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
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Objective Response Rate of neuroendocrine tumor (NET) of the lung
Secondary Outcome
Safety as assessed by number of treatment-emergent adverse events
Condition
Neuroendocrine Tumors
Intervention
Nivolumab
Study Arms / Comparison Groups
Nivolumab plus Ipilimumab
Description: Nivolumab-240 mg IV over 60 minutes Q2W Ipilimumab 1mg/kg IV over 30 minutes Q6W
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
64
Start Date
March 9, 2018
Completion Date
January 15, 2024
Primary Completion Date
January 15, 2023
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 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
Gender
All
Ages
18 Years - 100 Years
Accepts Healthy Volunteers
No
Contacts
Christine Hann, MD/PhD, 410-502-0678, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT03420521
Organization ID
J17156
Secondary IDs
IRB00151698
Responsible Party
Sponsor
Study Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Bristol-Myers Squibb
Study Sponsor
Christine Hann, MD/PhD, Principal Investigator, Johns Hopkins University
Verification Date
December 2019