Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors

Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03420521
Collaborator
Bristol-Myers Squibb (Industry)
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Study Details

Study Description

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 Nivolumab 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
9 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-Label, Single Arm Phase II Study of Nivolumab in Combination With Ipilimumab in Subjects With Advanced Neuroendocrine Tumors
Actual Study Start Date :
Mar 9, 2018
Anticipated Primary Completion Date :
May 1, 2023
Anticipated Study Completion Date :
May 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Other: Nivolumab plus Ipilimumab

Nivolumab-240 mg IV over 60 minutes Q2W Ipilimumab 1mg/kg IV over 30 minutes Q6W

Drug: Nivolumab
240mg IV over 60 minutes Q2W

Drug: Ipilimumab
1mg/kg IV over 30 minutes Q6W

Outcome Measures

Primary Outcome Measures

  1. Objective Response Rate of neuroendocrine tumor (NET) of the lung [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.

  2. Objective Response Rate of neuroendocrine tumor (NET) of the pancreas [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.

  3. Objective Response Rate of neuroendocrine tumor (NET) of the gastrointestinal (GI) tract [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.

Secondary Outcome Measures

  1. Safety as assessed by number of treatment-emergent adverse events [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.

  2. Safety as assessed by number of treatment dose interruptions [2 weeks post-intervention]

    Quantification of treatment dose interruptions in subjects with advanced well-differentiated nonfunctional NET of the lung, pancreas or GI tract.

  3. Efficacy as assessed by Progression Free Survival (PFS) at 6 months [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

  4. Efficacy as assessed by Progression Free Survival (PFS) at 12 months [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

  5. Efficacy as assessed by Progression Free Survival (PFS) at 24 months [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

  6. Median progression free survival [up to 2 years post-intervention]

    Median number months without disease progression

  7. Efficacy as assessed by disease control rate (DCR) [2 years post-intervention]

    Percentage of participants who achieve partial or complete response to combination of nivolumab and ipilimumab.

  8. Efficacy as assessed by Duration of Response (DOR) [Up to 2 years post-intervention]

    Number of months from documentation of tumor response to disease progression

  9. Efficacy as assessed by Overall Survival (OS) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 100 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Johns Hopkins Medical Institution Baltimore Maryland United States 21287

Sponsors and Collaborators

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Bristol-Myers Squibb

Investigators

  • Principal Investigator: Christine Hann, MD/PhD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier:
NCT03420521
Other Study ID Numbers:
  • J17156
  • IRB00151698
First Posted:
Feb 5, 2018
Last Update Posted:
May 27, 2022
Last Verified:
Dec 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of May 27, 2022