Nivolumab and Lutetium Lu 177-DOTA-TATE in Treating Patients with Relapsed or Refractory Extensive-Stage Small Cell Lung Cancer or Grade I-II Lung Neuroendocrine Tumors That Are Advanced or Cannot Be Removed by Surgery

Status: Active

Description

This partially randomized phase I / II trial studies the best dose of lutetium Lu 177-tetra-azacyclododecanetetra-acetic acid (DOTA)-Tyr3-octreotate (TATE) when given together with nivolumab and to see how well they work in treating patients with extensive-stage small cell lung cancer that has come back or does not respond to treatment or grade I-II lung neuroendocrine tumors that have spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as nivolmuab, may interfere with the ability of tumor cells to grow and spread. Radioactive drugs, such as lutetium Lu 177-DOTA-TATE, may carry radiation directly to tumor cells and not harm normal cells. Giving nivolumab and lutetium Lu 177-DOTA-TATE may work better in treating patients with small cell lung cancer or long neuroendocrine tumors.

Eligibility Criteria

Inclusion Criteria

  • PHASE I INCLUSION CRITERIA
  • 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 Response Evaluation Criteria in Solid Tumors (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 computed tomography (CT) scan
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Hemoglobin > 9 g/dL
  • Absolute neutrophil count > 1.5 x 10^9/L
  • Platelet counts > 100 x 10^9/L
  • Serum bilirubin < 2 x upper limit of normal (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
  • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception for 23 weeks after the last dose of investigational drug; men who are sexually active with WOCBP must use any contraceptive method(s) with a failure rate of less than 1% per year 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) do not require contraception; 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 INCLUSION CRITERIA: Patients must have cytologically or histologically confirmed ES-SCLC and must not have progressed after first line platinum-based chemotherapy regimen before randomization
  • PHASE II INCLUSION CRITERIA: 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
  • PHASE II INCLUSION CRITERIA: 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
  • PHASE II INCLUSION CRITERIA: 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
  • PHASE II INCLUSION CRITERIA: Prior radiotherapy or radiosurgery (including prophylactic cranial radiation and/or thoracic radiation) must have been completed at least 2 weeks prior to randomization
  • PHASE II INCLUSION CRITERIA: 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
  • PHASE II INCLUSION CRITERIA: ECOG performance status of 0-1
  • PHASE II INCLUSION CRITERIA: Hemoglobin > 9 g/dL
  • PHASE II INCLUSION CRITERIA: Absolute neutrophil count > 1.5 x 10^9/L
  • PHASE II INCLUSION CRITERIA: Platelet counts > 100 x 10^9/L
  • PHASE II INCLUSION CRITERIA: Serum bilirubin < 2 x ULN
  • PHASE II INCLUSION CRITERIA: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN or < 5 x ULN if liver metastases
  • PHASE II INCLUSION CRITERIA: Calculated creatinine clearance > 50 mL/min
  • PHASE II INCLUSION CRITERIA: Life expectancy of at least 3 months
  • PHASE II INCLUSION CRITERIA: Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception for 23 weeks after the last dose of investigational drug; men who are sexually active with WOCBP must use any contraceptive method(s) with a failure rate of less than 1% per year 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) do not require contraception; 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
  • PHASE II INCLUSION CRITERIA: 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
  • PHASE II INCLUSION CRITERIA: Women must not be pregnant or breastfeeding
  • PHASE II INCLUSION CRITERIA: Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • PHASE I EXCLUSION CRITERIA
  • 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 EXCLUSION CRITERIA: 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
  • PHASE II EXCLUSION CRITERIA: 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
  • PHASE II EXCLUSION CRITERIA: 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
  • PHASE II EXCLUSION CRITERIA: Patients with human immunodeficiency virus (HIV) infection, or active hepatitis B or C virus infection will be excluded
  • PHASE II EXCLUSION CRITERIA: Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) are not eligible for the study
  • PHASE II EXCLUSION CRITERIA: Prior major surgery within 12 weeks or prior major surgery from which the patient has not sufficiently recovered yet
  • PHASE II EXCLUSION CRITERIA: Untreated and uncontrolled second tumor in the past 2 years
  • PHASE II EXCLUSION CRITERIA: Logistical or psychological hindrance to participation in clinical research
  • PHASE II EXCLUSION CRITERIA: 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
  • PHASE II EXCLUSION CRITERIA: Any other medical condition that in the investigator’s opinion would not make the patient a good candidate for the study

Locations & Contacts

California

Los Angeles
UCLA / Jonsson Comprehensive Cancer Center
Status: In review
Contact: Randolph Hecht
Email: jrhecht@mednet.ucla.edu
San Francisco
UCSF Medical Center-Mount Zion
Status: In review
Contact: Thomas Hope
Email: Thomas.Hope@ucsf.edu

District of Columbia

Washington
MedStar Georgetown University Hospital
Status: Active
Contact: Giuseppe Giaccone
Phone: 202-687-7072
Email: gg496@georgetown.edu

Maryland

Bethesda
Walter Reed National Military Medical Center
Status: In review
Contact: Christina Ellen Brzezniak
Email: christina.e.brzezniak.mil@mail.mil

New Jersey

Hackensack
Hackensack University Medical Center
Status: Active
Contact: Martin E. Gutierrez
Email: Martin.Gutierrez@hackensackmeridian.org

New York

New York
Memorial Sloan Kettering Cancer Center
Status: In review
Contact: Lisa Bodei
Email: bodeil@mskcc.org

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: In review
Contact: jonathan Lehman
Email: jonathan.m.lehman@vanderbilt.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of lutetium Lu 177-DOTA-TATE (177Lu-DOTA0-Tyr3-octreotate) when given in combination with anti-PD-1 checkpoint inhibitor nivolumab in patients with small-cell lung cancer or advanced or inoperable grade I-II pulmonary neuroendocrine tumors (NET)s. (Phase I)

II. To compare the progression-free survival (PFS) in patients with extensive-stage (ES)-small cell lung cancer (SCLC) who were not progressing to first-line treatment with platinum-based therapy, after receiving combination treatment of 177Lu-DOTA0-Tyr3-octreotate and nivolumab as a maintenance therapy versus observation. (Phase II)

SECONDARY OBJECTIVES:

I. To characterize the safety profile of 177Lu-DOTA0-Tyr3-octreotate in combination with nivolumab. (Phase I and II)

II. In patients who were not progressing before initiating combo therapy: to assess disease control rate (DCR) and objective response rate (ORR) after treatment with 177Lu-DOTA0-Tyr3-octreotate plus nivolumab. (Phase II)

III. In patients who were not progressing before initiating combo therapy: to assess overall survival (OS). (Phase II)

IV. In patients who were not progressing before initiating combo therapy: to assess whether the metabolic response seen on a NETSPOT positron emission tomography (PET) scan obtained on cycle 2 day 1 will predict response to study treatment. (Phase II)

OUTLINE: This is a phase I, dose-escalation study lutetium Lu 177-DOTA-TATE followed by a phase II study. Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, 29, and 43. Beginning 2 weeks after first dose of nivolumab, patients receive lutetium Lu 177-DOTA-TATE IV over 30 minutes on day 15. Treatment repeats every 56 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo observation after completion of standard chemotherapy treatment.

After completion of study treatment, patients are followed up yearly for 2 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
MedStar Georgetown University Hospital

Principal Investigator
Giuseppe Giaccone

Trial IDs

Primary ID 2017-1081
Secondary IDs NCI-2017-02485
Clinicaltrials.gov ID NCT03325816