RECRUITING

Radiation Combined With BIspecific T-Cell Engager in DLL3 Expressing Tumors

Conditions

Melanoma Medullary Thyroid Cancer Sinonasal Undifferentiated Carcinoma Esthesioneuroblastoma Bladder Cancer Testicular Cancer Glioblastoma Multiforme Cervical Cancer Large Cell Neuroendocrine Carcinoma of the Lung Non Small Cell Lung Cancer Merkel Cell Carcinoma DLL3 Expressing tumors

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

Phase I study to examine safety of the addition of concurrent tarlatamab with standard palliative and consolidative RT regimens , with a main cohort of N=20-24 patients with extracranial anatomic radiation sites. I) After lead in of 10 patients demonstrating safety of treatment, allow for expansion to cranial sites of disease (N=6-10) with continued enrollment in main cohort II) If toxicity criteria is not met in concurrent RT tarlatamab cohort, we will continue with sequential RT, either A) delivered within 7 days prior to cycle 1 day 1, or B) delivered during cycle 1 -2 but with pre- and post-RT washout of 7 days with no drug during RT, to examine safety in a temporally spaced setting. III) If sequential tarlatamab and radiation is not deemed safe, we would allow for continued enrollment to assess efficacy of drug sans radiation treatment, enriching for tumors not of small cell lung cancer histology and allowing for patients without sites amenable to RT. A nested phase II study will attempt to assess for ORR and safety of study intervention amongst tumors not of small cell lung cancer histology.

Official Title

RAdiation comBined With BIspecific T-Cell Engager in DLL3 Expressing Tumors (RABBIT) Study: A Phase I/II Study of AMG757 / Tarlatamab and Concurrent Radiation Therapy in Tumors With High Prevalence of DLL3

Quick Facts

Study Start:2025-09

Study Completion:2030-05

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06814496

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 99 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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: 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. 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:	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. 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. 4. History of hypophysitis or pituitary dysfunction. 5. Exclusion of hepatitis infection based on the following results and/or criteria: 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. 1. Subject received prior therapy with tarlatamab. 2. Prior anti-cancer therapy within 30 days prior to first dose of tarlatamab. 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. 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.

Inclusion Criteria

Exclusion 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:
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.
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:

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.
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.
4. History of hypophysitis or pituitary dysfunction.
5. Exclusion of hepatitis infection based on the following results and/or criteria:
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.
1. Subject received prior therapy with tarlatamab.
2. Prior anti-cancer therapy within 30 days prior to first dose of tarlatamab.
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.
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.

Contacts and Locations

Study Contact

Rachel E Jarrett, MPH

CONTACT

520-626-0375

UACC-IIT@uacc.arizona.edu

Michele Chu, MS

CONTACT

520-626-1183

UACC-IIT@uacc.arizona.edu

Principal Investigator

Charles Hsu, MD

PRINCIPAL_INVESTIGATOR

University of Arizona

Ricklie Julian, MD

STUDY_CHAIR

University of Arizona

Study Locations (Sites)

Arizona Cancer Center at UMC North/University Medical Center

Tucson, Arizona, 85719

United States

Collaborators and Investigators

Sponsor: University of Arizona

Charles Hsu, MD, PRINCIPAL_INVESTIGATOR, University of Arizona
Ricklie Julian, MD, STUDY_CHAIR, University of Arizona

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2025-09

Study Completion Date2030-05

Study Record Updates

Study Start Date2025-09

Study Completion Date2030-05

Terms related to this study

Keywords Provided by Researchers

DLL3 Expressing tumors

Additional Relevant MeSH Terms

Melanoma
Medullary Thyroid Cancer
Sinonasal Undifferentiated Carcinoma
Esthesioneuroblastoma
Bladder Cancer
Testicular Cancer
Glioblastoma Multiforme
Cervical Cancer
Large Cell Neuroendocrine Carcinoma of the Lung
Non Small Cell Lung Cancer
Merkel Cell Carcinoma