Inclusion Criteria:
1. Written informed consent.
2. Failed prior platinum-based chemotherapy. 3. Histologically proven extrapulmonary small cell carcinoma or neuroendocrine
carcinoma from gastrointestinal tract, genitourinary tract, gynecologic origin, and
head and neck or unknown primary. When mixed histology (ex, adenocarcinoma, squamous
cell carcinoma or transitional carcinoma) is found, small cell carcinoma or
neuroendocrine carcinoma should be the predominant part.
4. Measurable lesions by RECIST 1.1 within 28 days prior to the first dose of
tarlatamab.
5. ECOG Performance Status (PS) of 0 or 1.
6. Age greater or equal to 18 years old.
7. Subjects willing to provide archived tumor tissue samples (formalin fixed, paraffin
embedded [FFPE] sample) or willing to undergo pretreatment tumor biopsy.
8. Subjects with treated brain metastases are eligible provided they meet the following
criteria:
1. Definitive therapy was completed at least 2 weeks prior to the first dose of
tarlatamab.
2. There is no evidence of radiographic central nervous system (CNS) progression
following definitive therapy and by the time of study screening.
3. Any CNS disease is asymptomatic for at least 7 days (unless symptoms are deemed
irreversible by the investigator), the patient is off steroids for at least 7
days (physiologic doses of steroids are permitted), and the subject is off or
on stable doses of anti-epileptic drugs for malignant CNS disease for at least
7 days.
9. Adequate organ function, defined as follows:
1. hematological function:
1. absolute neutrophil count ≥ 1.5 x 109/L. 2. platelet count ≥ 100 x 109/L. 3. hemoglobin > 9 g/dL (90 g/L)
2. coagulation function:
- (1) prothrombin time (PT)/international normalized ratio (INR) and partial
thromboplastin time (PTT) or activated partial thromboplastin time (APTT) ≤ 1.5
x institutional upper limit of normal (ULN).
Subjects on chronic
anticoagulation therapy who do not meet the criteria above may be eligible to
enroll after discussion with the chief investigator.
3. renal function:
- (1) estimated glomerular filtration rate (eGFR) based on Modification of Diet
in Renal Disease (MDRD) calculation > 30 mL/min/1.73 m2.
4. hepatic function:
1. aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
alkaline phosphatase (ALP) < 3 x ULN (or < 5 x ULN for subjects with liver
involvement).
2. total bilirubin < 1.5 x ULN (or < 2 x ULN for subjects with liver
metastases).
5. pulmonary function:
1. no clinically significant pleural effusion. 2. baseline oxygen saturation > 90% on room air. 6. cardiac function:
- (1) cardiac ejection fraction ≥ 50%, no clinically
significant pericardial effusion as determined by an echocardiogram (ECHO) and
no clinically significant electrocardiogram (ECG) findings.
Exclusion Criteria:
1. Uncontrolled brain metastasis and leptomeningeal disease.
2. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
3. Prior exposure to DLL3 targeting agent.
4. Subjects who experienced recurrent pneumonitis (grade 2 or higher) or severe,
life-threatening immune-mediated adverse events or infusion-related reactions
including those that lead to permanent discontinuation while on treatment with
immuno-oncology agents.
5. Unresolved toxicity from prior anti-tumor therapy, defined as not having resolved to
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, or to
levels dictated in the eligibility criteria with the exception of alopecia or
toxicities from prior anti-tumor therapy that are considered irreversible (defined
as having been present and stable for > 21 day) which may be allowed.
6. History of other malignancy within the past 2 years, with the following exceptions:
1. malignancy treated with curative intent and with no known active disease
present for > 2 years before enrollment and felt to be at low risk for
recurrence by the treating physician.
2. adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
3. adequately treated cervical carcinoma in situ without evidence of disease.
4. adequately treated breast ductal carcinoma in situ without evidence of disease.
5. prostatic intraepithelial neoplasia without evidence of prostate cancer.
6. adequately treated urothelial papillary non-invasive carcinoma or carcinoma in
situ.
7. Myocardial infarction and/or symptomatic congestive heart failure (New York Heart
Association > class II) within 12 months of first dose of tarlatamab.
8. History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 12
months of first dose of tarlatamab.
9. Presence of fungal, bacterial, viral, or other infection requiring oral or IV
antimicrobials for management within 7 days of first dose of tarlatamab with the
exception:
a. Those who have an active infection requiring parenteral antibiotic treatment:
simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted
if responding to active treatment. Subjects requiring oral antibiotics who have been
afebrile for >24 hours, have no leukocytosis, nor clinical signs of infection are
eligible.
10. History of hypophysitis or pituitary dysfunction.
11. Exclusion of hepatitis infection based on the following results and/or criteria:
1. Active hepatitis C infection (subjects with detectable hepatitis C antibody
[HCV Ab] and HCV RNA viral load above the limit of quantification)
- (1) Subjects with presence of HCV Ab and HCV RNA viral load below the limit of
quantification (HCV RNA negative) with or without prior treatment are allowed.
2. Active hepatitis B infection (presence of hepatitis B surface antigen [HBsAg]
and hepatitis B virus [HBV] DNA viral load above the limit of quantification
[HBV DNA positive])
1. Subjects with resolved HBV infection defined as absence of HBsAg and
presence of HBV core antibody (anti-HBc) followed by an HBV DNA viral load
below the limit of quantification (HBV DNA negative) are allowed, with a
requirement for regular monitoring for reactivation for the duration of
treatment on the study and assessing the need for HBV prophylaxis therapy
per local or institutional guidelines.
2. Subjects with chronic HBV infection inactive carrier state defined as
presence of HBsAg and HBV DNA viral load below the limit of quantification
[HBV DNA negative] are allowed, with a requirement for regular monitoring
for reactivation for the duration of treatment on the study and assessing
the need for HBV prophylaxis therapy per local or institutional
guidelines.
12. Major surgery within 28 days of first dose tarlatamab.
13. Subject received prior therapy with tarlatamab.
14. Prior anti-cancer therapy within 30 days prior to first dose of tarlatamab.
Exceptions:
1. Subjects who received conventional chemotherapy are eligible if at least 14
days have elapsed and if all treatment-related toxicity has been resolved to
grade ≤ 1.
2. Prior palliative radiotherapy must have been completed at least 7 days before
the first dose of tarlatamab.
15. Subjects has a diagnosis of immunodeficiency (e.g., positive/non-negative test for
human immunodeficiency virus) except subjects on antiviral therapy and undetectable
viral load are permitted with a requirement for regular monitoring for reactivation
for the duration of treatment on study per local or institutional guidelines or
subject is receiving systemic steroid therapy or any other form of immunosuppressive
therapy within 7 days prior to the first dose of tarlatamab.
16. The following vaccines (live and live-attenuated vaccines) are excluded during the
following study periods:
1. Screening and during study treatment: live and live-attenuated vaccines are
prohibited within 28 days prior to the first dose of tarlatamab and for the
duration of the study.
- (1) Live viral non-replicating vaccine (e.g., Jynneos) for Monkeypox infection
is allowed during the study (except during cycle 1) in accordance with local
standard of care and institutional guidelines.
2. End of study treatment: live and live-attenuated vaccines can be used when at
least 60 days (5 x half-life of tarlatamab) have passed after the last dose of
tarlatamab.
17. Subjects unwilling to use contraception or practice abstinence during treatment and
for an additional 60 days after the last dose of tarlatamab.
18. Female subjects who are breastfeeding or who plan to breastfeed while on study
through 60 days after the last dose of tarlatamab.
19. Male subjects unwilling to abstain from donating sperm during treatment and for an
additional 60 days after the last dose of tarlatamab.
20. Female subjects planning to become pregnant while on study through 60 days after the
last dose of tarlatamab.
21. Female subjects of childbearing potential with a positive pregnancy test assessed at
screening and/or day 1 by a highly sensitive urine or serum pregnancy test.
22. Subject has known sensitivity to any of the products or components to be
administered during dosing.
23. Subject likely to not be available to complete all protocol-required study visits or
procedures, and/or to comply with all required study procedures (e.g., Clinical
Outcome Assessments) to the best of the subject and investigator's knowledge.
24. History or evidence of any other clinically significant disorder, condition or
disease (with the exception of those outlined above) that, in the opinion of the
investigator would pose a risk to subject safety or interfere with the study
evaluation, procedures, or completion.
