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About
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
Enrollment
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Inclusion criteria
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:
Patients must have baseline oxygen saturation > 90% on room air
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.
Note : Methods considered as highly effective methods of contraception include:
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
Progestogen-only hormonal contraception associated with inhibition of ovulation:
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomized partner
Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 months for females after the last dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception
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
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
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
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
Patients must be affiliated to a Social Security System or beneficiary of the same
Exclusion criteria
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:
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
Patients with evidence of any leptomeningeal disease
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
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
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
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.
Patients with clinically significant pleural effusion will be excluded. Pleural effusion managed with indwelling pleural catheter (eg, PleurX) are allowed
Uncontrolled or significant cardiovascular disease prior to cycle 1 day 1, including:
Patient with history of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab
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.
Patients with past or resolved Hepatitis B virus (HBV) infection are eligible if:
Patients with a history of Hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection, is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer).
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)
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. The following are exceptions to this criterion:
Patient with diagnosis of human immunodeficiency virus (HIV). Patients with HIV infection on antiviral therapy and undetectable viral load are allowed with a requirement for regular monitoring for reactivation for the duration of treatment on study per local or institutional guidelines
Female patients who are pregnant or breastfeeding or intend to become pregnant during the study
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
Patients under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent
Prior history of severe or life-threatening events from any immune-mediated therapy
Participation in another clinical trial (<30 days or < 5 half-lives, whichever is longer) evaluating an experimental drug (except non-interventional research)
Primary purpose
Allocation
Interventional model
Masking
40 participants in 2 patient groups
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Central trial contact
Yohann Loriot, MD, PhD; Chloé Serhal, PhD
Data sourced from clinicaltrials.gov
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