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.
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.
SCLC
Other tumors of small cell histology
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.
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.
Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of tarlatamab.
Sequential
Tarlatamab
DrugTarlatamab 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 Radiation Therapy
RadiationStandard 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).
Sequential Radiation therapy
RadiationStandard 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).
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.
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.
ORR is defined as the percentage of subjects with measurable disease who have at least 1 confirmed response of complete response (CR) or partial response (PR) prior to any evidence of progression. ORR will be reported by cohort and site.
Toxicity of tarlatamab in tumors in all patients, not of SCLC histology, and stratified by histology in accordance with CTCAE v5.
Assess toxicity of therapy (tarlatamab with radiation therapy) by the incidence of treatment emergent adverse events reported (to include SAEs and AEs leading to discontinuation) based on CTCAE v5 and ASTCT (CRS and ICANS), stratified by histology and by SCLC vs. tumors that are not SCLC. Counts of all AEs by grade will be provided by cohort.
Overall survival (OS)
OS is defined as the time from registration to death and will be estimated using the Kaplan Meier method by cohort.
Progression free survival (PFS)
PFS according to RECIST guidelines is defined as the time from registration to progressive disease or death, whichever occurs first, and will be estimated using the Kaplan Meier method by cohort and site if applicable.
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University of Arizona
Lead sponsor
Amgen
Collaborator
