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Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors

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ClinicalTrials.gov Identifier: NCT03420521
Recruitment Status : Recruiting
First Posted : February 2, 2018
Last Update Posted : September 23, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE November 30, 2017
First Posted Date  ICMJE February 2, 2018
Last Update Posted Date September 23, 2019
Actual Study Start Date  ICMJE March 9, 2018
Estimated Primary Completion Date January 15, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Objective Response Rate of neuroendocrine tumor (NET) of the lung [ Time Frame: 6 weeks post-intervention ]
    Proportion of participants with reduction in size of advanced, progressive, well-differentiated nonfunctional neuroendocrine tumor (NET) of the lung treated with nivolumab plus ipilimumab.
  • Objective Response Rate of neuroendocrine tumor (NET) of the pancreas [ Time Frame: 6 weeks post-intervention ]
    Proportion of participants with reduction in size of advanced, progressive, well-differentiated nonfunctional neuroendocrine tumor (NET) of the pancreas treated with nivolumab plus ipilimumab.
  • Objective Response Rate of neuroendocrine tumor (NET) of the gastrointestinal (GI) tract [ Time Frame: 6 weeks post-intervention ]
    Proportion of participants with reduction in size of advanced, progressive, well-differentiated nonfunctional neuroendocrine tumor (NET) of the gastrointestinal (GI) tract treated with nivolumab plus ipilimumab.
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
Response [ Time Frame: 6 weeks ]
1.1.1 To determine the objective response rate (ORR) of advanced, progressive, well-differentiated nonfunctional NET of the lung, pancreas or gastrointestinal (GI) tract treated with nivolumab plus ipilimumab.
Change History Complete list of historical versions of study NCT03420521 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Safety as assessed by number of treatment-emergent adverse events [ Time Frame: 2 weeks post-intervention ]
    Number of treatment-emergent adverse events (safety and tolerability) of nivolumab plus ipilimumab by characterization of toxicities in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract.
  • Safety as assessed by number of treatment dose interruptions [ Time Frame: 2 weeks post-intervention ]
    Quantification of treatment dose interruptions in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract.
  • Efficacy as assessed by Progression Free Survival (PFS) at 6 months [ Time Frame: 6 months post-intervention ]
    Efficacy via progression free survival (PFS) at 6 months of the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract
  • Efficacy as assessed by Progression Free Survival (PFS) at 12 months [ Time Frame: 12 months post-intervention ]
    Efficacy via progression free survival (PFS) at 12 months of the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract
  • Efficacy as assessed by Progression Free Survival (PFS) at 24 months [ Time Frame: 24 months post-intervention ]
    Efficacy via progression free survival (PFS) at 24 months of the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract
  • Median progression free survival [ Time Frame: up to 2 years post-intervention ]
    Median number months without disease progression
  • Efficacy as assessed by disease control rate (DCR) [ Time Frame: 2 years post-intervention ]
    Percentage of participants who achieve partial or complete response to combination of nivolumab and ipilimumab.
  • Efficacy as assessed by Duration of Response (DOR) [ Time Frame: Up to 2 years post-intervention ]
    Number of months from documentation of tumor response to disease progression
  • Efficacy as assessed by Overall Survival (OS) [ Time Frame: Up to 2 years post-intervention ]
    Number of months participants stay alive after treatment with the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2018)
  • Safety [ Time Frame: 2 weeks ]
    1.2.1 To assess safety and tolerability of nivolumab plus ipilimumab by quantification of treatment dose interruptions and characterization of toxicities of the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract.
  • Survival [ Time Frame: Total of 2 years (to be assessed at 6, 12 and 24 months) ]
    1.2.2 To assess efficacy via progression free survival (PFS) at 6 months, 12 and 24 months of the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract
  • Survival [ Time Frame: 2 years total ]
    1.2.3 To further assess efficacy via median progression free survival PFS
  • Survival [ Time Frame: 2 years total ]
    1.2.3 To further assess efficacy via disease control rate (DCR)
  • Survival [ Time Frame: 2 years total ]
    1.2.3 To further assess efficacy via duration of response (DOR)
  • Survival [ Time Frame: 2 years total ]
    1.2.3 To further assess efficacy via overall survival (OS) of the combination of nivolumab and ipilimumab in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors
Official Title  ICMJE An Open-Label, Single Arm Phase II Study of Nivolumab in Combination With Ipilimumab in Subjects With Advanced Neuroendocrine Tumors
Brief Summary This is a single arm open-label design study looking at Nivolumab plus Ipilimumab in patients with Advanced Neuroendocrine Tumors. Patients will be dosed Nivoluma 240mg IV over 60 minutes every 2 weeks and Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks. Once cycle will include 3 doses of Nivolumab and 1 dose of Ipilimumab. The objective of this study is to evaluate the objective response rate of combination nivolumab and ipilimumab in advanced, well-differentiated neuroendocrine tumors. Durability of response, and PFS will also be described.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Neuroendocrine Tumors
  • Carcinoid Tumor
Intervention  ICMJE
  • Drug: Nivolumab
    240mg IV over 60 minutes Q2W
  • Drug: Ipilimumab
    1mg/kg IV over 30 minutes Q6W
Study Arms  ICMJE Nivolumab plus Ipilimumab
Nivolumab-240 mg IV over 60 minutes Q2W Ipilimumab 1mg/kg IV over 30 minutes Q6W
Interventions:
  • Drug: Nivolumab
  • Drug: Ipilimumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 26, 2018)
64
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 15, 2024
Estimated Primary Completion Date January 15, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects with histologically confirmed advanced, progressive, well-differentiated nonfunctional NET of the pancreas, lung or gastrointestinal (GI) tract per the 8th International Association for the Study of Lung Cancer classification (IASLC) or the American Joint Committee on Cancer (AJCC) Staging Handbook, 7th edition. Progression must be documented over the prior 12 months.

    • Measurable disease by CT or MRI per RECIST 1.1 criteria (Appendix 3); radiographic tumor assessment performed within 28 days before treatment. Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy.
    • Prior therapy, including everolimus, octreotide, surgery, chemoradiation, is all permitted after being properly noted. This prior therapy must have been completed at least 28 days prior to study enrollment.
    • Patients with lung NETs must have progressed after at least 1 line of therapy. Patients with GI NETs must have had at least 2 lines of prior therapy.
    • Subjects are to have tumor tissue sample available at central lab for PD -L1 IHC testing during the screening period. Subjects can initiate therapy before the result of IHC testing.
    • (Stage 2 only) Subjects must be willing to undergo 2 sets of core needle biopsies (pre-treatment and at 6-8 weeks on therapy) if there are lesions amenable to biopsy. Subjects without a lesion amendable to biopsy will still be permitted to enroll provided they have an archival tumor sample for PD-L1 IHC testing. An optional core biopsy will be requested at progression.
    • ECOG performance status ≤ 1 (see Appendix 1)
    • Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to treatment. Subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of first treatment are strongly encouraged to receive palliative radiotherapy prior to treatment.
    • Patients must have normal organ and marrow function as defined below:
  • - WBC ≥1,500/mcL
  • - absolute neutrophil count ≥1,000/mcL
  • - hemoglobin ≥ 8.0 g/dL
  • - platelets ≥75,000/mcL
  • - total bilirubin ≤ 1.5 x institutional ULN (patients with Gilbert's syndrome may have serum bilirubin ≤ 3 x ULN)
  • - AST/ALT ≤ 3 × institutional ULN (≤ 5 x ULN in the presence of liver metastases)

    - creatinine

  • ≤ 1.5 × institutional ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
  • Female:
  • CrCl = (140 - age in years) x weight in kg x 0.85

    o 72 x serum creatinine in mg/dL

  • Male:
  • CrCl = (140 - age in years) x weight in kg x 1.00

    - 72 x serum creatinine in mg/dL

    • Age ≥18 years of age
    • Patients must have recovered from adverse events due to prior treatment to ≤ grade 1, except for alopecia and sensory neuropathy ≤ grade 2.
    • Patients must be able to understand and the willingness to sign a written informed consent document.
  • Exclusion Criteria:

    • Subjects with poorly differentiated or small cell carcinoma histology
    • Subjects with disease that is amenable to surgical resection.
    • Subjects with history of or active symptoms of carcinoid or hormonal syndromes are permitted if symptoms are controlled with a somatostatin analog.
    • Hepatic intra-arterial embolization or peptide receptor radionuclide therapy (PRRT) within 4-8 weeks; cryoablation, radiofrequency ablation or trans-arterial chemoembolization of hepatic metastases within ≤ 4 weeks of study enrollment
    • Subjects with symptomatic untreated CNS metastases are excluded.
    • Subjects are eligible if CNS metastases are asymptomatic or adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to first treatment.
    • In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first treatment.
    • Subjects with carcinomatous meningitis
    • Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before first treatment.
    • Pregnant or breast-feeding women
    • Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception. Highly effective contraception must be used throughout the trial and up to 8 weeks after the last dose of study drug (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study drug.
    • Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    • Other active malignancy requiring concurrent intervention.
    • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. Inhaled or topical steroids, and adrenal replacement steroid 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
    • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
    • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    • Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interferes with the interpretation of safety results.
    • 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 co-stimulation or checkpoint pathways
    • Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
    • History of allergy or hypersensitivity to study drug components
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Christine Hann, MD/PhD 410-502-0678 chann1@jhmi.edu
Contact: Stella Krawiec 410-502-1962 skrawie1@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03420521
Other Study ID Numbers  ICMJE J17156
IRB00151698 ( Other Identifier: JHM IRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Christine Hann, MD/PhD Johns Hopkins University
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP