Nivolumab With Ipilimumab in Subjects With Neuroendocrine... | NCT03420521

NCT03420521

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
IRB00151698	Other Identifier	JHM IRB

Status Module

Sponsor/Collaborators Module

Name	Class
Bristol-Myers Squibb	INDUSTRY

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Nivolumab plus Ipilimumab	Other	Nivolumab 240 mg IV over 60 minutes every 2 weeks (Q2W) Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks (Q6W)	Drug: Nivolumab Drug: Ipilimumab

Name	Type	Description	Arm Group Labels	Other Names
Nivolumab	Drug	240mg IV over 60 minutes Q2W	Nivolumab plus Ipilimumab

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Objective Response Rate (ORR) of Neuroendocrine Tumor (NET) of the Lung, Pancreas, and Gastrointestinal (GI) Tract	The number of subjects who have at least one scan with an Objective Response (OR) of confirmed complete response (CR) or partial response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions as assessed by CT scan: Objective Response (OR), a response of CR or PR from baseline to PD, palliative local therapy, or subsequent anticancer therapy; Complete Response (CR), the disappearance of all target lesions and any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm; Partial Response (PR), >= 30% decrease in the sum of the longest diameters of target lesions, compared to baseline sum diameters	up to 24 months

Secondary Outcomes

Measure	Description	Time Frame
Number of Patients Experiencing Drug-related Adverse Events	Safety as assessed by number of patients experiencing drug-related adverse events (safety and tolerability).	up to 27 months
Number of Patients Experiencing Dose-limiting Toxicities

Eligibility Module

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

Contacts/Locations Module

Name	Affiliation	Role
Christine Hann, MD/PhD	Johns Hopkins University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Johns Hopkins Medical Institution		Baltimore	Maryland	21287	United States

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

Arm/Group Information

ID	Title	Description
FG000	Nivolumab Plus Ipilimumab	Nivolumab 240mg IV over 60 minutes every 2 weeks (Q2W) Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks (Q6W) Nivolumab: 240mg IV over 60 minutes Q2W Ipilimumab: 1mg/kg IV over 30 minutes Q6W

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Nivolumab Plus Ipilimumab	Nivolumab-240 mg IV over 60 minutes Q2W Ipilimumab 1mg/kg IV over 30 minutes Q6W Nivolumab: 240mg IV over 60 minutes Q2W Ipilimumab: 1mg/kg IV over 30 minutes Q6W

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Objective Response Rate (ORR) of Neuroendocrine Tumor (NET) of the Lung, Pancreas, and Gastrointestinal (GI) Tract

The number of subjects who have at least one scan with an Objective Response (OR) of confirmed complete response (CR) or partial response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions as assessed by CT scan: Objective Response (OR), a response of CR or PR from baseline to PD, palliative local therapy, or subsequent anticancer therapy; Complete Response (CR), the disappearance of all target lesions and any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm; Partial Response (PR), >= 30% decrease in the sum of the longest diameters of target lesions, compared to baseline sum diameters

One patient passed away during cycle 1 of therapy, from unrelated issue (colitis, not related to study drug) prior to first RECIST scans, thus was not assessable for ORR, DCR or DOR.

Posted

Count of Participants

Participants

up to 24 months

ID	Title	Description

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Nivolumab Plus Ipilimumab	Nivolumab-240 mg IV over 60 minutes Q2W Ipilimumab 1mg/kg IV over 30 minutes Q6W Nivolumab: 240mg IV over 60 minutes Q2W Ipilimumab: 1mg/kg IV over 30 minutes Q6W

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Colitis	Gastrointestinal disorders		Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anemia	Blood and lymphatic system disorders		Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Dr. Christine Hann	Johns Hopkins University	410-502-0678		chann1@jh.edu

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Nov 23, 2021	Oct 26, 2023	Prot_SAP_000.pdf

Submission Tracking

Condition Browse Module

ID	Term
D018358	Neuroendocrine Tumors
D002276	Carcinoid Tumor

ID	Term
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009369	Neoplasms

Intervention Browse Module

ID	Term
D000077594	Nivolumab
D000074324	Ipilimumab

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins

Masking Info

Bristol Myers Squibb (BMS), BMS-936558

Safety as assessed by number of patients experiencing dose-limiting toxicities (safety and tolerability).

EG0001 affected9 at risk

EG0007 events5 affected9 at risk