Inclusion Criteria:
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 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. 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 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.
- - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and alkaline
phosphatase (ALP) <3 x ULN (or <5 x ULN for patients with liver metastases)
- Total bilirubin (TBL) <.
5 x ULN (<3 x ULN in the presence of documented
Gilbert's Syndrome [unconjugated hyperbilirubinemia]) or <2 X ULN for patients
with liver metastases.
- - Serum albumin ≥2.5 g/dL.
- - Prothrombin time (PT) or Prothrombin time- international normalized ratio
(PT-INR) and activated partial thromboplastin time (aPTT)/partial
thromboplastin time (PTT)≤1.5 × (ULN), except for patients on
coumarin-derivative anticoagulants or other similar anticoagulant therapy, who
must have PT-INR within therapeutic range as deemed appropriate by the
Investigator.
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.
Note : Methods considered as highly effective methods of contraception include:
1. Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
2. Progestogen-only hormonal contraception associated with inhibition of
ovulation:
3. Intrauterine device (IUD)
4. Intrauterine hormone-releasing system (IUS)
5. Bilateral tubal occlusion. 6. Vasectomized partner. 7. 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. 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:
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:
1. Whole brain radiation therapy or stereotactic brain radiation therapy <14 days. 2. 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. 3. 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. 4. Major surgery (excluding placement of vascular access) < 21 days. 5. Live virus and live-attenuated vaccination <28 days. 6. 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 1. 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:
1. 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. 2. LVEF <50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan. 3. Myocardial infarction within 6 months. 4. NYHA > class II within 6 months. 5. 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.
Patients with past or resolved Hepatitis B virus (HBV) infection are eligible if:
1. Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody
(anti-HBc) positive; OR. 2. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to
be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12
weeks prior to the viral load evaluation with normal transaminases; OR. 3. HBsAg positive and HBV DNA viral load is documented to be ≤ 2000 IU/mL in the
absence of anti-viral therapy and during the previous 12 weeks prior to the
viral load evaluation with abnormal transaminases AST/ALT < 3 ULN.
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).
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. The following are exceptions to this criterion:
1. Patient with auto-immune alopecia. 2. Patient with Grave's disease, vitiligo or psoriasis not requiring systemic
treatment within the last 2 years. 3. Patient with hypothyroidism (e.g. following Hashimoto syndrome) stable on
thyroid hormone replacement. 21. 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. 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)
