Nivolumab and 177Lu-DOTA0-Tyr3-Octreotate for Patients With Extensive-Stage Small Cell Lung Cancer

Inclusion Criteria:

* Phase I

Patients must have cytologically or histologically confirmed relapsed or refractory extensive-disease small-cell lung cancer (ES-SCLC) or non-progressing ES-SCLC after first line chemotherapy, or advanced or inoperable grade I-II pulmonary NETs.

Patients with tumor tissue uptake during NETSPOT® PET that is equal to or higher than that in normal hepatic tissue (grade ≥2) will be eligible. At the discretion of the principal investigator, patients with SCLC whose tumors have lower levels of uptake than liver during NETSPOT® PET may be eligible for the study.

Patients must have measurable disease by RECIST criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan. See Section 7.1.2 for the evaluation of measurable disease.

Toxicities of prior therapy must be resolved to grade 1 or less as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

Prior radiotherapy or radiosurgery (including prophylactic cranial radiation and/or thoracic radiation) must have been completed at least 2 weeks prior to randomization.

ECOG performance status of 0-1.

Adequate organ and bone marrow function (hemoglobin \> 9 g/dL; absolute neutrophil count \> 1.5 x 109/L; platelet counts \> 100 x 109/L; serum bilirubin \< 2 x ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x ULN or \< 5 x ULN if liver metastases; calculated creatinine clearance \> 50 mL/min).

Life expectancy of at least 3 months.

Age \> 18 years.

Women of childbearing potential (WOCBP) must use avoid pregnancy for 23 weeks after the last dose of investigational drug. Men who are sexually active with WOCBP must avoid pregnancy for 31 weeks after the last dose of investigational drug. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) are not required to avoid pregnancy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic \[HCG\]) within 24 hours prior to the start of the study drug.

Women must not be pregnant or breastfeeding.

Ability to understand and willingness to sign a written informed consent document.

* Phase II

Patients must have cytologically or histologically confirmed ES-SCLC and must not have progressed after first line platinum-based chemotherapy regimen before randomization.

Patients with tumor tissue uptake during NETSPOT® PET that is equal to or higher than that in normal hepatic tissue (grade ≥2) will be eligible. It is recommended that NETSPOT® PET be obtained before initiation of chemotherapy, but NETSPOT® PET obtained during or after completion of chemotherapy could be used for screening purpose.

Patients must have measurable disease by RECIST criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan. See Section 7.1.2 for the evaluation of measurable disease.

Toxicities of prior therapy must be resolved to grade 1 or less as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

Prior radiotherapy or radiosurgery (including prophylactic cranial radiation and/or thoracic radiation) must have been completed at least 2 weeks prior to randomization.

For patients who do not receive radiotherapy after chemotherapy, the randomization must occur within 6 weeks of the last chemotherapy cycle. The study treatment must start within 2 weeks from randomization. For patients who receive radiotherapy (including prophylactic cranial radiation and/or thoracic radiation) after chemotherapy, the randomization must occur within 9 weeks of the last chemotherapy cycle but at least 2 weeks after completion of radiotherapy and the first dose of 177Lu-DOTA0-Tyr3-Octreotate cannot be given within 8 weeks of radiotherapy.

ECOG performance status of 0-1.

Adequate organ and bone marrow function (hemoglobin \> 9 g/dL; absolute neutrophil count \> 1.5 x 109/L; platelet counts \> 100 x 109/L; serum bilirubin \< 2 x ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 x ULN or \< 5 x ULN if liver metastases; calculated creatinine clearance \> 50 mL/min).

Life expectancy of at least 3 months.

Age \> 18 years.

Women of childbearing potential (WOCBP) must use avoid pregnancy for 23 weeks after the last dose of investigational drug. Men who are sexually active with WOCBP must avoid pregnancy for 31 weeks after the last dose of investigational drug. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) are not required to avoid pregnancy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic \[HCG\]) within 24 hours prior to the start of the study drug.

Women must not be pregnant or breastfeeding.

Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

* Phase I

Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.

Patients with human immunodeficiency virus (HIV) infection, or active hepatitis B or C virus infection will be excluded.

Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) are not eligible for the study.

Prior major surgery within 12 weeks or prior major surgery from which the patient has not sufficiently recovered yet.

Untreated and uncontrolled second tumor in the past 2 years.

Logistical or psychological hindrance to participation in clinical research.

Uncontrolled or significant cardiovascular disease, including any of the following:

* Symptomatic congestive heart failure (New York Heart Association Classification Class II).
* Cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), or unstable angina.
* Uncontrolled hypertension or uncontrolled cardiac arrhythmia.

Any other medical condition that in the Investigator's opinion would not make the patient a good candidate for the study.

* Phase II

Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.

Patients with human immunodeficiency virus (HIV) infection, or active hepatitis B or C virus infection will be excluded.

Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) are not eligible for the study.

Prior major surgery within 12 weeks or prior major surgery from which the patient has not sufficiently recovered yet.

Untreated and uncontrolled second tumor in the past 2 years.

Logistical or psychological hindrance to participation in clinical research.

Uncontrolled or significant cardiovascular disease, including any of the following:

* Symptomatic congestive heart failure (New York Heart Association Classification Class II).
* Cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), or unstable angina.
* Uncontrolled hypertension or uncontrolled cardiac arrhythmia.

Any other medical condition that in the Investigator's opinion would not make the patient a good candidate for the study.