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

NCT06814496 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY0000540120247128
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

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.

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

Keywords

DLL3 Expressing tumors

Outcome Measures

Primary Outcomes (1)

• Percentage of participants experiencing dose limiting toxicities (DLT) attributed to radiation or combination of radiation and tarlatamab.

  The primary endpoint is safety, which will be measured by DLT using adverse events graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and ASTCT (CRS and ICANS). DLT will be defined as having 1) grade 3 - 5 non-hematologic adverse events (AEs) possibly, probably or definitely related to protocol treatment (radiation or combination of radiation and tarlatamab) by 8 weeks from start of radiation therapy; or 2) AEs possibly, probably, or definitely related to radiation or combination of radiation and tarlatamab leading to early termination of radiation or permanent discontinuation of tarlatamab. Grade 3+ AEs (or discontinuation) due to tarlatamab alone (not attributable to combination therapy) will not contribute to the primary endpoint. Frequency (%) of the patients with DLT will be reported by cohort.

  Until radiographic or disease progression or up to 24 months, whichever is earlier.

Secondary Outcomes (5)

• Objective response rate (ORR) using RESIST/iRECIST and RANO/RANO-BM criteria of radiated and non-radiated sites stratified by anatomic RT site and tumor histology.

  Until radiographic or disease progression or up to 24 months, whichever is earlier.

• Toxicity of tarlatamab in tumors in all patients, not of SCLC histology, and stratified by histology in accordance with CTCAE v5.

  Until radiographic or disease progression or up to 24 months, whichever is earlier.

• Overall survival (OS)

  Until radiographic or disease progression or up to 24 months, whichever is earlier.

• Progression free survival (PFS)

  Until radiographic or disease progression or up to 24 months, whichever is earlier.

• Duration or Response (DOR)

  Until radiographic or disease progression or up to 24 months, whichever is earlier.

Study Arms (4)

Concurrent Main Cohort

EXPERIMENTAL

Patients enrolled to this cohort will receive tarlatamab with concurrent radiation therapy (RT) to extracranial sites (n=20-24 extracranial RT with a minimum of 10 thoracic patients). Patients will receive tarlatamab at a step-up dose of 1 mg on Cycle 1 Day 1 and then 10 mg on cycle 1 Day 8 and Cycle 1 Day 15 and every 2 weeks thereafter (on days 1 and 15 of each cycle) until radiographic progression or disease progression or 24 months, whichever is earlier. Patients will receive concurrent RT to extracranial sites as per standard of care starting as early as Cycle 1 Day 16 and as late as Cycle 2 Day 28, assuming there is no ongoing cytokine release syndrome (CRS) or immune-effector cell-associated neurotoxicity Syndrome (ICANS).

Drug: Tarlatamab; Radiation: Concurrent Radiation Therapy

Concurrent Cranial Cohort

EXPERIMENTAL

If the safety endpoint in the Concurrent Main Cohort is met, enrollment will expand to the Concurrent Cranial Cohort. 6-10 patients will receive tarlatamab with concurrent radiation therapy to cranial sites as described in the Concurrent Main Cohort.

Drug: Tarlatamab; Radiation: Concurrent Radiation Therapy

Sequential radiation therapy cohort

EXPERIMENTAL

If the concurrent main cohort safety endpoint is not met, then the study will proceed to de-escalation, where 20 patients will be enrolled on the sequential radiation therapy cohort. In this cohort patients will receive sequential tarlatamab and RT to cranial and extracranial RT sites. Standard of care RT can occur prior to Cycle 1 Day 1(if radiation treatment is completed \<7 days prior to the start of tarlatamab) or be interdigitated with tarlatamab with a 7-day washout between RT and infusion, with RT to begin as early as Cycle 1 Day 22 and as late as cycle 2 Day 28, assuming no ongoing CRS/ICANS.

Drug: Tarlatamab; Radiation: Sequential Radiation therapy

Tarlatamab Monotherapy Cohort

EXPERIMENTAL

If the sequential safety endpoint is not met, then the study will proceed to another de-escalation phase, where 10 patients will receive tarlatamab alone.

Drug: Tarlatamab

Interventions

Tarlatamab DRUG

Tarlatamab will be administered at a step-up dose of 1mg on Cycle 1 Day 1 and then 10 mg on Cycle 1 Day 8 and Cycle 1 Day 15 and every 2 weeks thereafter. For cycle 2 onwards, tarlatamab infusion will occur every 2 weeks on days 1 and 15 of each cycle.

Concurrent Cranial Cohort; Concurrent Main Cohort; Sequential radiation therapy cohort; Tarlatamab Monotherapy Cohort

Concurrent Radiation Therapy RADIATION

Standard of care RT can begin as early as Cycle 1 Day 16 and as late as Cycle 2 Day 28, assuming there is no ongoing CRS (extracranial)/ICANS (cranial).

Concurrent Cranial Cohort; Concurrent Main Cohort

Sequential Radiation therapy RADIATION

Standard of care radiation therapy can occur prior to Cycle 1 Day 1 (if radiation treatment is completed \<7 days prior to the start of tarlatamab) or be interdigitated with tarlatamab with a 7-day washout between RT and infusion, with RT to begin as early as Cycle 1 Day 22 and as late as cycle 2 Day 28, assuming no ongoing CRS (extracranial)/ICANS (cranial).

Sequential radiation therapy cohort

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures.
• Subjects ≥ 18 years of age at the time of signing the informed consent.
• Histologically or cytologically confirmed relapsed/refractory:
• SCLC
• Other tumors of small cell histology
• 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
• 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.
• Subjects who progressed or recurred after at least one line of therapy and are considered treatment refractory per standard of care.
• 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.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Minimum life expectancy of 12 weeks.
• 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.
• Measurable lesions as defined per RECIST 1.1 within 28 days prior to the first dose of tarlatamab.
• Eligible for external beam radiation therapy to a previously unirradiated, measurable lesion as per standard of care.
• For the concurrent / sequential cohort of extracranial RT sites:

You may not qualify if:

• 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
• Subjects are excluded from the study if any of the following criteria apply:
• No lesion(s)/site(s) amenable to radiation therapy (only eligible for tarlatamab monotherapy if open)
• Planned re-irradiation of a previously irradiated site
• Leptomeningeal disease requiring craniospinal irradiation
• Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
• 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.
• Other Medical Conditions
• Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association \> class II) within 12 months of first dose of tarlatamab.
• History of arterial thrombosis (i.e., stroke or transient ischemic attack) within 12 months of first dose of tarlatamab.
• 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.
• History of hypophysitis or pituitary dysfunction.
• a. Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B).

Sponsors & Collaborators

• University of Arizona: lead
• Amgen: collaborator

Study Sites (2)

Arizona Cancer Center at UMC North/University Medical Center

Tucson, Arizona, 85719, United States

RECRUITING

University of Washington Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Melanoma; Carcinoma, Medullary; Sinonasal undifferentiated carcinoma; Esthesioneuroblastoma, Olfactory; Urinary Bladder Neoplasms; Testicular Neoplasms; Glioblastoma; Uterine Cervical Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Merkel Cell

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Neuroendocrine; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Neuroblastoma; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Olfactory Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Genital Diseases, Male; Genital Diseases; Endocrine System Diseases; Testicular Diseases; Gonadal Disorders; Astrocytoma; Glioma; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Polyomavirus Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Study Officials

• Charles Hsu, MD

  University of Arizona

  PRINCIPAL INVESTIGATOR

• Ricklie Julian, MD

  University of Arizona

  STUDY CHAIR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be enrolled on the Concurrent Main Cohort (tarlatamab with concurrent radiation therapy to extracranial sites; N=20-24 extracranial RT site with a minimum of 10 thoracic patients). If the safety endpoint is met, enrollment will expand to the Concurrent Cranial Cohort (tarlatamab with concurrent radiation therapy to cranial sites; N=6-10 cranial RT sites). If the concurrent safety endpoint is not met, then the study will proceed to the de-escalation phase, where patients will be enrolled on the Sequential Cohort (sequential tarlatamab and radiation therapy; N=20 cranial and extracranial RT sites). If the sequential safety endpoint is not met, then the study will proceed to another de-escalation phase, where patients will be enrolled on the Tarlatamab Monotherapy Cohort (N=10 enriched for non-tumors not of SCLC tumorshistology and allowing for patients without amenable RT sites).

Study Record Dates

• First Submitted: January 29, 2025
• First Posted: February 7, 2025
• Study Start: September 8, 2025
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): May 1, 2030
• Last Updated: April 28, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)