Novartis Investigative Site 45147 Essen (Nordrhein-Westfalen) GermanyRekrutierend» Google-MapsNovartis Investigative Site 50937 Koeln (Nordrhein-Westfalen) GermanyRekrutierend» Google-MapsGeorgetown University Lombardi Cancer Center 20007 2197 Washington United StatesRekrutierend» Google-Maps Ansprechpartner:
University of Kentucky 40536 Lexington United StatesRekrutierend» Google-Maps Ansprechpartner:
Phone: 859-218-5151» Ansprechpartner anzeigenUniversity Hospitals Of Cleveland 44106 Cleveland United StatesRekrutierend» Google-Maps Ansprechpartner: Shauna Marie Johnson E-Mail: shauna.johnson@uhhospitals.org» Ansprechpartner anzeigenNovartis Investigative Site 59000 Lille FranceRekrutierend» Google-MapsNovartis Investigative Site 13885 Marseille Cedex 05 FranceRekrutierend» Google-MapsNovartis Investigative Site 34298 Montpellier FranceRekrutierend» Google-MapsNovartis Investigative Site 94800 Villejuif FranceRekrutierend» Google-MapsNovartis Investigative Site 29010 Malaga SpainRekrutierend» Google-MapsNovartis Investigative Site 08035 Barcelona SpainRekrutierend» Google-MapsNovartis Investigative Site 28009 Madrid SpainRekrutierend» Google-MapsNovartis Investigative Site 28041 Madrid SpainRekrutierend» Google-Maps
1. Phase 1b: Frequency of dose limiting toxicities (DLTs), Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to treatment discontinuation (Time Frame - Within the first six weeks of [177Lu]Lu-DOTA-TATE treatment]): A dose-limiting toxicity (DLT) is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications with an onset within the first cycle of initiation of [177Lu]Lu-DOTA-TATE treatment. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for AE grading.
2. Phase ll: Overall survival (OS) (Time Frame - In the phase II part: From date of randomization until date of death from any cause, assessed up to 3 years (estimated final Overall Survival (OS) analysis)): OS is defined as time from date of randomization to death due to any cause.
Secondary outcome:
1. Phase lb: Objective Response Rate (ORR) based on Investigator assessment (Time Frame - From date of randomization until date of progression or date of death from any cause, whichever come first, assessed for up to 3 years (estimated final Overall Survival (OS) analysis)): Objective response rate (ORR) is defined as the percentage of participants with confirmed best overall confirmed complete response (CR) or partial response (PR), as per local review and according to RECIST 1.1 by Investigator assessment.
ORR will be calculated based on the FAS. ORR and its 95% confidence interval will be presented by dose level combination and checkpoint inhibitor in Phase Ib and by treatment group in Phase II part.
2. Phase lb: Duration of Response (DOR) (Time Frame - From date of randomization until date of progression or date of death from any cause, whichever come first, assessed for up to 3 years (estimated final Overall Survival (OS) analysis)): Duration of Response (DOR), calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to underlying cancer. Participants continuing without progression or death due to underlying cancer will be censored at the date of their last adequate tumor assessment. DOR will be listed and summarized by dose level combination and checkpoint inhibitor in Phase Ib and by treatment group in Phase II part for all participants in the FAS with confirmed BOR of CR or PR.
3. Phase lb: Progression Free Survival (PFS) based on Investigator assessment (Time Frame - From date of randomization until date of progression or date of death from any cause, whichever come first, assessed for up to 3 years (estimated final OS analysis)): Progression Free Survival (PFS) is defined as the time from the date of first dose to the date of the first documented progression or death due to any cause. PFS will be assessed via local review according to RECIST 1.1. If no PFS event is observed, PFS will be censored at the date of the late adequate tumor assessment prior to data cut-off date and start of new anti-neoplastic therapy, whichever comes first.
PFS will be analyzed in the FAS population according to the assigned dose level combination and checkpoint inhibitor in Phase Ib and by treatment group in Phase II part. The PFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be presented for each dose level combination and checkpoint inhibitor in Phase Ib and by treatment group in Phase II part.
4. Phase lb: Overall Survival (OS) (Time Frame - From date of randomization until date of death from any cause, assessed up to 3 years (estimated final Overall Survival (OS) analysis)): OS is defined as the time from date of first dose to date of death due to any cause in Phase Ib. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive (on or before the cut-off date).
OS will be analyzed in the FAS population according to the assigned dose cohort and checkpoint inhibitor in Phase Ib. The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of the medians will be presented for each dose level combination and checkpoint inhibitor in Phase Ib Kaplan-Meier estimates with 95% confidence intervals every 6 months will be summarized as well by dose level combination, checkpoint inhibitor in Phase Ib and treatment group in Phase II part.
5. Phase lb: Time activity curves (TACs) (Time Frame - Week 7 Day 3): Time activity curves (TACs), describes percentage (%) of the activity injected vs time in blood, organs and tumor lesions.
6. Phase lb: Absorbed radiation doses of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3): Absorbed radiation doses of [177Lu]Lu-DOTA-TATE in organs and tumor lesions will be summarized with descriptive statistics.
7. Phase lb: Concentration of [177Lu]Lu-DOTA-TATE in blood over time (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): Blood samples for radioactivity measurement will be collected in all participants who undergo dosimetry assessments (i.e. first 3 participants at dose levels 1, 2a or 2b, 3a or 3b, and 4). For the rest of participants , blood samples will be taken before the start of [177Lu]Lu-DOTA-TATE infusion, at the end of infusion, and then at 2h, 6h after the end of [177Lu]Lu-DOTA-TATE infusion. Blood samples will be drawn in heparinized tubes. Radioactivity measurements on blood will be performed locally on site, using a gamma-counter.
8. Phase lb: Quantification of [177Lu]Lu-DOTA-TATE excreted from the body in urine (Time Frame - Week 7 Day 3 with urine collection from the start of [177Lu]Lu-DOTA-TATE infusion until the first whole body planar imaging (1-3 hours after [177Lu]Lu-DOTA-TATE infusion)): All excreted urine from the start of [177Lu]Lu-DOTA-TATE infusion until the first whole body planar imaging will be collected, its volume measured and the radioactivity concentration (kBq/mL) determined in order to calculate the total radioactivity excreted from the body from the start of [177Lu]Lu-DOTA-TATE infusion to the time of the first scan. If no urine is excreted from the start of [177Lu]Lu-DOTA-TATE infusion until the first whole body planar imaging, no urine dosimetry is necessary.
9. Phase ll: Progression free survival (PFS) by investigator assessment (Time Frame - From date of randomization until date of progression or date of death from any cause, whichever come first, assessed for up to 3 years (estimated final OS analysis)): Progression Free Survival (PFS) is defined as the time from the date of first dose to the date of the first documented progression or death due to any cause. PFS will be assessed via local review according to RECIST 1.1. If no PFS event is observed, PFS will be censored at the date of the late adequate tumor assessment prior to data cut-off date and start of new anti-neoplastic therapy, whichever comes first.
10. Phase ll: Objective Response Rate (ORR) by investigator assessment (Time Frame - From date of randomization until date of progression or date of death from any cause, whichever come first, assessed for up to 3 years (estimated final Overall Survival (OS) analysis)): Objective response rate (ORR) is defined as the percentage of participants with confirmed best overall confirmed complete response (CR) or partial response (PR), as per local review and according to RECIST 1.1 by Investigator assessment.
11. Phase ll: Duration of Response (DOR) by investigator assessment (Time Frame - From date of randomization until date of progression or date of death from any cause, whichever come first, assessed for up to 3 years (estimated final Overall Survival (OS) analysis)): Duration of Response (DOR), calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to underlying cancer. Participants continuing without progression or death due to underlying cancer will be censored at the date of their last adequate tumor assessment. DOR will be listed and summarized by dose level combination and checkpoint inhibitor in Phase Ib and by treatment group in Phase II part for all participants in the FAS with confirmed BOR of CR or PR.
12. Observed maximum plasma concentration (Cmax) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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.
13. Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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. Tmax will be listed and summarized using descriptive statistics.
14. Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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. AUClast will be listed and summarized using descriptive statistics.
15. Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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. AUCinf will be listed and summarized using descriptive statistics.
16. Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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. CL will be listed and summarized using descriptive statistics.
17. Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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.
18. Terminal elimination half-life (T^1/2) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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.
19. Terminal-Phase Disposition Rate Constant (λz) of [177Lu]Lu-DOTA-TATE (Time Frame - Week 7 Day 3 (pre-dose, before the end of infusion, 2 hours post-dose, 6 hours post-dose), Week 7 Day 4 (24 hours post-dose), Week 7 Day 5 (48 hours post-dose), Week 8 Day 3 (168 hours post-dose)): 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. Terminal-Phase Disposition Rate Constant will be listed and summarized using descriptive statistics.
20. Preliminary anti-tumor activity of [177Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide and atezolizumab in newly diagnosed participants with ES-SCLC (Time Frame - From date of randomisation until date of progression or date of death from any cause, whichever comes first, assessed for up to 3 years (estimated final OS analysis)): Objective response rate defined as the proportion of participants with a best overall confirmed complete response (CR) or partial response (PR) as assessed per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) by Investigator assessment
21. Incidence and severity of Adverse Events (AEs) and serious Adverse Events (SAEs) within 48 hours after [68Ga]Ga-DOTA-TATE administration (Time Frame - up to 48 hours following the start of [68Ga]Ga-DOTA-TATE administration]): The distribution of adverse events after [68Ga]Ga-DOTA-TATE administration 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.
Experimental: Dose Level 1 (DL1) Dose Level 1 (DL1): [177Lu]Lu-DOTA-TATE 100 mCi with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3, and atezolizumab 1200 mg in induction period, then [177Lu]Lu-DOTA-TATE 100 mCi plus atezolizumab 1200 mg in the maintenance period.
Experimental: Dose Level 2a (DL2a) Dose Level 2a (DL2a): [177Lu]Lu-DOTA-TATE 150 mCi with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 and atezolizumab 1200 mg in induction period, then [177Lu]Lu-DOTA-TATE 150 mCi plus atezolizumab 1200 mg in the maintenance period.
Experimental: Dose Level 2b (DL2b) Dose Level 2b (DL2b): [177Lu]Lu-DOTA-TATE 150 mCi with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 and atezolizumad 1200 mg in induction period, then [177Lu]Lu-DOTA-TATE 200 mCi plus atezolizumab 1200 in the maintenance period.
Experimental: Dose Level 3a (DL3a) Dose Level 3a (DL3a): [177Lu]Lu-DOTA-TATE 200 mCi with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3, and atezolizumab 1200 mg in induction period, then [177Lu]Lu-DOTA-TATE 200 mCi plus atezolizumab 1200 mg in the maintenance period.
Experimental: Dose Level 3b (DL3b) Dose Level 3b (DL3b): [177Lu]Lu-DOTA-TATE 200 mCi with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3, and atezolizumab 1200 mg in induction period, then [177Lu]Lu-DOTA-TATE 250 mCi plus atezolizumab 1200 mg in the maintenance period.
Experimental: Dose Level 4 (DL4) Dose Level 4 (DL4): [177Lu]Lu-DOTA-TATE 250 mCi with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 and atezolizumab 1200 mg in induction period, then [177Lu]Lu-DOTA-TATE 250 mCi plus atezolizumab 1200 mg in the maintenance period.
Experimental: Phase II Experimental arm [177Lu]Lu-DOTA-TATE at recommended dose declared in phase I part in combination with carboplatin, etoposide and atezolizumab (experimental arm)
Other: Phase II Control arm Carboplatin, etoposide and atezolizumab alone (control arm)
[177Lu]Lu-DOTA-TATE (Lutathera / Lutetium (177Lu) oxodotreotide / Lutetium Lu 177 dotatate / ): Solution for infusion of [177Lu]Lu-DOTA-TATE will be administered as follows:
2 administrations during the induction period on either Day 3, 4 or 5 of Week 1 and on Week 7 Day 3
1 to 4 administrations during the maintenance period on Week 13 Day 1, Week 16 Day 1, Week 19 Day 1 and Week 22 Day 1, depending on the dose assessed
Atezolizumab: Atezolizumab 1200 mg on Day 1 from Cycle 2 every 3 weeks in induction and maintenance period
[68Ga]Ga-DOTA-TATE: 2 MBq/kg of body weight (0.054 mCi/kg), with a minimum dose of 100 MBq (2.7 mCi) and maximum dose of 200 MBq (5.4 mCi)
Carboplatin: Four cycles of carboplatin AUC 5 on Day 1 every 3 weeks (Weeks 1, 4, 7 and 10) in induction period
Etoposide: Four cycles of etoposide 100 mg/m2 on Day 1-3, every 3 weeks (Weeks 1, 4, 7 and 10) in induction period
Quelle: ClinicalTrials.gov
Sie können folgenden Inhalt einem Kollegen empfehlen:
"A Study of [177Lu]Lu-DOTA-TATE in Newly Diagnosed ES-SCLC Patients in Combination With Carboplatin, Etoposide and Atezolizumab"
Bitte tragen Sie auch die Absenderdaten vollständig ein, damit Sie der Empfänger erkennen kann.
Die mit (*) gekennzeichneten Angaben müssen eingetragen werden!
