NSCLC
Conditions
Keywords
neo-adjuvant, immune therapy, in vivo imaging, PETscan, anti-PD1
Brief summary
This study investigates whether a single subcutaneous administration of anti-PD-1 antibody can induce CD8+ T-cell tumor-infiltration that can be non-invasively monitored with \[89Zr\]crefmirlimab berdoxam PET imaging as an imaging biomarker.
Detailed description
This is a two-armed open-label feasibility study with exploratory endpoints, where subjects are participating for 2 years after completement of enrollment to determine disease-free survival rates. The therapeutic intervention is a single subcutaneous administration of the humanized hinge region-stabilized IgG4 monoclonal anti-PD1 antibody PF-06801591 (sasanlimab) in a fixed dose of 300 mg in a neo-adjuvant setting, with or without radiation therapy, followed by curative-intended surgery. The diagnostic intervention is a radiolabeled imaging tracer \[89Zr\]Zr-crefmirlimab berdoxam that entails two intravenous administrations of a fixed dose of 1.5 mg protein dose labelled with activity dose 37 MBq Zirconium-89; one at baseline and one at 2 weeks after sasanlimab injection, to visualize CD8+ T-cells in vivo.
Interventions
DRUGSasanlimab
6 mL of the study drug will be administered subcutaneous injection in the abdominal fat fold. If SC injections in the abdominal location are not possible, SC injections can be administered in a distributed manner in the thighs. SC injections in the upper extremities (eg, deltoid, upper and lower arm) are not permitted. Any observed abnormality at the injection site (e.g. erythema, induration, ecchymosis, injection site pain, injection site pruritus) will be monitored and judged by the investigator to determine whether a corresponding AE should be reported.
RADIATIONnon-ablative radiotherapy
Patients will receive a total dose of 24Gy irradiation to the tumor, fractionated in 3 doses of 8Gy, on three consecutive days and starting on the day of first sasanlimab administration.
DRUG[89Zr]Zr-crefmirlimab berdoxam
Prior to sasanlimab injection and prior to surgery, \[89Zr\]Zr-crefmirlimab berdoxam (1.5 mg protein dose labelled with activity dose 37 MBq Zirconium-89) will be administered via an intravenous catheter. After 21-27 hours after injection patient will undergo a whole-body PETscan te detect CD8+ T-cell infiltration.
Sponsors
Pfizer
ImaginAb, Inc.
University Hospital Tuebingen
Radboud University Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Arm 1: n=10 patients, who will receive a single subcutaneous injection with sasanlimab at 4-5 weeks prior to surgery. Arm 2: n=10 patients, who will receive a single subcutaneous injection with sasanlimab at 4-5 weeks prior to surgery, and a single dose radiation therapy in the week following sasanlimab injection.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>50 years * Histologically or cytologically proven adenocarcinoma or squamous cell lung cancer * Primary tumors \>1 cm and \</= 5 cm largest diameter * Scheduled for curative surgery * Informed consent * Adequate bone marrow function (ANC \>/= 1500, platelets \>/=100k, Hgb \> 9), renal function (CLCr \>30 mL/min), liver function (TotalBili \</= 1.5 x ULN; AST and ALT \</=2.5 x ULN).
Exclusion criteria
* Inability to undergo SPECT or PET scans * Pleiomorphic, lepidic, mucinous or large cell neuro-endocrine histological subtypes of non-small cell lung carcinoma * Histologically confirmed druggable mutation (EGFR, RET, ROS, ALK, BRAF V600, NTRK, NRG1, MET ex14Sk) * Pregnancy or lactation * Active infection, auto-immune disease, prior organ-transplantation or haematological condition that requires medication that potentially interferes with immune cell activation. * Documented medical history of auto-immune disease, organ-transplantation or haematological condition that potentially interferes with immune cell behavior * Prior radiation therapy to the chest * Splenectomy * Enrolled in a current investigational drug trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with successful completion of curative surgery within 42 days after start of subcutaneous sasanlimab as neo-adjuvant treatment. | 2 years | Feasibility will be determined on all patients who have entered the treatment phase of the study, i.e. received at least one course of neo-adjuvant sasanlimab. Feasibility is defined as successful completion of curative surgery within 42 days after start of neo-adjuvant treatment (= day 1). No delays will be allowed. Results will be reported in a descriptive fashion, including percentages, mean and standard deviation, median and range for the time-related measures. |
| The number of CTC grade ≥3 toxicity related to subcutaneous sasanlimab as neo-adjuvant treatment. | 2 years | Safety will be defined as the number of CTC grade ≥3 toxicity related to neo-adjuvant sasanlimab. Results will be reported in a descriptive fashion. |
| Detection of treatment induced immune related responses after subcutaneous sasanlimab as neo-adjuvant treatment. | 2 years | Efficacy will be defined as the detection of treatment induced immune related responses in \>15% of the patients. Results will be reported in a descriptive fashion, for both cohorts of each n=10 patients (sasanlimab with and without radiotherapy). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Demonstrate induction of CD8+ T-cells | 2 years | Determine changes from baseline in immune profiles, including maturation stages, activation markers, chemokine receptors and functional markers on different lymphocyte (sub-)populations assessed by multipanel flowcytometry on samples obtained at 3 weeks and expressed in percentages and absolute numbers per mL. |
| Explore pathological response rate | 2 years | The conventional pathological response assessment will be compared for both study arms and reported as absolute number and percentage of total subjects who received sasanlimab prior to surgery in that study arm. Comparative and descriptive analyses of immune cell signatures in peripheral blood, \[89Zr\]Zr-crefmirlimab berdoxam and resected tumor specimen with respect to both study arms will be performed to explore potential effect of radiotherapy on immune responses. |
| Framework for PETscan interpretation | 2 years | Determine the (changes in) relative distributions of tracer uptake (e.g., CD8+ T-cell distributions) across tumor, tumor-draining lymph node(s), spleen, bone marrow, blood pool and distant lymph nodes computed from \[89Zr\]Zr-crefmirlimab berdoxam PET images. Correlative analyses of CD8+ T-cell profiles will be done in peripheral blood at the time point of scanning and resected tumor sections. |
| Identify immune signatures | 2 years | The absolute number, mean and maximum density of CD8+ T-cells/mm\^2 tumor tissue will be determined and correlated with conventional pathological response assessment and clinical endpoint of 1- and 2-year recurrence free survival. The absolute number, mean and maximum density of other immune cell (sub-)populations will be determined by multipanel immunohistochemistry and immunofluorescence analyses on the resected tumor tissue and correlated to pathological and clinical response, as above. |
Countries
Germany, Netherlands
Contacts
Primary ContactErik HJ Aarntzen, Dr.
Backup ContactEvelien AJ van Genugten, MSc
Outcome results
None listed