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)

Prior treatment

• 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 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
• 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 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)
• Patients with SCLC or other poorly differentiated NECs whatever the primary amenable for treatment with curative intent
• 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.
• 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)
• 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
• 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

Other illness

• Patients with evidence of any leptomeningeal disease
• 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
• Patient with history of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months of first dose of tarlatamab
• Participant with active hepatitis B or HCV (RNA detected by qualitative assay). HCV RNA testing is not required in participants with negative HCV antibody testing.
• 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
• 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 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 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: 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

Lab values

• 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

Other

• Patients unwilling to participate to the biological investigations and to perform blood and tissue sample collection as required in the protocol
• Patients with clinically significant pleural effusion will be excluded. Pleural effusion managed with indwelling pleural catheter (eg, PleurX) are allowed
• Female patients who are pregnant or breastfeeding or intend to become pregnant during the study
• Patients under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent
• Patients with well differentiated neuroendocrine tumors, whatever the grade, pheocromocytoma, paraganglyoma

• Age ≥18 years
• Patients must be affiliated to a Social Security System or beneficiary of the same
• 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
• 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
• 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
• 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