AMG 757 and AMG 404 in Subjects With Small Cell Lung Cancer (SCLC)

Phase 1

Completed

Conditions: Small Cell Lung Cancer

Interventions: Drug: Tarlatamab
Drug: AMG 404

Registration Number: NCT04885998

Lead Sponsor: Amgen

Brief Summary: The main purpose of this study is to evaluate the safety, tolerability, and recommended phase 2 target dose of tarlatamab in combination with AMG 404.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures
Age greater than or equal to 18 years old at the same time of signing the informed consent
Participants with histologically or cytologically confirmed Small Cell Lung Cancer (SCLC) who progressed or recurred following at least 1 platinum-based regimen
Eastern Cooperative Oncology Group (ECOG) 0 to 1
Participants with treated brain metastases are eligible provided they meet defined criteria
Adequate organ function as defined in protocol

Exclusion Criteria

History of other malignancy within the past 2 years with exceptions
Major surgery within 28 days of first dose of tarlatamab
Untreated or symptomatic brain metastases and leptomeningeal disease
Prior anti-cancer therapy, including anti-PD1 or anti-PDL1 antibody therapy: at least 28 days must have elapsed between any prior anti-cancer therapy and the first planned dose of tarlatamab

Exceptions:

Participants who received prior chemotherapy must have completed at least 14 days before the first dose of tarlatamab and all treatment-related toxicity resolved to grade ≤ 1.
Participants who received prior palliative radiotherapy must have completed at least 7 days before the first dose of tarlatamab
- Participants who received prior tarlatamab therapy or prior delta-like ligand 3 (DLL3) x cluster of differentiation 3 (CD3) bispecific therapy are not eligible
- Participants who experienced recurrent grade 2 pneumonitis or severe or life-threatening immune-mediated adverse events or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents
- History of any immune-related colitis. Infectious colitis is allowed if evidence of adequate treatment and clinical recovery exists and at least 3 months interval observed since diagnosis of colitis
- Participants with evidence of interstitial lung disease or active, non-infectious pneumonitis
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of tarlatamab
- History of solid organ transplantation
- History of hypophysitis or pituitary dysfunction
- Active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy while on study. Participants with Type I diabetes, vitiligo, psoriasis, hypo- or hyper-thyroid disease not requiring immunosuppressive treatment are permitted

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2: Dose Expansion	AMG 404	Participants will receive the RP2D of tarlatamab in combination with AMG 404 identified in Phase 1 (dose exploration) of the study.
Phase 1: Dose Exploration	AMG 404	The recommended phase 2 target dose (RP2D) of tarlatamab in combination with AMG 404 will be estimated using a modified toxicity probability interval (mTPI-2) design. A combination RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an maximum tolerated dose (MTD).
Phase 2: Dose Expansion	Tarlatamab	Participants will receive the RP2D of tarlatamab in combination with AMG 404 identified in Phase 1 (dose exploration) of the study.
Phase 1: Dose Exploration	Tarlatamab	The recommended phase 2 target dose (RP2D) of tarlatamab in combination with AMG 404 will be estimated using a modified toxicity probability interval (mTPI-2) design. A combination RP2D may be identified based on emerging safety, efficacy, and pharmacodynamic data prior to reaching an maximum tolerated dose (MTD).

Primary Outcome Measures

Name	Time	Method
Part 1: Number of Participants Who Experienced Dose-limiting Toxicity (DLT)	First dose of tarlatamab up to 28 days	A DLT was any of the following during the DLT window, assessed by Common Terminology Criteria for Adverse Events v4.0: * Grade 3 adverse event (AE) except for fatigue lasting \< 7 days, Grade 3 nonfebrile neutropenia that improved to ≤ Grade 1 within 3 weeks, endocrinopathies if managed with replacement therapy, Grade 3 nausea/vomiting or diarrhea for \< 72 hours, Grade 3 amylase or lipase values not associated with pancreatitis, Grade 3 hematologic laboratory abnormalities not clinically relevant, or Grade 3 electrolyte abnormality up to 72 hours. * Grade 4 AE except for Grade 4 nonfebrile neutropenia lasting ≤ 7 days, Grade 4 electrolyte abnormality lasting up to 72 hours, Grade 4 amylase or lipase values not associated with pancreatitis, or Grade 4 hematologic laboratory abnormalities no clinically relevant. * Grade 5 AE * Recurrent Grade ≥ 2 pneumonitis * Any other toxicity requiring permanent discontinuation of AMG 404.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Any TEAEs: From first IP dose up to last dose + 65 days or EOS, median duration was 4.2 months; TEAEs for EP: From last dose + 65 days up to snapshot date (15 November 2024), death, or last dose + 145 days or EOS, median duration was 2.6 months	An AE was defined as any untoward medical occurrence in a clinical trial participant. A TEAE was an AE that started on or after the first dose of investigational product (IP; tarlatamab) up to 65 days after the last dose of tarlatamab or AMG 404 or the end of study (EOS), whichever was earlier. A TEAE for the EP was an AE that occurred after the 65th day after the last dose of tarlatamab or AMG 404 up to 145 days after the last dose of tarlatamab or AMG 404 or end of study, whichever was later. A treatment-related AE was any TEAE where there was a reasonable possibility that the TEAE could have been caused by tarlatamab or AMG 404. Any clinically significant changes in vital signs, physical examinations, electrocardiograms, and clinical laboratory tests were included as TEAEs.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	From first dose of IP up to a minimum of last dose date + 65 days or EOS; median (min, max) duration was 4.2 (0.4, 25.4) months	The objective response rate was defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) based on the modified RECIST v1.1. CR: complete disappearance of all lesions and pathologic lymph nodes reduced in short axis to \< 10 mm. PR: decrease in tumor burden of ≥ 30% relative to baseline, or complete disappearance of all index lesions with the presence of non-index lesions. Confirmation scans were required within 4 weeks of the first documented response of CR or PR. Exact 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method.
Duration of Response Per Modified RECIST v1.1	From first dose of IP up to a minimum of last dose date + 65 days or EOS; median (min, max) duration was 4.2 (0.4, 25.4) months	The duration of response was defined as the time from first evidence of CR or PR to progressive disease (PD) or death due to any cause, whichever occurred first, estimated via Kaplan-Meier methods. CR: complete disappearance of all lesions and pathologic lymph nodes reduced in short axis to \< 10 mm. PR: decrease in tumor burden of ≥ 30% relative to baseline, or complete disappearance of all index lesions with the presence of non-index lesions. Confirmation scans were required within 4 weeks of the first documented response of CR or PR. PD: radiologic detection of ≥ 20% increase in tumor burden relative to nadir and ≥ 5 mm absolute increase, or unequivocal progression of non-index lesions, or presence of new lesions. 95% CIs were calculated using the Brookmeyer and Crowley method.
Disease Control Rate Per Modified RECIST v1.1	From first dose of IP up to a minimum of last dose date + 65 days or EOS; median (min, max) duration was 4.2 (0.4, 25.4) months	The disease control rate was defined as the percentage of participants with a best overall response of a confirmed response (CR/PR) or stable disease (SD) while on the study as defined by modified RECIST v1.1. CR: complete disappearance of all lesions and pathologic lymph nodes reduced in short axis to \< 10 mm. PR: decrease in tumor burden of ≥ 30% relative to baseline, or complete disappearance of all index lesions with the presence of non-index lesions. Confirmation scans were required within 4 weeks of the first documented response of CR or PR SD: Index lesions not meeting the criteria for CR, PR, or PD or the persistence of one or more non-index lesions. Exact 95% CIs were calculated using the Clopper-Pearson method.
Progression-free Survival Per Modified RECIST v1.1	From first dose of IP up to a minimum of EOS or death; median (min, max) time was 9.4 (0.4, 25.5) months	Progression-free survival was defined as the interval from the earlier date of the first dose of IP to the earlier of PD per modified RECIST v1.1 or death due to any cause, estimated via Kaplan-Meier methods. PD: radiologic detection of ≥ 20% increase in tumor burden to nadir and ≥ 5 mm absolute increase, or unequivocal progression of non-index lesions, or the presence of new lesions. Confirmation scans were required within 4 weeks of the first documented response of CR or PR, and 4-6 weeks for PD. 95% CIs were calculated using the Brookmeyer and Crowley method.
Overall Survival	From first dose of IP up to a minimum of EOS or death; median (min, max) time was 9.4 (0.4, 25.5) months	Overall survival was defined as the interval from the earlier date of the first dose of IP to the event of death due to any cause, estimated via Kaplan-Meier methods. Participants who were still alive were censored at the date last known to be alive. If the date last known to be alive was after the data cutoff date, the participant was censored at the analysis trigger date. 95% CIs were calculated using the Brookmeyer and Crowley method.
Maximum Observed Concentration (Cmax) of Tarlatamab in Combination With AMG 404	Cycle 2 Day 1 (pre-dose up to 7 days post-dose); Cycle 2 Day 15 (pre-dose up to 14 days post-dose)	Cmax was obtained using noncompartmental analysis, which was performed for tarlatamab PK parameter estimation. PK analysis is presented per dose received as pre-specified.
Trough Concentration (Ctrough) of Tarlatamab in Combination With AMG 404	Cycle 2 Day 15 (pre-dose)	Ctrough was obtained at the end of a dosing interval or just before the administration of the next planned dose using noncompartmental analysis, which was performed for tarlatamab PK parameter estimation. PK analysis is presented per dose received as pre-specified.
Area Under the Concentration-time Curve From Time 0 to 336 Hours (AUC0-336) of Tarlatamab in Combination With AMG 404	Cycle 2 Day 1 (pre-dose up to 7 days post-dose); Cycle 2 Day 15 (pre-dose up to 14 days post-dose)	AUC0-336 was defined as the actual body exposure to the drug over time following administration of a dose, calculated from time zero to 336 hours post-dose using noncompartmental analysis, which was performed for tarlatamab PK parameter estimation. PK analysis is presented per dose received as pre-specified.

Trial Locations

Locations (17): Northwestern University, Robert H Lurie Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
University of Kentucky
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Lexington, Kentucky, United States
Wake Forest Baptist Comprehensive Cancer Research Center
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Winston-Salem, North Carolina, United States
University Hospitals Cleveland Medical Center
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Cleveland, Ohio, United States
Medical University of South Carolina
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Charleston, South Carolina, United States
Tennessee Oncology, PLLC
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Nashville, Tennessee, United States
Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
Medizinische Universitaet Innsbruck
🇦🇹
Innsbruck, Austria
Universitaetsklinikum Allgemeines Krankenhaus Wien
🇦🇹
Vienna, Austria
Universitair Ziekenhuis Antwerpen
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Edegem, Belgium
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Northwestern University, Robert H Lurie Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States