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

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ClinicalTrials.gov Identifier: NCT03325816
Recruitment Status : Recruiting
First Posted : October 30, 2017
Last Update Posted : June 13, 2018
Sponsor:
Collaborators:
Bristol-Myers Squibb
Advanced Accelerator Applications
Information provided by (Responsible Party):
Giuseppe Giaccone, Georgetown University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Small Cell Lung Cancer Small Cell Lung Cancer Extensive Stage Drug: Nivolumab Radiation: 177Lu-DOTA0-Tyr3-Octreotate Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 20, 2017
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Phase II - Arm 1

Nivolumab 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.

Drug: Nivolumab
Nivolumab is administered intravenously
Other Names:
  • BMS-936558
  • Opdivo

Radiation: 177Lu-DOTA0-Tyr3-Octreotate

177Lu-DOTA0-Tyr3-Octreotate will be administered every 8 weeks. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Each dose is infused over 30 minutes. On the day of 177Lu-DOTA0-Tyr3-Octreotate infusion, an intravenous bolus of anti-emetics will be given (suggested options: ondansetron (8 mg), granisetron (3 mg), or tropisetron (5 mg)). Administration of 177Lu-DOTA0-Tyr3-Octreotate may be given one day earlier or delayed up to 1 week due to holidays, inclement weather, conflicts, or similar reasons.

Concurrent amino acids are given with each dose of 177Lu-DOTA0-Tyr3-Octreotate since co-infusion of amino acids leads to a significant reduction (47%) in the mean radiation dose to the kidneys. The amino acid solution and 177Lu-DOTA0-Tyr3-Octreotate are administered in parallel by peripheral vein infusion

Other Name: Lutathera

Experimental: Phase I - Dose Level -1

Nivolumab 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.

Drug: Nivolumab
Nivolumab is administered intravenously
Other Names:
  • BMS-936558
  • Opdivo

Radiation: 177Lu-DOTA0-Tyr3-Octreotate

177Lu-DOTA0-Tyr3-Octreotate will be administered every 8 weeks. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Each dose is infused over 30 minutes. On the day of 177Lu-DOTA0-Tyr3-Octreotate infusion, an intravenous bolus of anti-emetics will be given (suggested options: ondansetron (8 mg), granisetron (3 mg), or tropisetron (5 mg)). Administration of 177Lu-DOTA0-Tyr3-Octreotate may be given one day earlier or delayed up to 1 week due to holidays, inclement weather, conflicts, or similar reasons.

Concurrent amino acids are given with each dose of 177Lu-DOTA0-Tyr3-Octreotate since co-infusion of amino acids leads to a significant reduction (47%) in the mean radiation dose to the kidneys. The amino acid solution and 177Lu-DOTA0-Tyr3-Octreotate are administered in parallel by peripheral vein infusion

Other Name: Lutathera

Experimental: Phase I - Dose Level 0

Nivolumab 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.

Drug: Nivolumab
Nivolumab is administered intravenously
Other Names:
  • BMS-936558
  • Opdivo

Radiation: 177Lu-DOTA0-Tyr3-Octreotate

177Lu-DOTA0-Tyr3-Octreotate will be administered every 8 weeks. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Each dose is infused over 30 minutes. On the day of 177Lu-DOTA0-Tyr3-Octreotate infusion, an intravenous bolus of anti-emetics will be given (suggested options: ondansetron (8 mg), granisetron (3 mg), or tropisetron (5 mg)). Administration of 177Lu-DOTA0-Tyr3-Octreotate may be given one day earlier or delayed up to 1 week due to holidays, inclement weather, conflicts, or similar reasons.

Concurrent amino acids are given with each dose of 177Lu-DOTA0-Tyr3-Octreotate since co-infusion of amino acids leads to a significant reduction (47%) in the mean radiation dose to the kidneys. The amino acid solution and 177Lu-DOTA0-Tyr3-Octreotate are administered in parallel by peripheral vein infusion

Other Name: Lutathera

No Intervention: Phase II - Arm 2
Patients randomized to this arm will be followed (observation). Cross-over to Phase II Arm 1 at the time of disease progression will be allowed



Primary Outcome Measures :
  1. Phase I - Recommended phase II dose (RP2D) of 177Lu-DOTA0-Tyr3-Octreotate [ Time Frame: 12 months ]
    Maximum tolerated dose as determined during the phase I portion

  2. Phase II - Progression Free Survival [ Time Frame: 12 months ]
    Time between start of treatment and tumor progression or death


Secondary Outcome Measures :
  1. Safety profile of 177Lu-DOTA0-Tyr3-Octreotate in combination with nivolumab [ Time Frame: 24 months ]
    Adverse events and serious adverse events experienced by subjects

  2. Phase II - Overall survival [ Time Frame: 24 months ]
    Time between start of treatment and death

  3. Phase II - Disease Control Rate [ Time Frame: 12 months ]
    The percentage of patients who achieve complete response, partial response and stable disease

  4. Phase II - Objective Response Rate [ Time Frame: 12 months ]
    The proportion of patients with tumor size reduction

  5. Phase II - Metabolic Response [ Time Frame: 12 months ]
    As measured by NETSPOT PET scan



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03325816


Contacts
Contact: Jenny Crawford, RN 202-687-0893 crawfojg@georgetown.edu
Contact: Chul Kim, MD, MPH 202-444-2223 chul.kim@gunet.georgetown.edu

Locations
United States, District of Columbia
Georgetown Lombardi Comprehensive Cancer Center Recruiting
Washington, District of Columbia, United States, 20007
Contact: Jenny Crawford, RN    202-687-0893    crawfojg@georgetown.edu   
Contact: Tisdrey Torres, RN    202-687-9861    tt665@georgetown.edu   
Principal Investigator: Giuseppe Giaccone, MD, PhD         
Sub-Investigator: Chul Kim, MD, MPH         
United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Allison Abate    551-996-0233    alison.abate@hackensackmeridian.org   
Principal Investigator: Martin E Gutierrez, MD         
Sponsors and Collaborators
Giuseppe Giaccone
Bristol-Myers Squibb
Advanced Accelerator Applications
Investigators
Study Chair: Giuseppe Giaccone, MD, PhD Lombardi Comprehensive Cancer Center

Responsible Party: Giuseppe Giaccone, Associate Director for Clinical Research, Georgetown University
ClinicalTrials.gov Identifier: NCT03325816     History of Changes
Other Study ID Numbers: 2017-1081
First Posted: October 30, 2017    Key Record Dates
Last Update Posted: June 13, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Giuseppe Giaccone, Georgetown University:
nivolumab
177Lu-DOTA0-Tyr3-Octreotate
Lutathera

Additional relevant MeSH terms:
Lung Neoplasms
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs