Immunotherapy as Second-line in Patient With Small Cell Lung Cancer

A Randomized Non-comparative Phase II Study of Anti-PDL1 ATEZOLIZUMAB (MPDL3280A) or Chemotherapy as Second-line Therapy in Patients With Small Cell Lung Cancer (SCLC)

Chemotherapy still constitutes the backbone of small-cell lung cancer (SCLC) therapy, particularly in the extensive disease (ED) stage (ED-SCLC). Despite the fact that a substantial complete response rate could be achieved in SCLC patients receiving etoposide - cisplatin doublet, cure remains the exception. Overall survival in patients receiving this combination is 10 months and progression free survival 6.3 months. At time of progression two options are hitherto accepted: reinduction of carboplatin - etoposide doublet or, for patients unfit for reinduction, topotecan single-drug regimen. However, in both clinical cases, median survival hardly achieves 33 weeks. Consistent data using anti - PDL1 (Programmed death-ligand 1) or anti PD1 (programmed cell death 1) antibodies suggest that they are active as single drug regimens in many malignant diseases. Taking into account the rich tumor infiltrating lymphocyte in pathological specimens of SCLC, we can hypothesize that experimental use of ATEZOLIZUMAB (MPDL3280A) in patients is ethical pending that it demonstrates activity in the second line setting.

Inclusion Criteria:

1. Histologically confirmed small-cell lung cancer.

2. Extensive or limited disease according to the criteria of the Veteran's Administration Lung Cancer Group: (disease extended is defined as a disease beyond hemi thorax and supraclavicular lymph node areas. Tumor pleural effusion will be considered as extended disease).

3. Targetable tumor lesions according to RECIST 1.1. Tumor involvement encompassed into a radiotherapy field is eligible as target pending that progression is documented.

4. Tumor sample sent to IFCT for PD-L1 immunohistochemistry

5. Previous platinum - etoposide treatment for at least 2 cycles.

6. Demonstrated progression of the disease other than brain metastasis or carcinomatous meningitis.

   For the patient relapsing more than one year after the end of the previous treatment, a new histological confirmation is required before randomization.

7. Age over 18 years.

8. Weight loss ≤ 10% during the last three months.

9. Patients with brain metastases at diagnosis will be eligible pending that they have achieved brain response during the first line therapy (including brain radiotherapy is required) and remain in brain tumor response during the two months prior to randomization.

10. Performance Status 0-2

11. Creatinine clearance > 40 mL/min.

12. Neutrophils ≥ 2,000 µL-1 and platelets ≥ 100,000 µL-1.

13. Bilirubin ≤ 1.5 x normal.

14. Transaminases, alkaline phosphatases ≤ 2.5 x ULN except in case of liver metastases (5 x ULN).

15. Electrocardiogram without sign of progressive coronaropathy.

16. No approved or investigational anti-cancer therapy concurrently or in the 5 years prior to start of study drug except the first line of treatment of the SCLC, including tumor embolization, chemotherapy, radiation therapy, immunotherapy, hormone therapy, biologic therapy, or anti angiogenic therapy (e.g., inhibitors of VEGF or VEGFR (Vascular Endothelial Growth Factor Receptor).

17. Signed informed consent

18. A female is eligible to enter and participate in this study if she is of:

Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has undergone:

• Hysterectomy.
• Bilateral oophorectomy (ovariectomy).
• Bilateral tubal ligation.
• Or who is post-menopausal:
• Patients not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L).
• Subject using HRT must have experienced total cessation of menses for ≥ 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH (Follicle Stimulating Hormone) and estradiol concentrations prior to initiation of HRT (Hormone Replacement Therapy).

Childbearing potential, including any female who has had a negative serum pregnancy test within 1 week prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. Contraceptive methods acceptable to the IFCT, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:

• An intrauterine device with a documented failure rate of less than 1% per year.
• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry and is the sole sexual partner for that female.
• Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product.
• Double-barrier contraception: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
• Oral contraceptive, either combined or progestogen alone
• Injectable progestogen
• Implant of levonorgestrel
• Estrogenic vaginal ring
• Percutaneous contraceptive patches The contraceptive methods must be used during all the time of the treatment and must be maintained during 5 months after the end of the treatment in the Atezolizumab arm and 30 days for women, 90 days for men, after the end of the treatment in the chemotherapy arm.

Female patients who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 15 days following the last dose of study drug.

A male with a female partner of childbearing potential is eligible to enter and participate in the study if he uses a barrier method of contraception or abstinence during the study.

Exclusion Criteria:

1. Non-small cell lung cancer or mixed small-cell lung cancer - non small cell cancer.

2. Prior immunotherapy

3. Last dose of the previous treatment received less than 21 days before randomization (washout period).

4. Corticosteroid with a daily dose over 10 mg prednisolone or equivalent for more than 10 days during the previous month.

5. Unstable angina or uncontrolled cardiac disease.

6. Progressive infection (suggested by a fever associated with hyperleukocytosis, increase procalcitonin, and increase of C reactive protein without link with a paraneoplastic syndrome).

7. Patient not able to follow the therapeutic program.

8. Natremia < 125 mmol/L except in case of corrective treatment before the beginning of the therapy.

9. Hypercalcemia despite corrective treatment (corrected calcemia = Ca++ (mmol) + [(40-alb (g)) x 0.025].

10. Psychic or mental disease that do not allow the patient to give informed consent.

11. Pregnant or lactating female.

12. Systemic immunosuppressive therapy (eg cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-tumor necrosis factor [TNF]) during the two weeks preceding the day 1 of cycle 1.

13. Auto-immune disease. History of autoimmune disease, including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, syndrome Guillain-Barré, multiple sclerosis, vasculitis or glomerulonephritis. Patients with a history of hypothyroidism origin autoimmune treated with a stable dose replacement therapy may be eligible for this study. Patients with controlled type 1 diabetes treated with insulin are eligible in this study.

14. Idiopathic pulmonary fibrosis history, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced lung disease, idiopathic pulmonary or active signs of pneumonia or interstitial lung infiltrate (any cause) detected on the lung scan selection

15. Prior malignancy. Note: Patients who have had another malignancy and were treated more than 5 years ago and have since been considered cured, or patients with a history of basocellular skin carcinoma or in situ carcinoma of the uterine cervix are eligible.

16. Presence of any concurrent disease or condition that would make the subject inappropriate for study participation including any unresolved or unstable, serious toxicity from prior administration of another investigational drug or any serious medical disorder that would interfere with the subject's safety, obtaining informed consent, or compliance with all study related procedures.

17. Administration of a live attenuated vaccine during the four weeks preceding the day 1 of cycle 1, or administration of a vaccine of this type scheduled during the study. An influenza vaccine should be administered during the influenza season (approximately from October to March). Patients should not receive a live attenuated influenza vaccine during the four weeks preceding the day 1 of cycle 1, and shall not receive a vaccine of this type during the study.

18. History of human immunodeficiency virus infection or chronic hepatitis B or C.

19. Presence of active or uncontrolled infection.

20. Psoriasis patients

21. History of any one or more of the following cardiovascular conditions within the past 6 months:

    • Coronary/peripheral artery bypass graft, cardiac angioplasty or stenting.
    • Myocardial infarction.
    • Severe/unstable angina pectoris.
    • Symptomatic peripheral vascular disease, pulmonary embolism or untreated deep venous thrombosis (DVT), cerebrovascular accident or transient ischemic attack.
    • Note: Subject with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
    • Class III or IV congestive heart failure, as defined by the New York Heart Association.

22. Concurrent treatment with an investigational agent or participation in another clinical trial.