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A Pilot Study of Combination Immunotherapy With Ipilimumab and Nivolumab in Patients With Recurrent Extensive Stage Small Cell Lung Cancer (SCLC) Who Have Previously Received Platinum-based Chemotherapy

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ClinicalTrials.gov Identifier: NCT03670056
Recruitment Status : Not yet recruiting
First Posted : September 13, 2018
Last Update Posted : September 13, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Yale University

Brief Summary:
This is a pilot study of patients who previously received platinum chemotherapy with recurrent SCLC to evaluate the change in the ratio of intratumoral Teff/Treg cells and clinical benefit of treatment with nivolumab and ipilumumab.

Condition or disease Intervention/treatment Phase
Small Cell Lung Cancer Drug: Combination immunotherapy with Ipilimumab and Nivolumab Phase 2

Detailed Description:

The primary objective of this study is t assess whether the change in the ratio of effector T cells (Teff) to regulatory T cells (Treg), i.e. CD8 positive/FoxP3 expressing CD4 T cells, between pre- and on- treatment biopsies, will predict clinical response in patients with recurrent SCLC treated with combination therapy with nivolumab and ipilimumab.

Secondary bbjectives of the study include: to determine the objective response rate per RECIST 1.1 and immune-related response criteria, duration of response, progression free survival, and overall survival with nivolumab and ipilimumab in patients with recurrent SCLC; to evaluate changes in the tumor immune microenvironment and blood after treatment with ipilimumab and nivolumab; and to evaluate circulating tumor DNA (ctDNA) as a marker for response to therapy.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Combination Immunotherapy With Ipilimumab and Nivolumab in Patients With Recurrent Extensive Stage Small Cell Lung Cancer (SCLC) Who Have Previously Received Platinum-based Chemotherapy
Estimated Study Start Date : September 15, 2018
Estimated Primary Completion Date : September 30, 2020
Estimated Study Completion Date : September 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Nivolumab and Ipilumumab
Patients will be treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, starting on Day 1. Patients will receive 4 doses of each nivolumab and ipilimumab and then will receive nivolumab 240 mg starting week 13 (day 85) every 2 weeks until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.
Drug: Combination immunotherapy with Ipilimumab and Nivolumab
Patients will be treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg, starting on Day 1. Patients will receive 4 doses of each nivolumab and ipilimumab and then will receive nivolumab 240 mg starting week 13 (day 85) every 2 weeks until progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs first.




Primary Outcome Measures :
  1. Change in the ratio of Teff/Treg cells [ Time Frame: Up to 12 months ]
    The primary analysis will use the nonparametric Mann-Whitney sign test to compare the change in the ratio of Teff/Treg cells in those patients who respond or not to treatment. This test compares the rate of response in those with above and below Teff/Treg ratio.


Secondary Outcome Measures :
  1. Response rate [ Time Frame: Up to 12 months ]
    Objective response is defined as a complete or partial response, as determined by investigator assessment using RECIST v1.1 and immune-related response criteria (irRC) . Response will be confirmed by repeat assessments ≥4 weeks after initial documentation. Patients not meeting these criteria, including patients without any post baseline tumor assessment, will be considered non-responders in the analysis of objective response.

  2. Duration of response [ Time Frame: Up to 12 months ]
    Duration of response is defined as the time from the initial complete or partial response to the time of disease progression or death, whichever occurs first. If a patient does not experience death or disease progression before the end of the study, duration of response will be censored at the day of the last tumor assessment. If no tumor assessments were performed after the date of the first occurrence of a complete or partial response, duration of objective response will be censored at the date of the first occurrence of a complete or partial response plus 1 day.

  3. Progression-free survival [ Time Frame: Up to 12 months ]
    Progression-free survival (PFS) is defined as the time from the first day of treatment until progression of disease using RECIST v1.1 and immune-related response criteria (irRC) . If a patient has not experienced progressive disease or death, PFS will be censored at the day of the last tumor assessment. Patients with no post baseline tumor assessments will be censored at the date of first study treatment plus 1 day.


Other Outcome Measures:
  1. Change in ctDNA [ Time Frame: Up to 4 weeks ]
    Circulating tumor DNA (ctDNA) will be collected throughout the trial, including at 4 weeks, at the time of repeat biopsy. We will assess if the change in variant allele frequencies from baseline sample to the 4 week sample predicts response to therapy and correlate to objective response rate.

  2. Change in tumor microenvironment [ Time Frame: Up to 12 months ]
    Immunohistochemistry (IHC) and quantitative measurement (QiF) of fluorescent signals of tumor infiltrating lymphocytes after immunofluorescence statining of pre- and on-treatment biopsy samples will be used. The baseline and change in tumor microenvironment using IHC and QIF for tumor infiltrating lymphocytes will be evaluated.



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

Inclusion Criteria:

  • Histologically or cytologically documented ES-SCLC with documented disease progression after at least one prior systemic regimen, including one platinum-based regimen.
  • Patients previously diagnosed with limited stage SCLC treated with concurrent chemoradiation with a platinum doublet now diagnosed with recurrent extensive disease are eligible.
  • ECOG performance status of 0 to 2
  • Measurable disease with at least one tumor site amenable to biopsy
  • Patients may have untreated asymptomatic CNS metastases or treated CNS metastases if they are not currently receiving corticosteroids greater than dexamethasone 2 mg daily or equivalent for 7 days prior to the first dose of study drug. - Patients should have completed stereotactic radiation or whole-brain radiation at least 2 weeks prior to Cycle 1, Day 1.

Exclusion Criteria:

  • Patients with an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids > dexamethasone 2 mg daily (or equivalent dose of other corticosteroids) or other immunosuppressive agents.
  • Treatment with systemic immunosuppressive medications including but not limited to, dexamethasone at doses > 2 mg or equivalent dose of other corticosteroids, cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor (anti-TNF) agents within 2 weeks prior to initiation of trial therapy. Inhaled or topically applied steroids, and acute and chronic standard-dose NSAIDs are permitted. Replacement steroids are also permitted.
  • Prior treatment with anti-PD1, anti-PDL1 or anti-CTLA4 antibodies.
  • Symptomatic untreated CNS metastases. Patients with asymptomatic CNS metastases are eligible. Patients with symptomatic brain metastases are eligible, provided they meet all of the following criteria:

    • Completed stereotactic radiosurgery or whole- brain radiation at least 2 weeks prior to Cycle 1, Day 1.
    • No evidence of interim progression between the completion of CNS-directed therapy and the start of trial therapy.
    • No ongoing requirement for steroids greater than dexamethasone 2 mg daily (or equivalent dose of other corticosteroids) as therapy for CNS disease; anticonvulsants at a stable dose are allowed.
  • History of leptomeningeal carcinomatosis.
  • Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
  • Any systemic anti-cancer chemotherapy, within 21 days prior to initiation of study treatment.
  • Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 21 days prior to enrollment.
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Major surgery or traumatic injury within 4 weeks of starting study drug.
  • Women who are pregnant or lactating.
  • Known infection with HIV, HBV or HCV. Patients with prior exposure to hepatitis, but no evidence of active or chronic infection, may be eligible.
  • Evidence of end-organ damage as defined by the following laboratory results obtained within 14 days prior to the first study treatment:

    • ANC <1,000 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1).
    • Platelet count <75,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1).
    • Hemoglobin <8.0 g/dL (Patients may be transfused to meet this criterion).
    • AST and ALT ≥2.5 x ULN, with the following exceptions: Patients with documented liver metastases: AST and/or ALT≥5 x ULN.
    • Serum bilirubin ≥1.5 x ULN (Patients with known Gilbert disease who have serum bilirubin level ≥3 x ULN may be enrolled).
    • INR and aPTT ≥1.5 x ULN (This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose).

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): NCT03670056


Contacts
Contact: Kira Pavlik, MPH, CCRP (203) 785-6540 Kira.Pavlik@yale.edu
Contact: Anne Chiang, MD, PhD (203) 785-1689 anne.chiang@yale.edu

Locations
United States, Connecticut
Yale University, Yale Cancer Center Not yet recruiting
New Haven, Connecticut, United States, 06510
Contact: Kira Pavlik, MPH, CCRP    203-785-6540    Kira.Pavlik@yale.edu   
Contact: 24-Hour    (203) 200-5864      
Principal Investigator: Anne Chiang, MD, PhD         
Sponsors and Collaborators
Yale University
Bristol-Myers Squibb
Investigators
Principal Investigator: Anne Chiang, MD, PhD Yale University

Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03670056     History of Changes
Other Study ID Numbers: 2000023361
CA209-9YT ( Other Identifier: Bristol-Myers Squibb )
First Posted: September 13, 2018    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018

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

Keywords provided by Yale University:
combination immunotherapy
platinum-based chemotherapy

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
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs