A Safety Study of [177Lu]Lu-DOTA-TATE in Newly Diagnosed Extensive Stage Small Cell Lung Cancer (ES-SCLC) Patients in Combination With Carboplatin, Etoposide and Tislelizumab

A Safety Study of [177Lu]Lu-DOTA-TATE in Newly Diagnosed Extensive Stage Small Cell Lung Cancer (ES-SCLC) Patients in Combination With Carboplatin, Etoposide and Tislelizumab

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

This study aims to establish a safe and well tolerated dose of [177Lu]Lu-DOTA-TATE in combination with carboplatin, etoposide, and tislelizumab in induction treatment and with tislelizumab in maintenance treatment in newly diagnosed patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC).

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. 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. Eligible participants will be enrolled in cohorts of 3 to 6 participants to receive: Four cycles of carboplatin area under the curve (AUC) 5 on Day 1 and etoposide 100 mg/m2 on Day 1-3, every 3 weeks at Weeks 1, 4, 7 and 10 in induction period Tislelizumab 200 mg on Day 1 every 3 weeks in induction and maintenance period Two administrations of [177Lu]Lu-DOTA-TATE during the induction period: on either Day 3, 4 or 5 of Week 1 and on Week 7 Day 3 period followed by 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. Up to six different dose level combinations of [177Lu]Lu-DOTA-TATE will be assessed in the study as follows: Dose Level 1 (DL1): 100 mCi of [177Lu]Lu-DOTA-TATE in the induction period and 100 mCi of [177Lu]Lu-DOTA-TATE in the maintenance period. Dose Level 2a (DL2a): 150 mCi of [177Lu]Lu-DOTA-TATE in both the induction and the maintenance periods. Dose Level 2b (DL2b): 150 mCi of [177Lu]Lu-DOTA-TATE in the induction period and 200 mCi of [177Lu]Lu-DOTA-TATE in the maintenance period. Dose Level 3a (DL3a): 200 mCi of [177Lu]Lu-DOTA-TATE in both the induction and maintenance periods. Dose Level 3b (DL3b): 200 mCi of [177Lu]Lu-DOTA-TATE in the induction period and 250 mCi of [177Lu]Lu-DOTA-TATE in the maintenance period. Dose Level 4 (DL4): 250 mCi of [177Lu]Lu-DOTA-TATE in both the induction and maintenance periods. An infusion of sterile 2.5% Lysine - Arginine amino acid (AA) solution will be co-administered with each [177Lu]Lu-DOTA-TATE dose for renal protection. The dose escalation part in this study will be guided by the dose limiting toxicity (DLT) rate observed within the first 6 weeks (42 days) of treatment. In addition to DLTs the totality of safety data available at the time will be assessed for each dose escalation decision. Dose escalation/de escalation will be conducted using the Bayesian Optimal Interval Approach (BOIN).

Extensive Stage Small Cell Lung Cancer, ES-SCLC, Radioligand therapy, RLT, [177Lu]Lu-DOTA-TATE, Lutathera, Lutetium (177Lu) oxodotreotide, Lutetium Lu 177 dotatate, tislelizumab, carboplatin, etoposide

Dose Level 1 (DL1): [177Lu]Lu-DOTA-TATE 100 mCi Q6W with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 Q3W, and tislelizumab 200 mg Q3W in induction period, then [177Lu]Lu-DOTA-TATE 100 mCi Q3W plus Tislelizumab 200 mg Q3W in the maintenance period.

Dose Level 2a (DL2a): [177Lu]Lu-DOTA-TATE 150 mCi Q6W with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 Q3W, and tislelizumab 200 mg Q3W in induction period, then [177Lu]Lu-DOTA-TATE 150 mCi Q3W plus Tislelizumab 200 mg Q3W in the maintenance period.

Dose Level 2b (DL2b): [177Lu]Lu-DOTA-TATE 150 mCi Q6W with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 Q3W, and tislelizumab 200 mg Q3W in induction period, then [177Lu]Lu-DOTA-TATE 200 mCi Q3W plus Tislelizumab 200 mg Q3W in the maintenance period.

Dose Level 3a (DL3a): [177Lu]Lu-DOTA-TATE 200 mCi Q6W with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 Q3W, and tislelizumab 200 mg Q3W in induction period, then [177Lu]Lu-DOTA-TATE 200 mCi Q3W plus Tislelizumab 200 mg Q3W in the maintenance period.

Dose Level 3b (DL3b): [177Lu]Lu-DOTA-TATE 200 mCi Q6W with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 Q3W, and tislelizumab 200 mg Q3W in induction period, then [177Lu]Lu-DOTA-TATE 250 mCi Q3W plus Tislelizumab 200 mg Q3W in the maintenance period.

Dose Level 4 (DL4): [177Lu]Lu-DOTA-TATE 250 mCi Q6W with carboplatin AUC 5 D1, etoposide 100 mg/m2 D1-3 Q3W, and tislelizumab 200 mg Q3W in induction period, then [177Lu]Lu-DOTA-TATE 250 mCi Q3W plus Tislelizumab 200 mg Q3W in the maintenance period.

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

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)

Four cycles of etoposide 100 mg/m2 on Day 1-3, every 3 weeks (Weeks 1, 4, 7 and 10) in induction period

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 6 weeks (42 days) of treatment. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for AE grading.

Incidence and severity of adverse events (AEs), serious AEs (SAEs) after [177Lu]Lu-DOTA-TATE administration

The distribution of adverse events after [177Lu]Lu-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.

From date of randomization till 30 days safety follow-up, assessed for up to 3 years (estimated final Overall Survival (OS) analysis)

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.

Objective response rate (ORR) is defined as the proportion of participants with confirmed best overall response (BOR) of 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 Full Analysis Set (FAS). ORR and its 95% confidence interval will be presented by dose level combination.

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) only applies to participants whose best overall response is complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of 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 for all participants in the Full Analysis Set (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)

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 Full Analysis Set (FAS) population according to the assigned dose level combination. 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.

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)

Overall Survival (OS) is defined as the time from date of first dose to date of death due to any cause. 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 Full Analysis Set (FAS) population according to the assigned dose cohort. 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.

From date of randomization until date of death from any cause, assessed up to 3 years (estimated final Overall Survival (OS) analysis)

Time activity curves (TACs), describing percentage (%) of the activity injected vs time in blood, organs and tumor lesions

Absorbed radiation doses of [177Lu]Lu-DOTA-TATE in organs and tumor lesions will be summarized with descriptive statistics.

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

Individual tislelizumab concentrations will be tabulated by dose cohort along with descriptive statistics.

Predose (within 60 minutes before starting tislelizumab infusion) samples are required to be collected on Day 1 of Week 1, 4, 13 and 25

Predose (within 60 minutes before starting tislelizumab infusion) samples are required to be collected on Day 1 of Week 1, 4, 13 and 25

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 SSTR positive [68Ga]Ga-DOTA-TATE imaging positron emission tomography (PET) scan demonstrating uptake in at least one target or non-target lesion No prior systemic treatment for ES-SCLC 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 leptomeningeal disease or uncontrolled, untreated brain metastasis 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