Imaging Tumor-infiltrating T-cells in Non-small Cell Lung Cancer (Donan)

Imaging Tumor-infiltrating CD8+ T-cells in Non-small Cell Lung Cancer Upon Neo-adjuvant Treatment With Durvalumab (MEDI4736)

This is an interventional study, to assess feasibility and safety of durvalumab (MEDI4736) in neo-adjuvant setting in patients with resectable NSCLC. Additional analyses of potential imaging biomarkers, e.g. Zr-89 labelled durvalumab (MEDI4736), ex vivo In-111-oxine labelled CD8+ T-cells and high-resolution immune cell imaging, in relation to immunotherapy induced immune responses on quantitative immune histochemical analysis of the resected tumor specimen, will be performed.

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Radiation: Zr-89 labelled durvalumab PET/CT; Drug: Durvalumab (MEDI4736)

Detailed Description

This is an interventional study in 20 patients with resectable non-small cell lung cancer who will receive 2 courses of durvalumab (MEDI4736) in the neo-adjuvant setting, followed by surgery with curative intent.

Experimental imaging procedures include 1) Zr-89-labelled durvalumab (MEDI4736) scan prior to neo-adjuvant treatment to determine accessibility and intra-tumoral distribution of durvalumab (MEDI4736) and 2) (first cohort) injection of ex vivo [111In]-oxine labelled autologous CD8+ T-cells 48 hours prior to surgery, or (second cohort) injection of [89Zr]-Df-crefmirlimab prior to surgery. The scan is scheduled on the day of surgery and after surgery, the resected tumor specimen with ex vivo [111In]-oxine labelled or in vivo [89Zr]-Df-crefmirlimab labelled CD8+ T-cells in situ, is fixated for high-resolution ex vivo imaging on a preclinical U-SPECT scanner and quantitative histopathological analysis, next to standard histopathological evaluation.

Total duration of the study is maximum 42 days (from injection therapeutic dose durvalumab (MEDI4736) to surgery).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6500 HB
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female subjects aged >50 years at time of study entry
• Histopathological proven primary non-small cell lung cancer, with fully evaluable histological biopsies available
• ECOG performance status of 0 or 1
• AJCC stage I, II or IIIa as determined by contrast-enhanced CT chest-abdomen and F-18-FDG PET/CT: cT1cN0-1M0, cT2aN0-1M0 en cT3N0-1M0 (T3 separate nodule)
• Solid appearance of the tumor on contrast-enhanced CT
• Scheduled for resection with curative intent
• Patients should be medically operable defined by:
• Sufficient cardiopulmonary function
• Major contra-indications for surgery.
• No underlying immune disease (neutro- or lymphopenia, coagulation disorders) that could interfere with T-cell isolation
• Capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g, Health Insurance Portability and Accountability Act in the US, European Union Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Must have a life expectancy of at least 6 months

• Adequate normal organ and marrow function as defined below:

  • Haemoglobin ≥9.0 g/dL
  • Absolute neutrophil count (ANC) 1.5x (> 1500 per ml)
  • Platelet count ≥100 x10^9/L (>75,000 per ml)
• Serum bilirubin ≤1.5x upper limit of normal (ULN). Note: This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
• AST/ALT ≤2.5x upper limit of normal
• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (CCL):
• Males: CCL (mL/min) = (Weight (kg) x (140 - Age)) / 72 x serum creatinine (mg/dL)
• Females: CCL (mL/min) = (Weight (kg) x (140 - Age)) / 72 x serum creatinine (mg/dL), multiplied by correction factor 0.85
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Highly effective contraception for both male and female subjects throughout the study and for at least after durvalumab (MEDI4736) treatment administration intrinsic factor the risk of conception exists

Exclusion Criteria:

• Inability to lie supine for more than 30 minutes
• Documented previous severe allergic reaction to iodine-based contrast media, despite adequate pre-medication. In case of documented mild to moderate allergic reaction to iodine-based contrast media, patients will receive premedication according to the local protocol, consisting of 25mg prednisolone intravenously 30 minutes prior to iodine-based contrast media administration and 2mg clemastine intravenously just prior to administration.
• Indication for cervical mediastinoscopy according to the local multidisciplinary Thoracic-Oncology meeting
• Participation in another clinical study with an investigational product during the past 6 months
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) <6 months prior to the first dose of study drug
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab (MEDI4736) may be included only after consultation with the Study Physician.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 6 months of the first dose of study drug
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
• History of allogenic organ transplantation.

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent

• History of another primary malignancy except for:

  • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
• History of active primary immunodeficiency

• Active infection including:

  • tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice),
  • hepatitis B (known positive HBV surface antigen (HBsAg) result),
  • hepatitis C,
  • human immunodeficiency virus (positive HIV 1/2 antibodies),
  • Epstein Barr Virus (EBV, positive IgM antibodies)
  • cytomegalo virus (CMV, positive IgM antibodies) NOTE: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab (MEDI4736). The following are exceptions to this criterion:

  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions, e.g. CT scan
• Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab (MEDI4736). Note: Patients, if enrolled, should not receive live vaccine whilst receiving durvalumab (MEDI4736) and up to 30 days after the last dose of durvalumab (MEDI4736).
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab (MEDI4736) monotherapy.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Durvalumab (MEDI4736) neo-adjuvant; Patients will receive two courses of durvalumab (MEDI4736)at a fixed dose of 750mg Q2W intravenously, prior to scheduled resection of NSCLC. Patients are amendable to adjuvant chemo and/or radiation treatment, per standard-of-care. Additionally, patients will undergo a Zr-89 labelled durvalumab (MEDI4736) PET/CT and dedicated perfusion-CT prior to treatment with durvalumab (MEDI4736) and ex vivo In-111-oxine or in vivo [89Zr]-Df-crefmirlimab labelled CD8+ T-cells after two courses of treatment, prior to surgery.

Radiation: Zr-89 labelled durvalumab PET/CT; Patients will undergo a Zr-89 labelled durvalumab (MEDI4736) PET/CT and dedicated perfusion-CT prior to treatment with durvalumab (MEDI4736) and in- and ex-vivo In-111-oxine or in-vivo [89zr]-Df-crefmirlimab labelled CD8+ T-cells after two courses of treatment, prior to surgery.; Other Names: In-111-oxine labelled CD8+ T-cell scintigraphy OR [89Zr]-Df-crefmirlimab PET; Dedicated perfusion-CT; Drug: Durvalumab (MEDI4736); Patients will receive two courses of durvalumab (MEDI4736)at a fixed dose of 750mg Q2W intravenously, prior to scheduled resection of NSCLC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of neo-adjuvant durvalumab: number of NCI CTCAE v 5.0 grade ≥3	Demonstrate safety of two courses durvalumab (MEDI4736) 750 mg at two weeks interval in neo-adjuvant setting. Safety is defined as the number of NCI CTCAE v 5.0 grade ≥3 toxicity related to neo-adjuvant durvalumab (MEDI4736).	14 days
Feasibility of neo-adjuvant durvalumab: successful completion of curative surgery	Demonstrate feasibility of two courses durvalumab (MEDI4736) 750 mg at two weeks interval in neo-adjuvant setting. Feasibility is defined as successful completion of curative surgery within 42 days after start of neo-adjuvant treatment with durvalumab (MEDI4736) (= day 1).	42 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imaging related_response on CE-CT	Objective responses measured on contrast enhanced CT (RECIST1.1, immune related response criteria (irRC))	42 days
Imaging related_pathological response	The rate of (major and complete) pathological responses as previously defined.	42 days
Imaging related_correlation with Zr89-labelled durvalumab	Correlate the presence and localisation of TILs with the intra-tumoral distribution of Zr-89-labelled durvalumab (MEDI4736).	42 days
Imaging related_correlation with perfusion-CT	Correlate the presence and localisation of TILs and Zr-89-labelled durvalumab (MEDI4736) with (changes in) perfusion parameters on contrast-enhanced CT.	42 days
Biomarker related_future correlation with other biomarkers	Exploration of In-111-oxine or [89Zr]-Df-crefmirlimab labelled T-cells U-SPECT or PET findings with other potential biomarkers (not yet defined) for response to immune therapy and the number of immune therapy related conversions from VATS to open surgical procedures	42 days
Biomarker related_correlation with immune profiling	Correlate the presence of TILs with multi-dimensional immune profiling by flow cytometry of freshly isolated peripheral blood lymphocytes.	42 days
Clinical care related_evaluation of VATS conversions	Evaluate the number of VATS conversions after neo-adjuvant durvalumab (MEDI4736).	42 days
Clinical care related_number of patients with postoperative complications	Asses postoperative complications	42 days
Clinical care related_hospital stay	Asses length of hospital stay	42 days
Clinical care related_mortality	Asses 30 and 90 day mortality	30 and 90 days
Clinical care related_evaluation of patient related outcomes	Patient related outcome measurements (PROMS) will be evaluated based on the EORTC-QLQ-C30 (quality of life) questionnaire (in Dutch) at baseline, prior to surgery, at first post-operative visit and follow-up. The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.	42 days
Clinical care related_determination of recurrence-free survival	Determine recurrence-free survival by landmarking analysis, based on time since surgery.	42 days
Clinical care related_determination of overall survival	Determine overall survival by landmarking analysis, based on time since surgery.	42 days

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Erik Aarntzen, MD, PhD, Radboud University Medical Center; Principal Investigator: Michel van den Heuvel, MD, PhD, Radboud University Medical Center; Principal Investigator: Jolanda de Vries, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2019
• Primary Completion (Actual): December 6, 2022
• Study Completion (Actual): December 6, 2022

Study Registration Dates

• First Submitted: February 11, 2019
• First Submitted That Met QC Criteria: February 22, 2019
• First Posted (Actual): February 25, 2019

Study Record Updates

• Last Update Posted (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: December 6, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Durvalumab; Antibodies, Monoclonal
• Other Study ID Numbers: ESR-17-13332; NL68987.091.19 (Registry Identifier: Dutch trial registry); 2019-000670-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No