs and tumor lesions
Absorbed radiation doses in organs and tumor lesions will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.
Time frame: 6 weeks
Phase IIa (Cohort E): Concentration of [177Lu]-NeoB in blood over time and derived PK parameters
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Concentration of \[177Lu\]-NeoB will be listed and summarized using descriptive statistics.
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Oregon Health & Science University
Portland, Oregon, United States
Pittsburgh University
Pittsburgh, Pennsylvania, United States
MD Anderson Cancer Center
Houston, Texas, United States
Medical University of Innsbruck
Innsbruck, Austria
CHU de Grenoble
La Tronche, France
Erasmus MC
Rotterdam, Netherlands
Vall d'Hebron Institute of Oncology
Barcelona, Spain
...and 1 more locations
Time frame: 6 weeks
Phase I: identify maximum tolerated and/or recommended Phase II dose
Time frame: 18 months
Phase II: assess disease control rate 20 weeks after completion of treatment
Time frame: 18 months
Phase I: Tissue Activity Curves (ACs)
Tissue activity curves (ACs) will be generated from the amount of radioactivity in one given tissue at a given moment over the amount of radioactivity present in the blood at that given moment.
Time frame: 6 weeks
Phase I: Time Activity Curves (ACs)
Time Activity Curves (ACs) describe the percentage of the activity injected versus time.
Time frame: 6 weeks
Phase I: Absorbed radiation doses of [177Lu]-NeoB in critical organs
Absorbed radiation doses in critical organs (e.g. kidneys, bone marrow, pancreas) will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.
Time frame: 6 weeks
Phase I: Urinary excretion of [177Lu]-NeoB
Urine samples will be collected over specified time intervals and analyzed for radioactivity using a gamma counter. The radioactivity excreted in urine will be summarized using descriptive statistics.
Time frame: 6 weeks
Phase I: Half-life of [177Lu]-NeoB in blood
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics.
Time frame: 6 weeks
Phase I: Residence time of [177Lu]-NeoB in organs and tumor lesions
Residence time in organs and tumors lesions will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.
Time frame: 6 weeks
Phase I: Individual objective response and Duration of Response (DOR)
DOR is defined as the duration of time between the date of first documented response (CR or PR) in soft tissue according to PCWG3 modified RECIST 1.1, and the date of first documented progression or death due to any cause.
Time frame: 25 months
Phase IIa (Cohorts A, B and C): Absorbed radiation doses of [177Lu]-NeoB in organs and tumor lesions
Absorbed radiation doses in organs and tumor lesions will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.
Time frame: 6 weeks
Phase IIa (Cohorts A, B and C): Concentration of [177Lu]-NeoB in blood over time and derived PK parameters
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Concentration of \[177Lu\]-NeoB will be listed and summarized using descriptive statistics.
Time frame: 6 weeks
Phase IIa (Cohorts A, B and C): Changes from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient).
Time frame: 15 months
Phase IIa (Cohort E): Adverse Events for [177Lu]-NeoB when co-administered with the NEPi LCZ696 in Cycle 1
The distribution of adverse events for \[177Lu\]-NeoB when co-administered with the neprilysin inhibitor (NEPi) LCZ696 will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Time frame: 25 months
Phase IIa (Cohort E): Dose interruptions and modifications for [177Lu]-NeoB when co-administered with the NEPi LCZ696 in Cycle 1
Time frame: Within 42 days following the first administration of [177Lu]-NeoB (Cycle 1)
Phase I and Phase IIa: Adverse Events for [177Lu]-NeoB
The distribution of adverse events for \[177Lu\]-NeoB as monotherapy will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Time frame: 25 months
Phase I and Phase IIa: Adverse Events for [68Ga]-NeoB
The distribution of adverse events for \[68Ga\]-NeoB will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Time frame: 25 months
Phase I and Phase IIa: Dose interruptions and modifications
Time frame: 25 months
Determine Tissue Activity Curves (ACs) [177Lu-NeoB]
ratio of radioactivity in tissue vs blood
Time frame: 18 months
Determine Time Activity Curves
ratio of % activity injected vs time
Time frame: 18 months
Absorbed radiation dose
absorbed radiation dose to critical organs
Time frame: 18 months
Urinary excretion of [177Lu]-NeoB
measure amount of \[177Lu\]-NeoB excreted in Urine
Time frame: 18 months
Blood Half-life of [177Lu]-NeoB
Time frame: 18 months
Organ Residence time of [177Lu]-NeoB
Time frame: 18 months
Objective Response Rate
Time frame: 18 months
Duration of Response
Time frame: 18 months
Progression Free Survival
Time frame: 18 months
Adverse Events [177Lu-NeoB]
Time frame: 18 months
Dose modifications
Time frame: 18 months
Adverse Events [68Ga-NeoB]
Time frame: 18 months