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)

NCT07016230 | Recruiting Phase 2 DMC

• 2 other identifiers: 2024-515847-47-002024/4014
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

UNLOCK TARLATAMAB is an open-label, single arm, multicenter, phase 2 platform study that aims to evaluate the mechanisms of action and resistance to tarlatamab in metastatic/locally advanced Small-Cell Lung Cancer (SCLC) with any level of DLL3 expression and in other poorly differentiated Neuroendocrine Carcinomas (NECs) DLL3 positive. The two cohorts of patients are the following: i. cohort 1: patients with SCLC with any level of DLL3 expression. ii. cohort 2: patients with other poorly differentiated NECs whatever the primary or high grade medullary thyroid carcinoma (MTC, capped at 4 patients) DLL3 positive by immunohistochemistry (IHC). Patients enrolled in both cohorts will receive treatment with tarlatamab at the dose of 1 mg on D1, 10 mg on D8 and D15 and Q2W thereafter in a 28-day cycle. Tarlatamab will be administrated in intravenous route until disease progression, unacceptable toxicity, or consent withdrawal. Tumor and blood samples will be collected at baseline, on-treatment and at progression in order to identify biomarkers of drug response

Conditions

Metastatic/Locally Advanced Small-Cell Lung Cancer; Metastatic/Locally Advanced Poorly Differentiated NEC; Metastatic/Locally Advanced High-grade MTC

Keywords

Metastatic/Locally Advanced Poorly Differentiated Neuroendocrine Carcinomas; Metastatic/Locally Advanced Small-Cell Lung Cancer (SCLC); TARLATAMAB; metastatic/locally advanced high-grade medullary thyroid carcinoma

Outcome Measures

Primary Outcomes (1)

• To estimate the objective response rate (ORR)

  Within the 4 months of treatment initiation

Secondary Outcomes (13)

• Objective response rate at different timepoints (ORR)

  up to 18 months

• Duration of response (DOR)

  From cycle 3 (Week 6; each cycle is 28 days) up to 2 years after the EoT, an average of 26 months

• Clinical benefit rate (CBR)

  During treatment period, a median of 4 months

• Progression free survival (PFS)

  From the time date of the first dose until progression or death from any cause, whichever occurs first, assessed up to 18 months

• Frequency of all adverse events

  From enrollment until 24 months of EoT

Other Outcomes (4)

• mechanisms of action of tarlatamab

  from enrollment unti EoT, with a median of 4 months

• mechanisms of resistance of tarlatamab

  from enrollment unti EoT, with a median of 4 months

• Description of patient-reported outcomes (PROs)

  Treatment Period, median of 4 months

Study Arms (2)

Cohort 1

EXPERIMENTAL

patients with metastatic/locally advanced SCLC with any level of DLL3 expression

Drug: Tarlatamab

Cohort 2

EXPERIMENTAL

patients with metastatic/locally advanced other poorly differentiated NECs whatever the primary or high grade medullary thyroid carcinoma (MTC, capped at 4 patients) DLL3 positive by immunohistochemistry (IHC).

Drug: Tarlatamab

Interventions

Tarlatamab DRUG

Patients enrolled in both cohorts will receive treatment with tarlatamab at the dose of 1 mg on D1, 10 mg on D8 and D15 and Q2W thereafter in a 28-day cycle. Tarlatamab will be administrated in intravenous route until disease progression, unacceptable toxicity, or consent withdrawal.

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years
• 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
• 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
• High-grade MTC should be defined according to international medullary cancer grading system (IMCGS)
• 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 Specific cases: Patients with NEPC must have received at least 1 line of prior therapy, including a platinum containing regimen for de novo NEPC or an androgen signaling inhibitor (eg. abiraterone, enzalutamide, darolutamide and/or apalutamide) if treatment-emergent NEPC. Patients with high-grade MTC (capped at 4 patients) must have been treated with at least 1 prior therapy including a RET selective inhibitor if the presence of a RET mutation
• 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
• Patients must have an ECOG performance status ≤2 at the time of screening
• Patients must have a minimum life expectancy of 3 months
• Patients must have at least one radiologically measurable lesion according to response evaluation criteria in solid tumors (RECIST) v1.1 criteria
• 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
• Patients must have adequate bone marrow reserve and organ function, based on local laboratory data within 21 days prior to cycle 1, day 1 defined as:
• Platelet count ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to cycle 1 Day 1 to meet eligibility)
• Hemoglobin (Hgb) ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
• Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 × 109/L (use of growth factors is not allowed in the 14 days prior cycle 1)
• Creatinine clearance (CrCl): Creatinine clearance (CrCl) ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl; confirmation of CrCl is only required when SCr is \>1.5 × ULN

You may not qualify if:

• Patients unwilling to participate to the biological investigations and to perform blood and tissue sample collection as required in the protocol
• Patients with SCLC or other poorly differentiated NECs whatever the primary or high-grade MTC amenable for treatment with curative intent
• Patients with well differentiated neuroendocrine tumors, whatever the grade, pheocromocytoma, paraganglyoma, or low grade MTC
• 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
• 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
• Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients of tarlatamab
• Inadequate washout period prior to cycle 1 day 1, defined as:
• 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
• 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
• Major surgery (excluding placement of vascular access) \< 21 days
• Live virus and live-attenuated vaccination \<28 days
• Systemic steroid therapy or other immunosuppressive therapy \< 7 days
• Prior treatment with tarlatamab or any selective inhibitor of the DLL3 pathway
• 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 1

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead
• Amgen: collaborator

Study Sites (1)

Gustave Roussy

Villejuif, France

RECRUITING

MeSH Terms

Conditions

Neoplasm Metastasis

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Yohann Loriot, MD, PhD

CONTACT

+33 (0)1 42 11 42 11; Yohann.LORIOT@gustaveroussy.fr

Chloé Serhal, PhD

CONTACT

+33 (0)1 42 11 42 11; chloe.serhal@gustaveroussy.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2025
• First Posted: June 11, 2025
• Study Start: July 2, 2025
• Primary Completion (Estimated): April 15, 2027
• Study Completion (Estimated): January 15, 2030
• Last Updated: November 26, 2025

Record last verified: 2025-11

Locations

FR (1)