An Open-label, Randomized, Phase 3 Study of Nivolumab or Chemotherapy in subjects with Relapsed Small-cell Lung Cancer after Platinum-based First Line Chemotherapy

1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.;Target Population
a) Histologically or cytologically confirmed Small-cell Lung Cancer
b) Must have recurrence or progression after platinum-based, first line chemotherapy or chemoradiation therapy for the treatment of limited or extensive disease stage Small-cell Lung Cancer:
i)Subjects must have received at least 4 cycles of platinum-based, first-line chemotherapy for either limited or extensive stage disease or if they received less than 4 cycles, they must have had a best overall response (BOR) of a partial or complete response after completion of chemotherapy.
ii) Subjects must have had only 1 prior regimen of platinum-based, first-line treatment.
d) Evaluable disease by CT/MRI per RECIST 1.1 criteria
e) Subject must have demonstrated disease progression based on at least one tumour assessment done after completion of chemotherapy and prior to randomization. The tumour assessments performed during screening will be used as a baseline for efficacy assessments.
f) A formalin-fixed, paraffin-embedded tumour tissue block or unstained slides of tumour sample (archival or recent) must be available for biomarker evaluation, as described in Section 5.6.1. Specimens must be received by the central laboratory prior to randomization. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is insufficient.
g) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
h) Subject Re-enrolment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated) after obtaining agreement from the medical monitor prior to re enrolling a subject. If re-enrolled, the subject must be re-consented. Only the screening procedures performed outside of the protocol specified timing (eg, > 28 days) must be repeated.
i) Prior Radiotherapy or radiosurgery to metastases of the brain or bone must have been completed at least 2 weeks prior to randomization.;3. Age and Reproductive Status
a) Men and women, less than or equal to 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotrophin) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with plus 5 half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post-treatment completion (for subjects treated in Arm A).
WOCBP must also agree to follow instructions for method(s) of contraception for the duration of treatment plus 5-half lives of chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days post treatments completion or a duration specified by the local labels of the chemotherapy drugs received, whichever is longer (for Subjects treated with Arm B).;e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks post treatment completion (for subjects treated in Arm A).
Males who are sexually active with WOCBP must also agree to follow instructions for method(s) of contraception for the duration of treatment with chemotherapy plus 5 half-lives of chemotherapy plus 90 days (duration of sperm turnover) for a total of 90 days post treatment completion or a duration specified by the local labels of the chemotherapy drugs received, whichever is longer or a duration specified by the local labels of the chemotherapy drugs received, whichever is longer (for subjects treated in Arm B).;f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section.

1. Target Disease Exceptions
a) Active symptomatic central nervous system (CNS) metastases. Subjects are eligible if CNS metastases have been treated and subjects have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization. In addition, subjects must have been either off corticosteroids, or on a stable or decreasing dose of < or equal to 10mg daily prednisolone (or equivalent) for at least 2 weeks prior to enrolment. ;2. Medical History and Concurrent Diseases
a) Women who are childbearing potential or breastfeeding
b) Documented carcinomatous meningitis
c) Active known or suspected autoimmune disease. Subjects with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. However, subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
d) A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisolone equivalent) or other immunosuppressive medications within 14 days of randomization. However, corticosteroids with minimal systemic absorption (inhaled or topical steroids or as specified in Section 3.4.3), and adrenal replacement steroid does > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
e) Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
f) Prior treatment with toptecan or amrubicin.
g) Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
h) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have been resolved to Grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events {NCI CTCAE} version 4) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy that re not expected to resovle and resulted in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll.
I) Other active malignancy requiring concurrent intervention
j) Previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.
k) Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
l) Treatment with any chemotherapy, biologics for cancer, or investigational therapy within 28 days of first administration of study drug (subjects with prior cytotoxic or investigational products <4 weeks prior to treatment might be eligible after discussion between investigator and sponsor, if toxicities from the prior treatment have been resolved to CTC Grade 1 Level).
m) Major surgery or significant traumatic injury that is not recovered at least 4 days before the first dose of study drug.;3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
c) Inadequate hematologic function defined by
i) White Blood cells <2000/mm3
ii) Absolute Neutrophil count <1000/mm3 or
iii) Platelet count <100,000mm3, or
iv) Hemoglobin level <9 g/dL.
d) Inadequate hepatic function as defined by either:
i) Total Bilirubin level * 2.5 times the UNL or
ii)Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels * 2.5 times the ULN or * 5 times the ULN if live metastates are present. ;4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to any of the study drugs or study drug components.;5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness