Clinical Trials /

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

NCT03325816

Description:

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.

Related Conditions:
  • Lung Neuroendocrine Neoplasm
  • Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and 177Lu-DOTA0-Tyr3-Octreotate for Patients With Extensive-Stage Small Cell Lung Cancer
  • Official Title: Phase I/II Trial of Anti-PD-1 Checkpoint Inhibitor Nivolumab and 177Lu-DOTA0-Tyr3-Octreotate for Patients With Extensive-Stage Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2017-1081
  • NCT ID: NCT03325816

Conditions

  • Small Cell Lung Cancer
  • Small Cell Lung Cancer Extensive Stage

Interventions

DrugSynonymsArms
NivolumabBMS-936558, OpdivoPhase II - Arm 1

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase II - Arm 1ExperimentalNivolumab will be administered 240mg every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities. The Phase II dose of 177Lu-DOTA0-Tyr3-Octreotate will be the maximum tolerated dose as determined in the Phase I portion.
  • Nivolumab
Phase I - Dose Level -1ExperimentalNivolumab will be administered 240mg every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities. 177Lu-DOTA0-Tyr3-Octreotate dose will be 3.7 GBq (100 mCi) every 8 weeks for 4 doses.
  • Nivolumab
Phase I - Dose Level 0ExperimentalNivolumab will be administered 240mg every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities. 177Lu-DOTA0-Tyr3-Octreotate dose will be 7.4 GBq (200 mCi) every 8 weeks for 4 doses.
  • Nivolumab
Phase II - Arm 2No InterventionPatients randomized to this arm will be followed (observation). Cross-over to Phase II Arm 1 at the time of disease progression will be allowed

    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.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Phase I - Recommended phase II dose (RP2D) of 177Lu-DOTA0-Tyr3-Octreotate
    Time Frame:12 months
    Safety Issue:
    Description:Maximum tolerated dose as determined during the phase I portion

    Secondary Outcome Measures

    Measure:Safety profile of 177Lu-DOTA0-Tyr3-Octreotate in combination with nivolumab
    Time Frame:24 months
    Safety Issue:
    Description:Adverse events and serious adverse events experienced by subjects
    Measure:Phase II - Overall survival
    Time Frame:24 months
    Safety Issue:
    Description:Time between start of treatment and death
    Measure:Phase II - Disease Control Rate
    Time Frame:12 months
    Safety Issue:
    Description:The percentage of patients who achieve complete response, partial response and stable disease
    Measure:Phase II - Objective Response Rate
    Time Frame:12 months
    Safety Issue:
    Description:The proportion of patients with tumor size reduction
    Measure:Phase II - Metabolic Response
    Time Frame:12 months
    Safety Issue:
    Description:As measured by NETSPOT PET scan

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Giuseppe Giaccone

    Trial Keywords

    • nivolumab
    • 177Lu-DOTA0-Tyr3-Octreotate
    • Lutathera

    Last Updated

    March 1, 2018