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

This research study is being done to assess the safety and tolerability of study drugs, 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) and nivolumab in subjects with small cell lung cancer or advanced or inoperable neuroendocrine tumor of the lung that has overexpressed somatostatin receptors (SSRT). Lutathera is an investigational radioactive agent that targets tumor cells that express SSRT. Nivolumab is an investigational agent that targets and inhibits a pathway that prevents your immune system from effectively fighting your cancer. The combination of these 2 study drugs is investigational. The term "Investigational" in this context means that the drugs have not been approved for clinical use by the US Food and Drug Administration (FDA).

Giving Lutathera and nivolumab together may increase the effectiveness of this therapy. We first need to find out the highest dose of Lutathera that can be given safely together with nivolumab. This study will be the first study to test giving Lutathera together with nivolumab. Once we have found the highest dose of Lutathera that can be given with nivolumab, we will treat more patients with this combination to determine how effective it is.

The purposes of this study are:

To find the highest doses of Lutathera that can be given with nivolumab without causing severe side effects.

To find out the side effects seen by giving Lutathera at different dose levels with nivolumab.

To determine if the amount of something in your tumor called PD-L1 makes you more likely to have a response to the combination of Lutathera and nivolumab.

The purpose of this project to see if the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is safe and tolerable, and provides PFS benefit compared to observation alone in the maintenance setting in patients with ES-SCLC and no disease progression after first-line platinum-based chemotherapy.

Treatment will be administered on an outpatient basis. A standard dose-escalation phase I design will be used. Three subjects will be enrolled at each dose level in the absence of DLT.

Selection of the starting dose of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is based on the results from previous clinical studies with each compound used as single agent and the fact that the combination has not been tested in clinical trials. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Studies have shown that intravenous administration of amino acids has a renal protective effect \[46\]. An infusion of amino acids (lysine 2.5% and arginine 2.5% in 1 L 0.9% NaCl; 250 mL/h) will be started 30 minutes before the administration of 177Lu-DOTA0-Tyr3-Octreotate and last 4 hours.

Nivolumab will be administered as a fixed dose of 240 mg as an intravenous infusion over 30 minutes every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal or toxicities.

The phase II portion will consist of patients with ES-SCLC who completed platinum based standard first-line chemotherapy (e.g. 4-6 cycles of platinum plus etoposide or irinotecan) without disease progression (responders plus stable disease) at the time of initiation of the combination therapy with 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. Eligible patients will then be randomly allocated in two arms: one will be treated with the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab, and the other arm will continue be followed (observation) after completion the standard chemotherapy treatment.

Randomization:

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. 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.
* The first dose of 177Lu-DOTA0-Tyr3-Octreotate cannot be given within 8 weeks of radiotherapy.

Randomization process:

* Randomization will be stratified according to NETSPOT® PET tumor uptake score (Grade 2, 3 and 4).
* OnCore will be used as statistical center and the randomization algorithm will be developed by the study biostatistician.
* The project management department will be the first point of contact for assessment through email.

Courses are defined as 56 days of dosing. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities. For patients randomized to the observation group, cross-over at the time of disease progression will be allowed, since the primary endpoint is PFS and not OS.

Eligibility Criteria:
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.