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Single Agent Chemotherapy +/- Nivolumab in Patients With Advanced Squamous or Non-squamous NSCLC With Primary Resistance to Prior PD-1 or PDL-1 Inhibitor

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ClinicalTrials.gov Identifier: NCT03041181
Recruitment Status : Recruiting
First Posted : February 2, 2017
Last Update Posted : June 5, 2018
Sponsor:
Collaborators:
Hoosier Cancer Research Network
Bristol-Myers Squibb
Information provided by (Responsible Party):
Nasser Hanna, M.D., Hoosier Cancer Research Network

Brief Summary:

This is a randomized phase II study assessing the activity of single agent chemotherapy combined with nivolumab (Arm A) compared to single agent chemotherapy alone (Arm B) in squamous or non-squamous NSCLC subjects with primary resistance to prior PD-1 or PDL-1 inhibitor. The single agent chemotherapy chosen is at the discretion of the site investigator and may include pemetrexed, gemcitabine or taxotere. Institutional standards should be used for administration of the single agent chemotherapy. For both treatment arms, 21 days equals 1 cycle of therapy and subjects will be eligible to continue treatment until progressive disease by RECIST v1.1 or unacceptable toxicity.

Upon registration, subjects will be randomized in a 1:1 ratio to either treatment with single agent chemotherapy or single agent chemotherapy in combination with nivolumab. Randomization is un-blinded and open-label; therefore there will be no placebo treatment for subjects randomized to single agent chemotherapy


Condition or disease Intervention/treatment Phase
Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Adenocarcinoma of the Lung Lung Cancer Squamous Cell Lung Cancer Drug: Docetaxel Drug: Nivolumab Drug: Gemcitabine Drug: Pemetrexed Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Open-Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Single Agent Chemotherapy Plus Nivolumab or Single Agent Chemotherapy Alone in Patients With Advanced Squamous or Non-squamous NSCLC With Primary Resistance to Prior PD-1 or PDL-1 Inhibitor
Actual Study Start Date : January 27, 2017
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A

Single Agent Chemotherapy of choice plus nivolumab:

Taxotere Pemetrexed Gemcitabine

Drug: Docetaxel
Docetaxel 75 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Other Name: Taxotere

Drug: Nivolumab
Nivolumab 360 mg IV Day 1 of each cycle (21 days = 1 cycle)
Other Names:
  • BMS-936558-01
  • Opdivo

Drug: Gemcitabine
Gemcitabine 1000 mg/m2 IV Day 1 and Day 8 of each cycle (21 days = 1 cycle)
Other Name: Gemzar

Drug: Pemetrexed
Pemetrexed 500 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Other Name: Alimta

Active Comparator: Arm B
Single Agent Chemotherapy of choice Taxotere Pemetrexed Gemcitabine
Drug: Docetaxel
Docetaxel 75 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Other Name: Taxotere

Drug: Gemcitabine
Gemcitabine 1000 mg/m2 IV Day 1 and Day 8 of each cycle (21 days = 1 cycle)
Other Name: Gemzar

Drug: Pemetrexed
Pemetrexed 500 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Other Name: Alimta




Primary Outcome Measures :
  1. Progression free survival (PFS), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. [ Time Frame: 24 months ]
    Compare PFS rates for subjects on each treatment arm, per RECIST 1.1. Subjects who have not progressed will be right-censored at the date of the last follow up.


Secondary Outcome Measures :
  1. Overall Response rate (ORR) for subjects on each treatment arm, as defined by RECIST 1.1 and immune-related response criteria (irRECIST) [ Time Frame: Every 6 weeks beginning with C3D1 and every odd numbered cycle thereafter, assessed for up to 24 months ]
    Proportion of subjects on each arm with complete response or partial response, per RECIST 1.1 and irRECIST

  2. Clinical benefit rate (CBR) for subjects on each treatment arm, as defined by RECIST 1.1 and irRECIST [ Time Frame: From D1 of treatment until documented disease progression/recurrence, assessed for up to 24 months ]
    Proportion of subjects on each arm with complete response, partial response or stable disease for at least 3 months, per RECIST 1.1 and irRECIST

  3. Progression free survival (PFS), as defined by irRECIST [ Time Frame: 24 months ]
    Compare PFS rates for subjects on each treatment arm, per irRECIST. From date of randomization until the criteria for disease progression is met or death as a result of any cause, assessed up to 24 months

  4. Assess adverse events [ Time Frame: 24 months ]
    Assess toxicity of Nivolumab plus single agent chemotherapy compared with single agent chemotherapy alone. Grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.



Information from the National Library of Medicine

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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:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

  1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  2. Age ≥ 18 years at the time of consent.
  3. ECOG Performance Status of 0-2 within 28 days prior to randomization.
  4. Histological or cytological confirmed squamous or non-squamous non-small cell lung cancer.
  5. Measurable disease according to RECIST 1.1 within 28 days prior to randomization.
  6. A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to randomization, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic.
  7. Subjects must have primary resistance to PD-1 or PDL-1 inhibitors; defined as PD after 3 or fewer treatments with a PD-1 or PDL-1 inhibitor
  8. Subjects must have progressed on or after previous platinum-based chemotherapy. Chemotherapy may have previously been given with a PD-1 or PD-L1 inhibitor. Subjects must have also progressed on or after receiving any PD-1 or PD-L1 inhibitor (including nivolumab) as their most recent therapy.
  9. Most recent PD-1 or PD-L1 inhibitor infusion must be completed at least 6 weeks of randomization. The subject must have recovered from all reversible acute toxic effects (other than alopecia) to ≤ Grade 1 or baseline.
  10. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to randomization.

    White blood cell (WBC) ≥ 2 k/mm3 Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3 Hemoglobin (Hgb) ≥ 9 g/dL Platelet >100k Estimated creatinine clearance OR ≥ 40 cc/min Serum creatinine ≤ 1.5 x upper limit of normal (ULN) Bilirubin 1.5 ≤ (ULN)2 Aspartate aminotransferase (AST) ≤ 1.5 × ULN Alanine aminotransferase (ALT) ≤ 1.5 × ULN International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 2 × ULN (Note: use of vitamin K antagonist is not allowed)

  11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to registration. These women must also have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab then every 6 weeks thereafter. NOTE: Women are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are post-menopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL.
  12. Women of childbearing potential must be willing to abstain from heterosexual activity or use an effective method of contraception from the time of informed consent until 5 months after treatment discontinuation. Women cannot breast feed from the time of informed consent to 5 months after last dose of study treatment. See below for adequate methods of contraception.
  13. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. See below for methods of contraception.
  14. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria

  1. Prior treatment with the single agent chemotherapy the site investigator chooses to use for this protocol (pemetrexed, taxotere or gemcitabine).
  2. Previous autoimmune complication from PD-1 or PD-L1 requiring discontinuation of therapy or treatment with steroids (ongoing treatment with more than 10 mg of prednisone or steroid equivalent daily, excluding inhaled or topical steroids).
  3. Previous discontinuation from PD-1 or PD-L1 due to an adverse event.
  4. Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy.
  5. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
  6. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.
  7. Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for [lowest minimum is 4 weeks or more] after treatment is complete and within 28 days prior to the first dose of Nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
  8. Treatment with any investigational drug within 30 days prior to registration.
  9. Subjects whose tumors express EGFR mutations on exons 19 and 21, ALK rearrangement, or ROS1 rearrangement who still have other FDA approved targeted agents available for treatment.
  10. Subjects with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with vitiligo, autoimmune thyroiditis, or type I diabetes mellitus are permitted to enroll.)
  11. As there is potential for hepatic toxicity with Nivolumab, drugs with a predisposition to hepatoxicity should be used with caution in subjects treated with Nivolumab-containing regimen.
  12. Subjects should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  13. Subjects should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  14. History of allergy to study drug components.
  15. Prior solid organ or stem cell transplant

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): NCT03041181


Contacts
Contact: Donna Sullivan 317.634.5842 ext 40 dsullivan@hoosiercancer.org
Contact: Nasser Hanna, M.D. 317.656.4260 nhanna@iu.edu

Locations
United States, Indiana
St. Vincent Anderson Regional Hospital Recruiting
Anderson, Indiana, United States, 46016
Contact: Kellie Ballman    765-648-4106    kellie.ballman@ascension.org   
Principal Investigator: Praveen Ranaganath, MD         
Indiana University Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Nasser Hanna, M.D.       nhanna@iu.edu   
Contact: Maggie Uhrich    317-274-4505    muhrich@iu.edu   
IU Health Central Indiana Cancer Center Recruiting
Indianapolis, Indiana, United States, 46219
Contact: Melody Sands    317-678-2700    MSands1@iuhealth.org   
Principal Investigator: Andrew Greenspan, MD         
Community Regional Cancer Care Recruiting
Indianapolis, Indiana, United States, 46256
Contact: Kelly Verel    317-497-2836    KVerel@ecommunity.com   
Principal Investigator: Radhika Walling, MD         
IU Health Ball Memorial Hospital Cancer Center Recruiting
Muncie, Indiana, United States, 47303
Contact: Stacey Cadogan    765-281-2030    scadogan@iuhealth.org   
Principal Investigator: William Fisher, MD         
United States, Texas
University of Texas Medical Branch at Galveston Recruiting
Galveston, Texas, United States, 77555
Contact: Renee Brown    409-772-9583    renbrown@utmb.edu   
Principal Investigator: Maurice Willis, MD         
Sponsors and Collaborators
Nasser Hanna, M.D.
Hoosier Cancer Research Network
Bristol-Myers Squibb
Investigators
Principal Investigator: Nasser Hanna, M.D. Hoosier Cancer Research Network

Additional Information:
Responsible Party: Nasser Hanna, M.D., Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03041181     History of Changes
Other Study ID Numbers: HCRN LUN15-233
First Posted: February 2, 2017    Key Record Dates
Last Update Posted: June 5, 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
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Nasser Hanna, M.D., Hoosier Cancer Research Network:
Nivolumab
BMS-936558-01
Anti-PD-1 Antibody
Docetaxel
Pemetrexed
Gemcitabine

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gemcitabine
Pemetrexed
Docetaxel
Nivolumab
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators