Phase II, Two-cohorts, Randomized Trial Comparing Standard of Care Versus Immune- Based Combination in Relapsed Stage III Non-small-cell Lung Cancer (NSCLC) Pretreated With Chemoradiotherapy and Durvalumab (MEDI4736)
This is a randomized, non-comparative, phase II study investigating whether: 1) the addition of durvalumab to investigator's choice second line chemotherapy prolongs survival versus investigator's choice second line chemotherapy in NSCLC patients with locally advanced disease progressing on durvalumab given after concomitant chemoradiotherapy; 2) whether the addition of olaparib to durvalumab improves survival over durvalumab alone after induction chemoimmunotherapy in patients relapsing after completing durvalumab maintenance therapy for stage III disease. After evaluation of inclusion and exclusion criteria and after consent form signature, all eligible patients progressing during durvalumab therapy will be in the Part A of the trial randomized to in a 1:1 ratio to investigator's choice single-agent chemotherapy plus durvalumab (Arm A: experimental arm) or to investigator's choice single-agent chemotherapy (Arm B: standard arm). In the clinical trial's Part B, patients progressing after completion of durvalumab therapy will be further randomized in a 1:1.7 ratio to investigator's choice platinum doublet chemotherapy plus durvalumab for 4 cycles followed by maintenance durvalumab plus olaparib (Arm C: experimental arm) or to investigator's choice platinum doublet chemotherapy plus durvalumab for 4 cycles followed by durvalumab (Arm D: experimental arm). Therapy will be continued up to disease progression, toxicity or patient refusal.
• Body weight \>30kg
• Recurrent or metastatic NSCLC relapsed during or after completion of chemoradiotherapy with curative intent and maintenance durvalumab for stage III disease. Patients are eligible if they receive at least two cycles of platinum based chemotherapy or radical radiotherapy
• Tumor tissue available for biomarker testing.
• Evidence of disease progression during durvalumab maintenance or at the end of planned treatment. Patients who have interrupted planned durvalumab treatment after at least 6 months for reasons other than toxicity or progression (e.g. patient's choice, logistic reasons, intercurrent acute illnesses) are eligible. Patients progressing during the first three months of Durvalumab are not eligible
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• 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
• Age \>18 years at time of study entry
• 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.
• Life expectancy of at least 16 weeks
⁃ Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below::
∙ Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days
‣ Absolute neutrophil count (ANC) ≥1.5 × 109 /L
‣ Platelet count ≥100 × 109/L
‣ 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.
‣ AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
‣ creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test:
⁃ Males:
⁃ Creatinine CL = Weight (kg) x (140 - Age) (mL/min) ---------------------------------------- 72 x serum creatinine (mg/dL)
⁃ Females:
⁃ Creatinine CL = Weight (kg) x (140 - Age) (mL/min) ----------------------------------------- x 0.85 72 x serum creatinine (mg/dL)
⁃ Female patients should be using adequate contraceptive measures (highly effective method of contraception are present in table 3 of protocol Highly Effective Methods of Contraception (\<1% Failure Rate)), should not be breastfeeding, from the time of screening throughout the total duration of the drug treatment and the drug washout period (90 days after the last dose of durvalumab monotherapy) or for at least 1 month after last dose of olaparib, or they must totally/truly abstain from any form of sexual intercourse. Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.
⁃ Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.
⁃ Postmenopausal is defined as:
‣ Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
‣ Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
‣ radiation-induced oophorectomy with last menses \>1 year ago
‣ chemotherapy-induced menopause with \>1 year interval since last menses
‣ surgical sterilisation (bilateral oophorectomy or hysterectomy)
⁃ The following age-specific requirements apply:
‣ Women \<50 years of age would be considered post-menopausal if they have been amenorrheic 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.
‣ Women ≥50 years of age would 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.
⁃ Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential. Male patients should not donate sperm throughout the period of taking olaparib and for 3 months following the last dose of Olaparib.