Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors
Condition: Neuroendocrine Tumors; Carcinoid Tumor
MeSH terms: Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor
Intervention: Nivolumab; Ipilimumab
Intervention description: 240mg IV over 60 minutes Q2W; 1mg/kg IV over 30 minutes Q6W
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No

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 Nivolumab 240mg IV over 60
      minutes every 2 weeks (Q2W) and Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks (Q6W). One
      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 progression
      free survival (PFS) will also be described.
    

Eligibility criteria:

        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 programmed
                  cell death ligand 1 (PD-L1) immunohistochemistry (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.

               -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (see Appendix 1)

               -  Prior palliative radiotherapy to non-central nervous system (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:

          -  - white blood cell (WBC) ≥1,500/microliters (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)

          -  - aspartate aminotransferase (AST)/alanine aminotransferase (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-cytotoxic
                  T-lymphocyte-associated protein 4 (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