IRB Study Number 21-1232
Status Recruiting
Phase Phase 2
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess the antitumour activity of neoadjuvant treatment administered prior to surgery in terms of pCR
To assess the safety and tolerability of neoadjuvant and adjuvant treatment.
Secondary Objectives
To assess the efficacy of neoadjuvant treatment administered prior to surgery followed by adjuvant treatment post-surgery in terms of EFS
To assess the efficacy of neoadjuvant treatment administered prior to surgery followed by adjuvant treatment post-surgery in terms of DFS (event from surgery onwards)
To assess the feasibility of receiving the planned surgical tumour resection in patients receiving neoadjuvant treatment.
To assess the antitumour activity of neoadjuvant treatment administered prior surgery in terms of mPR
To assess the efficacy of neoadjuvant treatment administered prior to surgery in terms of ORR
To assess the efficacy of neoadjuvant and adjuvant treatment in terms of OS
To describe the PK of study drugs in patients receiving neoadjuvant/adjuvant treatment
To assess the immunogenicity of study drugs in patients receiving neoadjuvant/adjuvant treatment.
To investigate baseline PD-L1 expression in patients treated with neoadjuvant and adjuvant treatment, and associations with clinical endpoints.
To evaluate changes in ctDNA during neoadjuvant treatment in patients with evaluable ctDNA and associations with clinical endpoints.
Inclusion Criteria
Informed consent
1 Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2 Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.
3 Provision of signed and dated written ICF prior to collection of samples for genetic analysis.
The ICF process is described in Appendix A 3.
Age
4 Patients must be ≥ 18 years at the time of screening.
Type of Patient and Disease Characteristics
5 Newly diagnosed and previously untreated patients with histologically or cytologically documented NSCLC. Patients should have resectable (Stage IIA to Stage IIIB) disease (according to Version 8 of IASLC Staging Manual in Thoracic Oncology 2016. Patients with N2 disease are eligible) if they are candidate for lobectomy, sleeve resection, or bilobectomy at the time of screening. Patients with N3 disease are excluded.
At screening, complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a multidisciplinary evaluation, which must include a thoracic surgeon who performs lung cancer surgery as a prominent part of his/her practice.
o T4 tumours will only be eligible if they are defined as T4 based only on their size (more than 7 cm); any other reason for T4 (eg, adherent to any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina) will be considered ineligible.
o Nodal status should be investigated with whole body FDG-PET, plus contrast enhanced CT. If PET/CT scan is positive in the mediastinum, or if scan is negative but there is T > 3 cm, central tumour, or cN1, then it is recommended that nodal status be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. See Section 6.1.3 (preoperative mediastinal lymph node staging) for more details.
6 WHO or ECOG performance status of 0 or 1 at enrolment.
7 Adequate organ and marrow function as defined below:
Haemoglobin ≥ 9.0 g/dL.
Absolute neutrophil count ≥ 1.5 × 109/L.
Platelet count ≥ 100 × 109/L.
Serum bilirubin ≤ 1.5 × ULN. This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician.
ALT and AST ≤ 3.0 × ULN.
Measured CrCL > 45 mL/min or calculated CrCL > 45 mL/min as determined by Cockcroft-Gault (using actual body WT) using https://www.kidney.org/professionals/KDOQI/gfr\_calculatorCoc
LVEF ≥ 50% as assessed by echocardiogram or MUGA scan.
Troponin I or T ≤ ULN (per institutional guidelines and/or not clinically significant per investigator judgement).
8 Must have a life expectancy of at least 12 weeks.
Weight
9 Body WT > 35 kg.
Sex
10 Male and/or female.
Females of childbearing potential should agree to use an acceptable method of contraception (see Appendix G) from the time of screening throughout the total duration of the study and (for drugs that are potentially genotoxic) the drug washout period (90 days after last dose of study interventions for patients receiving durvalumab; 180 days after the last dose for patients receiving oleclumab or monalizumab; 228 days after the last dose for patients receiving MEDI5752. For the chemotherapy agents follow the local prescribing information relating to contraception, the time limits for such precautions, and any additional restrictions for the agents administered. For patients receiving more than one study intervention, the longest washout period must be followed) after the last dose of study interventions to prevent pregnancy. Female patients must not donate, bank or retrieve for their own use, ova during this same time period. For more details on contraceptive requirements of the study, see Appendix G.
Non sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period. Male patients who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening throughout the total duration of the study and (for drugs that are potentially genotoxic) the drug washout period (90 days after last dose of study interventions for patients receiving durvalumab; 180 days after the last dose for patients receiving oleclumab or monalizumab; 228 days after the last dose for patients receiving MEDI5752. For the chemotherapy agents follow the local prescribing information relating to contraception, the time limits for such precautions, and any additional restrictions for the agents administered. For patients receiving more than one study intervention, the longest washout period must be followed) after the last dose of study interventions to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period.
11 Negative pregnancy test (serum or urine) for women of childbearing potential.
Tumour sample requirements:
12 Provision of tumour samples (newly acquired or archival tumour tissue [≤ 6 months old]) to confirm PD-L1 status, EGFR, or ALK status where required during screening and prior to randomisation. Newly acquired or archival tumour tissue must be available from core needle biopsy, punch biopsy, excisional biopsy or surgical specimen. Fine needle aspirate is not acceptable. Core needle biopsies obtained by EBUS are acceptable. Tissue cores must contain cells and stroma. Cytology samples and specimens with limited tumour content are considered inadequate and will not be acceptable.
(a) PD-L1 status:
(i) If the patient’s PD-L1 status has already been assessed using the analytically validated Ventana PD-L1 (SP263) IHC assay, 22C3 pharmDx assay, or 28-8 pharmDx assay, this test result can be used.
(ii) Local laboratory results can be used if performed using the analytically validated Ventana PD-L1 (SP263) IHC assay, 22C3 pharmDx assay, or 28-8 pharmDx assay
(iii) If appropriate local testing and/or previous results are not available, PD-L1 testing using the Ventana PD-L1 (SP263) IHC assay will be performed centrally using either newly acquired tumour tissue (preferred) or archival tissue (≤ 6 months old).
(b) ALK and EGFR status:
(i) Local laboratory results for ALK and EGFR can be used if performed on well-validated, local-regulatory-approved assay; if not feasible, central testing will be performed. Patients with an EGFR mutation, ALK rearragement or unknown EGFR/ALK status will not be randomised, with the following exceptions:
o Patients with squamous cell carcinoma do not require ALK status.
o If appropriate local testing and/or previous results are not available, EGFR/ALK testing using a validated assay will be performed centrally using either newly acquired tumour tissue (preferred) or archival tissue (≤ 6 months old).
13 Provision of tumour appropriate for exploratory biomarker analyses (See Section 8.6 and the laboratory manual for details).
Surgery eligibility (assessments performed at screening):
14 Patients will be suitable for inclusion if the planned surgery to be performed will be lobectomy, sleeve resection, or bilobectomy, as determined by the attending surgeon based on the baseline findings.
15 A pre- or post-bronchodilator FEV1 of 1.0 L and DLCO > 40% postoperative predicted value. Use of these cut-off values to assess candidacy for resection should be guided by the results of cardiopulmonary exercise testing as outlined in the ESMO guidelines on pre-treatment risk assessment. Both an FEV1 and a DLCO test are required for assessing lung function at screening.
Exclusion Criteria
Medical Conditions
1 Patients with sensitising EGFR mutations or ALK translocations.
2 History of allogeneic organ transplantation.
3 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, or uveitis]). The following are exceptions to this criterion:
Patients with vitiligo or alopecia.
Patients with hypothyroidism (eg, 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/Medical Scientist.
Patients with celiac disease controlled by diet alone.
4 Uncontrolled intercurrent illness, including but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic gastrointestinal conditions associated with diarrhoea, 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.
5 History of another primary malignancy, except for the following:
Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drugs 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.
6 Patients with small-cell lung cancer or mixed small-cell lung cancer.
7 History of active primary immunodeficiency.
8 Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBsAg result) and HCV. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
9 Patients who have preoperative radiotherapy treatment as part of their care plan.
10 Patients who require or may require pneumonectomy, segmentectomies, or wedge resections, as assessed by their surgeon, to obtain potentially curative resection of primary tumour.
11 QTcF interval ≥ 470 ms (NOTE: If prolonged, then 2 additional ECGs should be obtained and the average QTcF interval should be used to determine eligibility).
12 Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
13 Any medical contraindication to treatment with chemotherapy as listed in the local labelling.
14 Patients with moderate or severe cardiovascular disease:
Presence of cardiac disease, including myocardial infarction or any other arterial thrombotic event including cerebrovascular accident, transient ischemic attack, or unstable angina pectoris within 6 months prior to study entry.
NYHA Class 3 or 4 congestive heart failure, or uncontrolled hypertension. Prior/Concomitant Therapy
15 Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
16 Receipt of live attenuated vaccine within 30 days prior to the first dose of study drugs. Note: Patients, if enrolled, should not receive live vaccine while receiving study drugs and up to 30 days after the last dose of study drugs.
17 Major surgical procedure (as defined by the Investigator) within 30 days prior to the first dose of study drugs.
18 Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies. Patients who received agents targeting the adenosine pathway (eg, anti-CD73, anti-A2AR, anti-CD39) and anti-NKG2A agents are also excluded.
19 Current or prior use of immunosuppressive medication within 14 days before the first dose of study drugs. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection).
Systemic corticosteroids ≤ 12 mg/day of prednisone or its equivalent.
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
Prior/concurrent clinical study experience
20 Participation in another clinical study with an investigational product administered within 30 days prior to enrolment.
21 Previous study drugs (durvalumab, oleclumab, or monalizumab) assignment in the present study.
Other Exclusions
22 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 180 days after the last dose of study drugs administration.
23 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
24 Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
25 Exclusion criteria for participation in the optional (DNA) genetics research component of the study include the following:
Previous allogeneic bone marrow transplant.
Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection.
