Phase 2, Multicenter, Open label, Platform Study investigating Tarlatamab (AMG 757) in patients with Metastatic/Locally Advanced Small-Cell Lung Cancer (SCLC) and Other Poorly Differentiated Neuroendocrine Carcinomas (NECs), with biomarker analysis to characterize response/resistance (UNLOCK TARLATAMAB)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Jun 2025 → ongoing

Decision date (initial)

2025-04-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AMGEN

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To estimate the objective response rate (ORR) at 4 months

Secondary objectives 1

1. a. To evaluate efficacy of tarlatamab, based on investigator assessment, in terms of: - Objective response rate at different timepoints (ORR) - Duration of response (DOR) - Clinical benefit rate (CBR) - Progression-free survival (PFS) b. To evaluate the safety and tolerability of tarlatamab, in terms of: - Frequency and severity of all adverse events (AEs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)

Conditions and MedDRA coding

Metastaic small cell lung cancer (SCLC) and other poorly differentitated neuroendocrine carcinomas (NECs)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Age ≥18 years
2. Patients with histologically confirmed diagnosis of metastatic/locally advanced SCLC with any level of DLL3 expression (Cohort 1) or other poorly differentiated NECs whatever the primary or high-grade MTC (Cohort 2) based on the most recent biopsy of a metastatic site. Tumors from Cohort 2 must be DLL3 positive defined as DLL3 ≥1% or H-score ≥1 by IHC
3. For patients with poorly differentiated NECs whatever the primary, the biopsy of the disease diagnosis should be reviewed by an expert pathologist. Large cell, small cell or not otherwise specified are eligible. In addition, the tumor must have a Ki67 >20% or mitotic rate >20 per 10 high-power fields. For prostate cancer, the diagnosis of NEPC must be based on phenotype analysis, which may include IHC markers such as neuron-specific enolase (NSE), Chromogranin A or CD56 in the majority of the tumor sample, or molecular alterations such as TP53, Rb1, and PTEN
4. High-grade MTC should be defined according to international medullary cancer grading system (IMCGS)
5. Patients with metastatic/locally advanced SCLC and other poorly differentiated NECs must have been treated with at least 1 line of prior therapy, including a platinum-based regimen (resistant or sensitive to platinum), have experienced progression on standard treatment, as determined by the investigator. Prior treatment with PD-(L) 1 inhibitors is allowed
6. Patients with NEPC and without a history of bilateral orchiectomy are required to remain on luteinizing hormone-releasing hormone (LHRH) analogue therapy during the course of protocol therapy
7. Patients must have an ECOG performance status ≤2 at the time of screening
8. Patients must have a minimum life expectancy of 3 months
9. Patients must have at least one radiologically measurable lesion according to response evaluation criteria in solid tumors (RECIST) v1.1 criteria
10. Patients must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patient must have accepted to perform pre-treatment, on-treatment, and end-of-treatment tumor and blood biopsies
11. Patients must have adequate bone marrow reserve and organ function, based on local laboratory data within 21 days prior to cycle 1, day 1
12. Patients must have baseline oxygen saturation > 90% on room air
13. Females of reproductive/childbearing potential must have a negative serum pregnancy test at screening and must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 60 days for females after the last dose of study drug
14. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 60 days after the final study drug administration
15. Male patients must be surgically sterile or must withhold heterosexual intercourse or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 60 days following the last dose of study drug
16. Male patients must not freeze or donate sperm starting at screening and throughout the study period, and at least 60 days after the final study drug administration
17. Patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed. Patients should be able and willing to comply with study visits and procedures as per protocol
18. Patients must be affiliated to a Social Security System or beneficiary of the same

Exclusion criteria 26

1. Patients unwilling to participate to the biological investigations and to perform blood and tissue sample collection as required in the protocol
2. Patients with SCLC or other poorly differentiated NECs whatever the primary or high-grade MTC amenable for treatment with curative intent
3. Patients with well differentiated neuroendocrine tumors, whatever the grade, pheocromocytoma, paraganglyoma, or low grade MTC
4. Patients with evidence of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis) or is suspected to have such disease by imaging during screening
5. Patients who experienced recurrent pneumonitis (grade 2 or higher) or severe, life-threatening immune-mediated AEs or infusion-related reactions including those that lead to permanent discontinuation while on treatment with immuno-oncology agents
6. Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients of tarlatamab
7. Inadequate washout period prior to cycle 1 day 1, defined as: a. Whole brain radiation therapy or stereotactic brain radiation therapy <14 days Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <7 days c. Any investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study <30 days or < 5 half-lives, whichever is longer, prior to first dose of tarlatamab. Conventional chemotherapy eligible if at least 14 days or < 5 half-lives, whichever is longer, have elapsed and if all treatment-related toxicity has been resolved to grade ≤1 d. Major surgery (excluding placement of vascular access) < 21 days e. Live virus and live-attenuated vaccination <28 days f. Systemic steroid therapy or other immunosuppressive therapy < 7 days
8. Prior treatment with tarlatamab or any selective inhibitor of the DLL3 pathway
9. Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patients must have a stable neurologic status for at least 2 weeks prior to cycle 1 day
10. Patients with evidence of any leptomeningeal disease
11. Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade 1 or baseline according to the NCI-CTCAE v5.0
12. Any evidence of primary malignancy other than metastatic/locally advanced SCLC, poorly differentiated NEC or high-grade MTC within 3 years prior to cycle 1 day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated
13. Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required
14. Patients with symptoms and/or clinical signs and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection within 7 days prior to the first dose of study treatment.
15. Patients with clinically significant pleural effusion will be excluded. Pleural effusion managed with indwelling pleural catheter (eg, PleurX) are allowed
16. Uncontrolled or significant cardiovascular disease prior to cycle 1 day 1,including: a. Corrected QT interval >470 ms for females and >450 ms for males according to Fridericia's formula (QTcF) and assessed based on triplicate ECGs, approximately 1 minute apart b. LVEF <50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan c. Myocardial infarction within 6 months d. NYHA > class II within 6 months e. Clinically significant pericardial effusion as determined by an ECHO or MUGA scan
17. Patient with history of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab
18. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of cycle 1, day 1.
19. Patients with history or evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patient is eligible if no acute symptoms of coronavirus disease 2019 (COVID-19) within 14 days prior to first dose of tarlatamab (counted from day of positive test for asymptomatic subjects)
20. Patient with active or prior documented autoimmune or inflammatory disorders, including but not limited to inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangitis), rheumatoid arthritis, hypophysitis, uveitis within the past 3 years prior to the start of treatment.
21. Patient with diagnosis of human immunodeficiency virus (HIV). Patients with HIV infection on antiviral therapy and undetectable viral load are allowded with a requirement for regular monitoring for reactivation for the duration of treatment on study per local or institutional guidelines
22. Female patients who are pregnant or breastfeeding or intend to become pregnant during the study
23. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
24. Patients under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent
25. Prior history of severe or life-threatening events from any immune-mediated therapy
26. Participation in another clinical trial (<30 days or < 5 half-lives, whichever is longer) evaluating an experimental drug (except non-interventional research)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response rate (ORR) at 4 months.

Secondary endpoints 2

1. Objective response rate (ORR) at different timepoints - Duration of response (DOR) - Clinical benefit rate (CBR) - Progression-free survival (PFS)
2. Frequency and severity of any AEs, TEAEs, SAEsgraded by NCI-CTCAE v5.0; frequency and severity of CRS and ICANS graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria (Lee et al, 2019); proportion of treatment discontinuations, interruptions, and dose reductions due to any AEs; frequency and severity of laboratory abnormalities defined by NCI-CTCAE v5.0;The use of immune modulating concomitant medication will be also summarized

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC-Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC-Regulatory Affairs Officer

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications