Clinical trial NCT03853187: Imaging Tumor-infiltrating T-cells in Non-small Cell Lung Cancer
Official title: Imaging Tumor-infiltrating CD8+ T-cells in Non-small Cell Lung Cancer Upon Neo-adjuvant Treatment With Durvalumab (MEDI4736)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2019-02-25
Enrollment: 20
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Safety of neo-adjuvant durvalumab: number of NCI CTCAE v 5.0 grade ≥3
timeFrame: 14 days
measure: Feasibility of neo-adjuvant durvalumab: successful completion of curative surgery
timeFrame: 42 days
Secondary outcomes:
measure: Imaging related_response on CE-CT
timeFrame: 42 days
measure: Imaging related_pathological response
timeFrame: 42 days
measure: Imaging related_correlation with Zr89-labelled durvalumab
timeFrame: 42 days
measure: Imaging related_correlation with perfusion-CT
timeFrame: 42 days
measure: Biomarker related_future correlation with other biomarkers
timeFrame: 42 days
measure: Biomarker related_correlation with immune profiling
timeFrame: 42 days
measure: Clinical care related_evaluation of VATS conversions
timeFrame: 42 days
measure: Clinical care related_number of patients with postoperative complications
timeFrame: 42 days
measure: Clinical care related_hospital stay
timeFrame: 42 days
measure: Clinical care related_mortality
timeFrame: 30 and 90 days
measure: Clinical care related_evaluation of patient related outcomes
timeFrame: 42 days
measure: Clinical care related_determination of recurrence-free survival
timeFrame: 42 days
measure: Clinical care related_determination of overall survival
timeFrame: 42 days
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
Study officials:
affiliation: Radboud University Medical Center
name: Erik Aarntzen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Michel van den Heuvel, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Jolanda de Vries, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: