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)
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 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
Eligibility criteria
This trial does not accept healthy volunteers
Qualifiers
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 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
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.
Disqualifiers
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 amenable for treatment with curative intent
Patients with well differentiated neuroendocrine tumors, whatever the grade, pheocromocytoma, paraganglyoma.
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
Trial design
Design model
Parallel
Treatments tested in this trial
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.
Treatment groups
40 Participants
are divided into 2 treatment groups
Group A: Cohort 1Experimental treatment 1 intervention
Group B: Cohort 2Experimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
To estimate the objective response rate (ORR)
Time frame
Within the 4 months of treatment initiation
Secondary outcomes
1
Objective response rate at different timepoints (ORR)
Time frame
up to 18 months
2
Duration of response (DOR)
defined as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of progression (PD) or death due to any cause. Duration of response will be measured for responding patients (CR or PR) only
Time frame
From cycle 3 (Week 6; each cycle is 28 days) up to 2 years after the EoT, an average of 26 months
3
Clinical benefit rate (CBR)
defined as the presence of at least a PR or CR, or a stable disease (SD) \>6 months
Time frame
During treatment period, a median of 4 months
4
Progression free survival (PFS)
defined as the time from date of first dose until the date of the first objective documentation of disease progression or death from any cause, whichever occurs first. For patients without documented radiological progression, follow-up will be censored at the date of last radiological assessment without progression, unless death occurs within 12 weeks following the date of last known progression-free, in which case the death will be counted as a PFS event
Time frame
From the time date of the first dose until progression or death from any cause, whichever occurs first, assessed up to 18 months
Other outcomes
1
mechanisms of action of tarlatamab
Time frame
from enrollment unti EoT, with a median of 4 months
2
mechanisms of resistance of tarlatamab
Time frame
from enrollment unti EoT, with a median of 4 months
3
Description of patient-reported outcomes (PROs)
physical functioning sub-scale score of the EORTC QLQ-C30
Time frame
Treatment Period, median of 4 months
4
Description of patient-reported outcomes (PROs)
QoL scale score of the EORTC QLQ-LC13
Time frame
Treatment Period, median of 4 months
Sponsors and contacts
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