Canakinumab with Chemoradiation and Durvalumab for the Treatment of Stage IIIA-C Non-Small Cell Lung Cancer, CHORUS Study
- Capable of giving signed informed consent which includes 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 obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
- Patient age >= 18 at time of consent.
- Stage IIIA-C Lung non-small cell cancer (NSCLC) (as per the American Joint Commission on Cancer [AJCC] 8th edition).
- Not a candidate for surgical resection as determined by one or more of the following criteria in multidisciplinary evaluations: technically unresectable, medically inoperable, patient declines operative approach.
- Candidate for concurrent chemoradiation therapy as determined by the treating radiation and thoracic oncologist.
- Histologic confirmation of NSCLC with pathological review done at Memorial Sloan Kettering Cancer Center (MSK).
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Candidate for definitive thoracic radiation (defined 60Gy +/- 10% in 2 Gy fractions).
- Body weight > 30 kg.
- Hemoglobin >= 9.0 g/dL.
- Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3).
- Platelet count >= 100 x 10^9/L (> 100,000 per mm3).
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional 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.
- 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 amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women >= 50 years of age would be considered post-menopausal if they have been amenorrhoeic 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).
- 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.
- Participation in another clinical study with an investigational (non-Food and Drug Administration [FDA] approved) product during the last 4 weeks.
- Concurrent enrollment in another clinical study for lung cancer, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
- Previous thoracic radiation precluding definitive radiation therapy (RT).
- Contraindication to durvalumab.
- 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 not on biologic therapy without active disease in the last 3 years may be included but only after consultation with the study physician. * Patients with celiac disease controlled by diet alone.
- Prior/current therapies: * Treatment with a monoclonal antibody within 4 weeks prior to study day 1 or has not recovered (i.e., >= grade 1 at baseline) from adverse events due to agents administered > 4 weeks earlier (intraocular bevacizumab is acceptable). * Patients receiving biologic drugs targeting the immune system (e.g. TNF blockers, anakinra, abatacept, tocilizumab) within 4 weeks prior to study day 1. * Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. * Prior treatment with canakinumab. * Current or prior use of a systemic immunosuppressive medication within 14 days before the first dose of canakinumab. 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 for less than 30 days. ** Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication). ** Systemic glucocorticoid replacement for conditions such as adrenal or pituitary insufficiency.
- Major surgical procedure (e.g. intra-cranial, intra-thoracic, intra-abdominal, or intra-pelvic) within 28 days prior to the first dose of canakinumab.
- Prior history of malignant disease, other than NSCLC, that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include: completely resected basal cell and squamous cell skin cancers, completely resected carcinoma in situ of any type, and definitely treated stage 0-I breast cancers on hormonal maintenance therapy or definitely treated stage I-IIA prostate cancer.
- History of allogenic organ transplantation.
- Known severe concurrent illness: * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Active or recurrent hepatic disorders including cirrhosis, hepatitis B and C. Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of hepatitis B surface antigen [HBsAg]) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). * Active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice). * Human immunodeficiency virus (positive HIV 1/2 antibodies). * Active infection requiring systemic therapy. * Evidence of interstitial lung disease or active, non-infectious pneumonitis. * Clinically significant (i.e., active) cardiovascular disease: symptomatic cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential unless they are willing to employ a highly effective birth control from screening to 130 days after the last dose of canakinumab. * Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Note that condom use during intercourse among sexually actives males will be required. Note that some contraception methods are not considered highly effective (e.g. female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills).
- Connective tissue disorders involving the lung(s) and/or esophagus requiring active treatment or idiopathic pulmonary fibrosis.
- Known history of active primary immunodeficiency.
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
- Receipt of live vaccination within 3 months prior to the first dose of the study drug. Note that this only applies to live vaccines.
I. To assess the improvement in 2-year progression-free survival rate.
I. Rate of Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade >= 2 pneumonitis.
II. 2-year overall survival.
III. Objective response rate as evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
IV. Safety and tolerability of canakinumab concurrent with chemoradiation and consolidative durvalumab using CTCAE version 5.0.
I. Blood biomarker correlatives for response.
II. 2-year rate of symptomatic cardiac toxicity.
Patients receive canakinumab subcutaneously (SC) every 3 weeks for 3 cycles, and receive standard radiation therapy daily over 20 minutes for 30 days and standard chemotherapy (consisting of either carboplatin or cisplatin with etoposide, paclitaxel, nab-paclitaxel or pemetrexed) intravenously (IV) over 90 minutes for 2 cycles (6 weeks). Beginning 3-8 weeks post-chemoradiation patients receive durvalumab IV over 90 minutes every 2 weeks and canakinumab intravenously IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for up to 2 years.
Trial Phase Phase I/II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
- Primary ID 21-004
- Secondary IDs NCI-2021-05942
- Clinicaltrials.gov ID NCT04905316