Non-Squamous Non-small Cell Lung Cancer, Squamous Non-small Cell Lung Cancer
Conditions
Brief summary
This is a multicenter, 2-arm open-label, randomized comparative phase II study in each of two separate cohorts (non-squamous NSCLC and squamous NSCLC) according to histology.
Detailed description
Patients will receive four cycles of standard platinum-based doublet chemotherapy. Upon confirmation of response or tumor stabilization, patients will be registered and allocated into two cohorts based on the tumor histology and each cohort will be randomized into two arms. The experimental arm will receive combination of durvalumab + tremelimumab, the other arm is according to standard of care. The objective of this trial is to evaluate whether a maintenance approach with the combination immunotherapy with durvalumab + tremelimumab improves progression-free survival (PFS) compared to standard of care in patients with advanced NSCLC. Each cohort is powered separately based on PFS.
Interventions
DRUGDurvalumab
Combination of durvalumab + tremelimumab treatment
DRUGTremelimumab
Combination of durvalumab + tremelimumab treatment
Sponsors
European Organisation for Research and Treatment of Cancer - EORTC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
2-arm open-label randomized study in each of two separate cohorts (non-squamous and squamous NSCLC) according to histology.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* For inclusion in the study, patients should fulfill the following criteria * Histological diagnosis of NSCLC; for non-squamous NSCLC: no known sensitizing EGFR-mutation, no known EML4-ALK translocation. When a patient with non-squamous NSCLC has a KRAS mutation, further testing for EGFR and EML4-ALK is not necessary. For squamous NSCLC, EGFR and EML4-ALK testing is not necessary. * Availability of adequate in quality and quantity archived tumor material for IHC PD-L1 testing; (Preferably 15 but 8 mandatory slides or block of tumor tissue will be collected); * Stage IIIB or IIIC not eligible for radical treatment or stage IV according to TNM8 (Ref. 6); * Brain metastases should be treated with local therapy (stereotactic radiotherapy or whole brain radiotherapy), and patients should be asymptomatic, without treatment with steroids for four weeks before enrollment. Before enrollment, new brain imaging (contrast-CT or gadolinium-MRI) is needed to demonstrate that there is no progression in the brain when the last brain imaging is more than four weeks earlier. Screening for brain metastases is not necessary in patients that were previously not diagnosed with brain metastases and that are without signs indicative of brain metastases. * ≥ 18 years of age at time of study entry; * WHO performance status 0 or 1; at enrollment * Body weight \> 30 kg at enrollment * Evaluable disease with CT or MRI according to RECIST 1.1 (except for patients with a CR after 4 cycles of platinum-based doublet chemotherapy, these patients are also eligible); * Stable disease or response by RECIST criteria response after 4 cycles of platinum-based doublet chemotherapy; * Adequate normal organ and marrow function: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3) * Platelet count ≥ 100 x 109/L (\>100,000 per mm3) * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology)AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal; for patients with liver metastases ≤ 5 x institutional upper limit of normal * Measured or calculated creatinine clearance ≥45 mL/min by the Cockcroft-Gault formula (Appendix E) * Haemoglobin ≥ 9.0 g/dL * Patient with following autoimmune or inflammatory disorders are eligible: * Vitiligo or alopecia * Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Active disease in the last 5 years may be included but only after consultation with the study investigator * Celiac disease controlled by diet alone * Patient with history of another primary malignancy are eligible in the following cases: * 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 * Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the first dose of study treatment. Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons. * Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include: * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) * Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient) * Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment, from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy or pemetrexed. * Subject 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; * Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.
Exclusion criteria
* Patients should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) | 4.3 years from FPI | The time interval between the date of randomization and the date of disease progression or death, whichever comes first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate according to RECIST 1.1; | 5 years from FPI | Patients with response categories progression, early death and unknown will be considered as failing to respond to treatment. The response rates in each arm and their 95% confidence intervals will be provided. |
| Progression-free survival -2 | 5 years from FPI | PFS-2 calculated as the time between randomization and the 2nd PD or death, not of the maintenance treatment/observation but the PD after the subsequent treatment thus taking into account the influence of the treatment under investigation on the following treatment line. |
| Overall Survival (OS) | 5 years from FPI | Overall Survival (OS) is defined as the time interval between the date of randomization and the date of death from any cause. |
| Safety | 5 years from FPI | All adverse events will be recorded according to CTCAE version 4. |
| Quality of life | 5 years from FPI | The hypothesis to test is whether the possible benefit with respect to PFS/OS of the intense maintenance treatment will also translate in a better QoL or will the higher risk of Adverse events cause a reduction in QoL. (methodology: quality of life questionnaires) |
| Time to failure of 2nd treatment | 5 years from FPI | Defined as the time between randomization and the permanent treatment interruption of the subsequent/second treatment (treatment received after progression of the first treatment) due to progressive disease, PS worsening, unacceptable toxicity that does not allow continuing the treatment according to the investigator. |
Outcome results
None listed