Clinical Trials /

Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors

NCT03420521

Description:

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.

Related Conditions:
  • Gastrointestinal Neuroendocrine Tumors
  • Lung Neuroendocrine Neoplasm
  • Pancreatic Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors
  • Official Title: An Open-Label, Single Arm Phase II Study of Nivolumab in Combination With Ipilimumab in Subjects With Advanced Neuroendocrine Tumors

Clinical Trial IDs

  • ORG STUDY ID: J17156
  • SECONDARY ID: IRB00151698
  • NCT ID: NCT03420521

Conditions

  • Neuroendocrine Tumors
  • Carcinoid Tumor

Interventions

DrugSynonymsArms
NivolumabNivolumab plus Ipilimumab
IpilimumabNivolumab plus Ipilimumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Nivolumab plus IpilimumabOtherNivolumab-240 mg IV over 60 minutes Q2W Ipilimumab 1mg/kg IV over 30 minutes Q6W
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

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

               -  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.

               -  Previously untreated patients who decline standard therapy for their cancer are
                  allowed to enroll.

               -  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. The tumor tissue sample must be a core needle biopsy,
                  excisional or incisional biopsy. It may be fresh or archival if obtained within 6
                  months prior to enrollment, and there can have been no systemic therapy (e.g.,
                  adjuvant or neoadjuvant chemotherapy) given after the sample was obtained.

               -  (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 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 × 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 syndrome

               -  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
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate of neuroendocrine tumor (NET) of the lung
Time Frame:6 weeks post-intervention
Safety Issue:
Description:Proportion of participants with reduction in size of advanced, progressive, well-differentiated nonfunctional neuroendocrine tumor (NET) of the lung treated with nivolumab plus ipilimumab.

Secondary Outcome Measures

Measure:Safety as assessed by number of treatment-emergent adverse events
Time Frame:2 weeks post-intervention
Safety Issue:
Description: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.
Measure:Safety as assessed by number of treatment dose interruptions
Time Frame:2 weeks post-intervention
Safety Issue:
Description:Quantification of treatment dose interruptions in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract.
Measure:Efficacy as assessed by Progression Free Survival (PFS) at 6 months
Time Frame:6 months post-intervention
Safety Issue:
Description: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
Measure:Efficacy as assessed by Progression Free Survival (PFS) at 12 months
Time Frame:12 months post-intervention
Safety Issue:
Description: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
Measure:Efficacy as assessed by Progression Free Survival (PFS) at 24 months
Time Frame:24 months post-intervention
Safety Issue:
Description: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
Measure:Median progression free survival
Time Frame:up to 2 years post-intervention
Safety Issue:
Description:Median number months without disease progression
Measure:Efficacy as assessed by disease control rate (DCR)
Time Frame:2 years post-intervention
Safety Issue:
Description:Percentage of participants who achieve partial or complete response to combination of nivolumab and ipilimumab.
Measure:Efficacy as assessed by Duration of Response (DOR)
Time Frame:Up to 2 years post-intervention
Safety Issue:
Description:Number of months from documentation of tumor response to disease progression
Measure:Efficacy as assessed by Overall Survival (OS)
Time Frame:Up to 2 years post-intervention
Safety Issue:
Description: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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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