IRB Study Number 24-659
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To demonstrate superiority of durvalumab + oleclumab relative to durvalumab + placebo in participants with unresectable, Stage III NSCLC who have not progressed on prior platinum-based cCRT
• To demonstrate superiority of durvalumab + monalizumab relative to durvalumab + placebo in participants with unresectable, Stage III NSCLC who have not progressed on prior platinum-based cCRT
Secondary Objectives
• To demonstrate superiority of durvalumab + oleclumab relative to durvalumab + placebo in participants with unresectable Stage III NSCLC who have not progressed on prior platinum-based cCRT
• To demonstrate superiority of durvalumab + monalizumab relative to durvalumab + placebo in participants with unresectable Stage III NSCLC who have not progressed on prior platinum-based cCRT
• To demonstrate superiority of durvalumab + oleclumab and durvalumab + monalizumab relative to durvalumab + placebo in participants with unresectable Stage III NSCLC who have not progressed on prior platinum-based cCRT
• To investigate the relationship between a patient’s PD-L1 expression on tumour cells and efficacy outcomes with durvalumab + oleclumab, durvalumab + monalizumab and durvalumab + placebo
• To assess the PK of durvalumab when in combination with oleclumab and with monalizumab
• To assess the PK of oleclumab when in combination with durvalumab
• To assess the PK of monalizumab when in combination with durvalumab
• To investigate the immunogenicity of durvalumab
• To investigate the immunogenicity of oleclumab
• To investigate the immunogenicity of monalizumab
• To assess time to deterioration in pulmonary symptoms (cough, dyspnoea, chest pain)
Inclusion Criteria
Part I Screening:
In order to expedite tissue analysis, part I screening procedures may begin before cCRT has been completed. Participants are eligible to be included in the study only if all of the following criteria apply:
Age
- Participant must be ≥ 18 years at the time of screening.
Type of Participant and Disease Characteristics
- Participants must have histologically- or cytologically-documented NSCLC and have been treated with concurrent CRT for locally advanced, unresectable (Stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology]).
Initial staging procedures performed prior to initiation of any component of definitive treatment should include:
Positron Emission Tomography – Computed Tomography (PET-CT) scan. Full-body scan is preferred, but a scan from at least the base of skull to mid-thigh is permissible (the entire pelvis must be imaged). The PET-CT scan must have been performed up to 3 months prior to the first dose of concurrent chemoradiotherapy (CRT) or induction chemotherapy cycles, if utilized.
Brain imaging with MRI (preferred) or high-quality CT with IV contrast is strongly encouraged during initial staging.
Except for overt cT4 disease, biopsy strongly preferred to prove nodal status N2 or N3 via endobronchial ultrasound, mediastinoscopy, or thoracoscopy.
Tumour sample requirements as follows: Provision of a tumour tissue sample (obtained ≤ 3 months prior to Screening is preferred; ≤ 6 months prior to Screening is acceptable). The tumour sample must be obtained prior to CRT; irradiated samples are not acceptable (refer to Section 8.6.1 and the Laboratory Manual for details). An FFPE block sufficient for sectioning 20 slides (4-5 micron thickness) is preferred. If FFPE blocks cannot be submitted, then a set of newly-cut, unstained slides that enables necessary testing may be provided. Please refer to the Pathology Manual for details of the sample acceptance criteria.
Documented tumour PD-L1 status as determined by a central laboratory testing using the Ventana SP263 PD-L1 IHC assay prior to randomization. Patients with unknown PD-L1 status are not eligible for study.
Documented EGFR and ALK wild-type status. If a local laboratory performs the test, a well-validated, locally-approved test must be used. If local EGFR and ALK results are not available at time of screening, the assays will be performed in the central laboratory. Participants with sensitizing EGFR mutations (e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 insertion or S768I mutation) or ALK rearrangements are excluded from the study.
Tumours harbouring mutations in any of the following genes, if known, as determined by existing local test results: ROS1, RET, MET, NTRK1, NTRK2 and ERBB2 are excluded.
Informed Consent
Capable of giving signed informed consent for tumour sample collection that includes compliance with the requirements and restrictions listed in the pre-screening informed consent form (part I screening ICF) as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and this protocol.
Provision of signed and dated written part I screening ICF prior to any mandatory study-specific procedures and analyses.
Part II Screening
Participants may enter part II screening even if the results of the Part I screening procedures are still pending.
Participants are eligible to be randomised to the study only if all of the following Part II inclusion criteria and none of the exclusion criteria apply:
Type of Participant and Disease Characteristics
1 Patients must not have progressed following definitive, platinum-based, cCRT as demonstrated by the following imaging studies performed after completion of CRT:
(a) Screening baseline RECIST 1.1 imaging of chest and abdomen by CT (preferred) or MRI (see schedule of assessments Table 1)
(b) Brain MRI (preferred) or high-quality CT with IV contrast (See schedule of assessments Table 1).
2 Participants must have received at least 2 cycles of platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 42 days prior to first dose of investigational product in the study (one chemotherapy cycle is defined as 21 or as 28 days). Sites are encouraged to complete screening and initiate study treatment as soon as possible after completion of cCRT. For weekly chemotherapy regimens (i.e. carboplatin/paclitaxel) 4 weekly doses administered concurrently with radiation therapy are considered equivalent to 2 cycles.
3 The platinum-based chemotherapy regimen must be cisplatin or carboplatin-based and contain one of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed, according to the local standard of care regimens. Gemcitabine is not permitted.
4 The last dose of chemotherapy must be administered prior to, or concurrently with, the final dose of radiation. Consolidation chemotherapy after radiation is not permitted. Up to 2 cycles of induction chemotherapy prior to cCRT is permitted.
5 Where possible, chemotherapy regimens should be given according to National Comprehensive Cancer Network (NCCN) Guidelines or European Society for Medical Oncology (ESMO) Guidelines.
6 Participants must have received a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy) as part of the chemoradiation therapy, to be randomised. Radiation therapy should be administered by intensity modulated RT (preferred) or 3D-conforming technique. Sites are encouraged to adhere to the following organ dosimetric specifications:
Mean lung dose must be <20 Gy and/or V20 must be <35%
Mean eosophagus dose must be <34 Gy
Heart V45 <35% or V30 <50%.
7 Minimum life expectancy of 12 weeks at randomization
8 WHO performance status of 0 or 1 at randomization
9 Adequate organ and marrow function as defined below:
Absolute neutrophil count > 1.5 x 109/L (1500 per mm3)
Platelets > 75 x 109/L (75000 per mm3)
Haemoglobin ≥ 9.0 g/dL (5.59 mmol/L)
Serum creatinine CL >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance:
Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL)
Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85 72 x serum creatinine (mg/dL)
Serum bilirubin ≤1.5 x upper limit of normal (ULN) or < 3 x ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia).
AST and ALT ≤2.5 x ULN.
Weight
10 Minimum body weight ≥ 40 kg at enrolment and randomization.
Reproduction
11 Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
12 Negative pregnancy test (serum) for women of childbearing potential.
13 Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) Women of childbearing potential must agree to use one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study to 150 days after the last dose (see Appendix G for complete list of highly effective birth control methods). 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.
14 Male participants 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 the drug washout period (150 days after the last dose of study intervention) to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period.
Informed Consent
15 Capable of giving signed informed consent as described in 0, which includes compliance with the requirements and restrictions listed in the ICF and this protocol.
16 For optional genomic initiative participation only: Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of sample for optional genomics initiative research that supports Genomic Initiative. If a patient declines to participate in the genetics research, there will be no penalty or loss of benefit to the patient. A patient who declines genetics research participation will not be excluded from any other aspect of the main study.
Exclusion Criteria
Medical Conditions
1 As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active interstitial lung disease/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations), chronic diverticulitis or previous complicated diverticulitis which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
2 History of another primary malignancy except for malignancy treated with curative intent with no known active disease > 5 years before the first dose of study intervention and of low potential risk for recurrence, adequately resected non-melanoma skin cancer and curatively treated in situ disease, or adequately treated carcinoma in situ or Ta tumours without evidence of disease.
3 Mixed small cell and non-small cell lung cancer histology.
4 Participants who have had disease considered for surgical treatment as part of their care plan, such as Pancoast or superior sulcus tumours.
5 Participants with T4 lesions that invade major vascular structures such as pulmonary artery or cardiac tissues are not eligible.
6 Participants who receive sequential (not inclusive of induction) chemoradiation therapy for locally advanced (Stage III) unresectable NSCLC.
7 Participants with locally advanced (Stage III) unresectable NSCLC who have progressed during platinum-based cCRT.
8 Any unresolved toxicity CTCAE >Grade 2 from the prior chemoradiation therapy (excluding alopecia). Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
9 Participants with ≥grade 2 pneumonitis from prior chemoradiation therapy.
10 Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
11 History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, or idiopathic pneumonitis – regardless of time of onset prior to randomisation. Evidence of active non-CRT induced pneumonitis (≥ Grade 2), active pneumonia, active ILD, active or recently treated pleural effusion, or current pulmonary fibrosis.
12 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis and autoimmune myocarditis, etc). The following are exceptions to this criterion:
− Participants with vitiligo or alopecia.
− Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
− Any chronic skin condition that does not require systemic therapy.
− Participants without active disease in the last 5 years may be included based on the Investigator’s judgement
− Participants with coeliac disease controlled by diet alone.
13 Known active hepatitis infection, positive HCV antibody, HBsAg, or anti-HBc, at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA. Participants co-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND
− HCV positive (presence of anti-HCV antibodies); OR
− HDV positive (presence of anti-HDV antibodies).
14 Tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
15 Investigator judgment of 1 or more of the following:
− Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening.
− History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes (TdP).
− Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden cardiac death under 40 years of age in first-degree relatives.
16 History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the Investigator judgement with cardiologist consultation recommended.
17 Subjects with a history of myocardial infarction, transient ischemic attack, stroke, or pulmonary embolism diagnosed in the past 6 months or venous thrombosis diagnosed in the past 3 months prior to the scheduled first dose of study treatment.
18 History of primary immunodeficiency.
19 Prior allogeneic bone marrow transplant or stem cell/solid organ transplant.
20 History of leptomeningeal carcinomatosis.
21 Severe infection within 4 weeks prior to initiation of study treatment.
Prior / Concomitant Therapy
22 Participants who are expected to require any other form of antineoplastic therapy while participating in the trial are excluded.
23 Receipt of prior or current cancer treatment for NSCLC, including but not limited to, radiation therapy, investigational agents, chemotherapy, and mAbs. Patients with a prior surgical resection of metachronous (stage I or II) NSCLC are permitted, provided no other treatment modality including chemotherapy, radiotherapy or immunotherapy was administered. A subject’s tumour is considered metachronous if either:
• The histologic subtype of the prior resected NSCLC is of different histology from disease under treatment with definitive chemoradiation therapy OR
• The subject’s lung Cancer-free interval is at least 2 years (regardless of histology) and second cancer is in a different lobe or lung with no carcinoma in lymphatics common to both and no extrapulmonary metastases at time of diagnosis.
24 Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2 antibodies, anti-CD73 antibodies, and anti NKG2A antibodies, excluding therapeutic anticancer vaccines.
25 Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
− Intranasal, inhaled, topical steroids or local steroid injections (eg, 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 or as an anti-emetic (eg, CT scan premedication).
26 Receipt of live attenuated vaccination within 30 days prior the first dose of study intervention (see Appendix I 2).
27 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
28 Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
Prior/Concurrent Clinical Study Experience
29 Previous randomization in the present study or a previous durvalumab, monalizumab, or oleclumab clinical study regardless of treatment arm assignment.
30 Concurrent participation in another clinical study, unless it is an observational (non-interventional) clinical study, or the follow-up period of an interventional study.
31 Participation in another clinical study with a study intervention during the last 3 months prior to randomization or concurrent enrolment in another clinical study, unless it is and observational, non-interventional clinical study during the follow-up period of an interventional study.
32 Receipt of any immunotherapy, or investigational drug within 4 weeks prior to the first dose of study intervention; and in the case of monoclonal antibodies 6 weeks prior to the first dose of study intervention.
33 Participants with a known allergy or hypersensitivity to durvalumab, oleclumab or monalizumab, or any excipients of the products.
Other Exclusions
34 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
35 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
36 Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 150 days after the last dose of study intervention.
