A Study of [177Lu]Lu-DOTA-TATE in Newly Diagnosed ES-SCLC Patients in Combination With Carboplatin, Etoposide and Atezolizumab

Extensive Stage Small Cell Lung Cancer Clinical Trial

Official title:

A Phase Ib/II Dose Finding Study Assessing Safety and Efficacy of [177Lu]Lu-DOTA-TATE in Newly Diagnosed Extensive Stage Small Cell Lung Cancer (ES-SCLC) in Combination With Carboplatin, Etoposide, and Atezolizumab in Induction and With Atezolizumab in Maintenance Phase

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05142696
• Other study ID #: CAAA601A42101
• Secondary ID: 2021-004155-16
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: July 13, 2022
• Est. completion date: May 3, 2028

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to establish a safe and well tolerated dose of [177Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide and atezolizumab in this setting and to assess preliminary efficacy of this combination treatment versus the combination of carboplatin, etoposide, and atezolizumab.The study will be essential to assess a new potential therapeutic option in participants with this aggressive cancer type.

Description:

The study for each participant consists of a Screening period, a Treatment period that includes an Induction treatment period and a Maintenance treatment period, and a Follow-up period.

The study will consist of a Phase Ib dose escalation with concurrent backfill part and a randomised controlled Phase II part.

During the screening period of up to 28 days before starting SCLC treatment, each participant will be assessed for somatostatin receptor (SSTR) expression by [68Ga]Ga-DOTA-TATE imaging PET/scan.

The dose escalation part in this study will be guided by the dose limiting toxicity (DLT) rate observed during the DLT period. To achieve a more robust dataset and to aid dose decisions, additional participants may be backfilled in each dose level.

Upon dedclaring RD, a 1:1 randomised Phase II with approximately 140 participants with newly diagnosed ES-SCLC will be enrolled and receive either [177Lu]Lu-DOTA-TATE at the RD in combination with carboplatin, etoposide and atezolizumab (experimental arm) or carboplatin, etoposide and atezolizumab alone (control arm).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: May 3, 2028
• Est. primary completion date: May 5, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Participant is >= 18 years on the day of signing informed consent form

• Histologically or cytologically confirmed ES-SCLC

• Presence of measurable disease (at least one target lesion) according to RECIST v1.1 assessed by conventional computed tomography (CT) scan

• No prior systemic treatment for ES-SCLC (except the first cycle of chemotherapy with or without atezolizumab of the induction period

• ECOG status =< 1

• Provision of tumor tissue to support exploratory biomarker analysis

• Life expectancy of >= 6 months

Key Exclusion Criteria:

• Participant has received prior therapy with an antibody or drug against immune checkpoint pathways

• Active autoimmune diseases or history of autoimmune diseases that may relapse

• Severe chronic or active infections (including active tuberculosis, HBV, or HCV infection) requiring systemic antibacterial, antifungal or antiviral therapy within 2 weeks before Cycle 1 Day 1

• Any major surgical procedure requiring general anesthesia =< 28 days before Cycle 1 Day 1

• History or current diagnosis of electrocardiogram (ECG) abnormalities indicating significant risk of safety for participants participating in the study

• Known hypersensitivity to the active substances or any of the excipients of the study drugs

• Concurrent participation in another therapeutic clinical study

Related Conditions & MeSH terms

• Extensive Stage Small Cell Lung Cancer
• Lung Neoplasms
• Small Cell Lung Carcinoma

Intervention

Drug:
• [177Lu]Lu-DOTA-TATE
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)

Other:
• 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

Locations

Country	Name	City	State
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Marseille Cedex 05
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Koeln
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
United Kingdom	Novartis Investigative Site	Guildford	Surrey
United States	University Hospitals Of Cleveland	Cleveland	Ohio
United States	University of Kentucky	Lexington	Kentucky
United States	Georgetown University Lombardi Cancer Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  France,  Germany,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1b: Frequency of dose limiting toxicities (DLTs), Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to treatment discontinuation	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.	Within the first six weeks of [177Lu]Lu-DOTA-TATE treatment]
Primary	Phase ll: Overall survival (OS)	OS is defined as time from date of randomization to death due to any cause.	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)
Secondary	Phase lb: Objective Response Rate (ORR) based on Investigator assessment	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.	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)
Secondary	Phase lb: Duration of Response (DOR)	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.	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)
Secondary	Phase lb: Progression Free Survival (PFS) based on Investigator assessment	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.	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)
Secondary	Phase lb: Overall Survival (OS)	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.	From date of randomization until date of death from any cause, assessed up to 3 years (estimated final Overall Survival (OS) analysis)
Secondary	Phase lb: Time activity curves (TACs)	Time activity curves (TACs), describes percentage (%) of the activity injected vs time in blood, organs and tumor lesions.	Week 7 Day 3
Secondary	Phase lb: Absorbed radiation doses of [177Lu]Lu-DOTA-TATE	Absorbed radiation doses of [177Lu]Lu-DOTA-TATE in organs and tumor lesions will be summarized with descriptive statistics.	Week 7 Day 3
Secondary	Phase lb: Concentration of [177Lu]Lu-DOTA-TATE in blood over time	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.	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)
Secondary	Phase lb: Quantification of [177Lu]Lu-DOTA-TATE excreted from the body in urine	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.	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)
Secondary	Phase ll: Progression free survival (PFS) by investigator assessment	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.	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)
Secondary	Phase ll: Objective Response Rate (ORR) by investigator assessment	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.	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)
Secondary	Phase ll: Duration of Response (DOR) by investigator assessment	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.	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)
Secondary	Observed maximum plasma concentration (Cmax) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Terminal elimination half-life (T^1/2) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Terminal-Phase Disposition Rate Constant (?z) of [177Lu]Lu-DOTA-TATE	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.	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)
Secondary	Preliminary anti-tumor activity of [177Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide and atezolizumab in newly diagnosed participants with ES-SCLC	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	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)
Secondary	Incidence and severity of Adverse Events (AEs) and serious Adverse Events (SAEs) within 48 hours after [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.	up to 48 hours following the start of [68Ga]Ga-DOTA-TATE administration]