Inclusion Criteria:
1. Subject has provided informed consent/assent prior to initiation of any study
specific activities/procedures.
2. Subjects ≥ 18 years of age at the time of signing the informed consent.
3. Histologically or cytologically confirmed relapsed/refractory:
1. SCLC. 2. Other tumors of small cell histology. 3. High grade / poorly differentiated neuroendocrine histology tumor histologies
with high prevalence of DLL3 (≥50% prevalence of ≥1% positivity), including but
not limited to: melanoma, medullary thyroid cancer, esthesioneuroblastoma,
bladder cancer, testicular cancer, glioblastoma multiforme, cervical cancer;
large cell neuroendocrine tumor of lung, non-small cell lung cancers with mixed
neuroendocrine features, and Merkel cell carcinoma OR. 4. DLL3+ (≥1% by IHC) Note: If patients are DLL3 negative per IHC but have a DLL3
prevelant tumor type, they will be allowed to enroll on the study.
4. Subjects who progressed or recurred after at least one line of therapy and are
considered treatment refractory per standard of care.
5. Subjects willing to provide archived tumor tissue samples (formalin fixed, paraffin
embedded [FFPE] sample). If no archived tumor tissue is available, we request to
undergo pretreatment tumor biopsy. Subjects who do not have archived tumor tissue
available and are unable or unwilling to undergo a pretreatment tumor biopsy due to
extenuating circumstances (i.e., cannot be performed safely or inaccessible, as
determined by the investigator) may be allowed to enroll without a tumor biopsy upon
agreement with sponsor.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
7. Minimum life expectancy of 12 weeks.
8. Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen.
9. Measurable lesions as defined per RECIST 1.1 within 28 days prior to the first dose
of tarlatamab.
10. Eligible for external beam radiation therapy to a previously unirradiated,
measurable lesion as per standard of care.
1. For the concurrent / sequential cohort of extracranial RT sites:
i. A minimum of 10 subjects with thoracic lesions (lung, mediastinum, thoracic
spine, rib, or other thoracic sites) will be treated ii. Subjects with treated brain
metastases are eligible (untreated brain metastases are ineligible) 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 therapy and by the time of study screening.
3. Patients manifesting progression in lesions previously treated with stereotactic
radiosurgery may still be eligible if pseudoprogression can be demonstrated by
appropriate means.
4. 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.
b. For the concurrent/sequential cohort of cranial RT sites: i. Previously untreated
brain lesions / metastases are eligible ii. Subjects with previously irradiated
brain lesions are eligible provided they meet one of the following criteria:
1. Prior PCI or whole brain radiation therapy per standard of care with new and/or
recurrent brain metastases to be treated with SRS or hfSRT. 2. Prior course(s) of SRS or hfSRT or other localized therapy with new lesion(s) to be
treated with whole brain radiation therapy iii. Whole brain re-irradiation will be
ineligible iv. Re-irradiation with SRS or hfSRT of previously irradiated lesion with
SRS or hfSRT will be ineligible v. Craniospinal irradiation will not be allowed c.
For the tarlatamab monotherapy cohort: i. Patient must have at least one measurable
lesion, however that lesion does not need to be amenable to RT. 1. Patients with previously irradiated lesions that have recurred or progressed are
eligible 11. Adequate organ function, defined as follows:
a. Hematological function: i. Absolute neutrophil count ≥ 1.5 x 109/L ii. Platelet count
≥ 100 x 109/L iii. Hemoglobin > 9 g/dL (90 g/L) b. Coagulation function: i. 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 medical monitor.
c. Renal function: i. Estimated glomerular filtration rate (eGFR) based on Modification
of Diet in Renal Disease (MDRD) calculation > 30 mL/min/1.73 m2 d. hepatic function: i.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) < 3 x ULN (or < 5 x ULN for subjects with liver involvement) ii. Total
bilirubin < 1.5 x ULN (or < 2 x ULN for subjects with liver metastases) e. Pulmonary
function: i. No clinically significant pleural effusion ii. Baseline oxygen saturation >
90% on room air f. cardiac function (if obtained as part of standard of care): i. Cardiac
ejection fraction ≥ 50%, no clinically significant pericardial effusion as determined by
an echocardiogram (ECHO) or multigated acquisition (MUGA) scan, and no clinically
significant electrocardiogram (ECG) findings.
Exclusion Criteria:
Re-irradiation, unless it is SRS/hfSRT after whole-brain radiation therapy (WBRT) or PCI
or WBRT after SRS/hfSRT; re-irradiation of same lesion, unless verified with the
Principal Investigator; patients with lesions not amenable to RT (including previously
irradiated) will be only allowable on the tarlatamab monotherapy cohort.
Disease Related. 1. Subjects are excluded from the study if any of the following criteria apply:
1. No lesion(s)/site(s) amenable to radiation therapy (only eligible for
tarlatamab monotherapy if open)
2. Planned re-irradiation of a previously irradiated site. 3. Leptomeningeal disease requiring craniospinal irradiation. 2. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
3. 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.
4. 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 days) which may be allowed if they are
not otherwise described in the exclusion criteria AND there is agreement to allow by
both the investigator and Amgen.
Other Medical Conditions. 1. Myocardial infarction and/or symptomatic congestive heart failure (New York Heart
Association > class II) within 12 months of first dose of tarlatamab.
2. History of arterial thrombosis (i.e., stroke or transient ischemic attack) within 12
months of first dose of tarlatamab.
3. Subject 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 tarlatamab.
NOTE: Simple urinary tract infection and uncomplicated bacterial pharyngitis are
permitted if responding to active treatment. Subjects requiring oral antibiotics who
have been afebrile > 24 hours, have no leukocytosis and have no clinical signs of
infection are eligible. Subjects who meet these criteria and who were previously on
IV antimicrobials should have been off IV antimicrobials for > 48 hours.
4. History of hypophysitis or pituitary dysfunction.
5. Exclusion of hepatitis infection based on the following results and/or criteria:
a. Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic hepatitis
B or recent acute hepatitis B).
b. Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA
by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA
suggests occult hepatitis B.
c. Positive hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is
necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C.
6. Major surgery requiring hospitalization for more than 3 days within 28 days of first
dose of tarlatamab.
7. Evidence of interstitial lung disease or active, non-infectious pneumonitis.
8. Active autoimmune disease that has required systemic treatment (except replacement
therapy) within the past 2 years or any other diseases requiring immunosuppressive
therapy while on study.
9. Human immunodeficiency virus (HIV) infection.
1. Subjects with HIV infection 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.
Prior/Concomitant Therapy. 1. Subject received prior therapy with tarlatamab.
2. Prior anti-cancer therapy within 30 days prior to first dose of tarlatamab.
Exceptions:
a. 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.
3. Has a diagnosis of immunodeficiency (i.e., positive/non-negative test for human
immunodeficiency virus) or is receiving systemic steroid therapy or any other form
of immunosuppressive therapy within 7 days prior to the first dose of tarlatamab.
4. 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.
2. Live viral non-replicating vaccine (i.e., Jynneos) for Monkeypox infection is
allowed during the study (except during cycle 1) in accordance with local
standard of care (SOC) and institutional guidelines.
3. 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.
Other Exclusions. 1. Female subjects of childbearing potential unwilling to use protocol specified method
of contraception during treatment and for an additional 60 days after the last dose
of tarlatamab. Contraception methods for female subjects include:
1. Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation (oral, intravaginal, or transdermal)
2. Progestogen-only hormonal contraception associated with inhibition of ovulation
(oral, injectable, and implantable)
3. Intrauterine device. 4. Intrauterine hormonal-releasing system. 5. Bilateral tubal ligation/occlusion. 6. Vasectomized partner (provided that partner is the sole sexual partner of the female
subject of childbearing potential and that the vasectomized partner has received
medical assessment of the surgical success)
7. Sexual abstinence (defined as refraining from heterosexual intercourse during the
entire period of risk associated with the study treatments; the reliability of
sexual abstinence must be evaluated in relation to the duration of the trial and the
preferred and usual lifestyle of the subject) 2. Female subjects who are
breastfeeding or who plan to breastfeed while on study through 60 days after the
last dose of tarlatamab.
3. Female subjects planning to become pregnant while on study through 60 days
after the last dose of tarlatamab.
4. 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.
5. Male subjects with a female partner of childbearing potential who are unwilling
to practice sexual abstinence (refrain from heterosexual intercourse) or use
contraception (use a condom) during treatment and for an additional 60 days
after the last dose of tarlatamab.
6. Male subjects with a pregnant partner who are unwilling to practice abstinence
or use a condom during treatment and for an additional 60 days after the last
dose of tarlatamab.
7. Male subjects unwilling to abstain from donating sperm during treatment and for
an 60 days after the last dose of tarlatamab.
8. Subject has known sensitivity to any of the products or components to be
administered during dosing.
9. Subject likely to not be available to complete all protocol-required study
visits or procedures, and/or to comply with all required study procedures
(i.e., Clinical Outcome Assessments) to the best of the subject and
investigator's knowledge.
10. 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, if consulted, would pose a risk to subject safety or
interfere with the study evaluation, procedures, or completion.
