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Neuroendocrine TumorsPhase 2NCT03420521

Nivolumab With Ipilimumab in Subjects With Neuroendocrine Tumors

A Phase 2 study testing Nivolumab and Ipilimumab in people with Neuroendocrine Tumors and Carcinoid Tumor, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 100 years
Conditions the study is for
Neuroendocrine Tumors, Carcinoid Tumor
What is being tested?
Nivolumab and Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
1 siteUnited States
Study dates
9 Mar 2018to 24 Nov 2021
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 100 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Johns Hopkins Medical Institution

    Baltimore, Maryland, 21287

Other trials in United States

About this study

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

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.

Read the detailed description

Subjects with progressive, non-functional advanced or metastatic thoracic, GI or pancreatic well-differentiated neuroendocrine tumors (NET) have few treatment options. The only FDA approved treatment regimen offers little response potential. In currently unpublished data with inhibitory immune checkpoint agents, patients with NET have shown promising clinical benefit. This therapy offers a novel approach to potentially provide long term benefit, but must be further explored. The safety profile of nivolumab plus ipilimumab is characterized by immune-related toxicities, such as diarrhea, rash, pneumonitis, liver toxicity, and endocrinopathies (Nivolumab, Ipilimumab Investigator's Brochures). The frequencies and intensities of these events in the combination are variable and depend on the specific doses and schedule used. In the dosing schedules selected, these events were mostly low grade and manageable with the use of corticosteroids. Nivolumab and ipilimumab combination therapy has shown improved efficacy over either agent alone in melanoma. Rationale for Single Arm Design This study will use a single arm open-label design. 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.

Being tested
Nivolumab, Ipilimumab
Medical subject headings
Neuroendocrine Tumors, Carcinoid Tumor

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NivolumabDrug

    Also called Bristol Myers Squibb (BMS), BMS-936558

    240mg IV over 60 minutes Q2W

  • IpilimumabDrug

    Also called Bristol Myers Squibb (BMS), BMS-734016

    1mg/kg IV over 30 minutes Q6W

Study groups in NCT03420521
Study groupRoleWhat they receive
Nivolumab plus IpilimumabOtherNivolumab 240 mg IV over 60 minutes every 2 weeks (Q2W) Ipilimumab 1mg/kg IV over 30 minutes every 6 weeks (Q6W)
Receives: Drug: Nivolumab; Drug: Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: up to 24 months

Secondary outcomes (9)

  1. Number of Patients Experiencing Drug-related Adverse Events

    Safety as assessed by number of patients experiencing drug-related adverse events (safety and tolerability).

    Measured: up to 27 months

  2. Number of Patients Experiencing Dose-limiting Toxicities

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

    Measured: up to 24 months

  3. Progression Free Survival (PFS) at 6 Months

    Percentage of patients treated with nivolumab and ipilimumab with no progressive disease (PD) at 6 months using Kaplan Meier estimate, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan: Progressive Disease (PD), >= 20% increase in sum of target lesions' diameters, compared to smallest sum on study (including baseline sum, if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of new lesions.

    Measured: 6 months

  4. Progression Free Survival (PFS) at 12 Months

    Percentage of patients treated with nivolumab and ipilimumab with no progressive disease (PD) at 12 months using Kaplan Meier estimate, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan: Progressive Disease (PD), >= 20% increase in sum of target lesions' diameters, compared to smallest sum on study (including baseline sum, if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of new lesions.

    Measured: 12 months

  5. Progression Free Survival (PFS) at 24 Months

    Percentage of patients treated with nivolumab and ipilimumab with no progressive disease (PD) at 24 months using Kaplan Meier estimate, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan: Progressive Disease (PD), >= 20% increase in sum of target lesions' diameters, compared to smallest sum on study (including baseline sum, if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of new lesions.

    Measured: 24 months

  6. Median Progression Free Survival (PFS)

    Time (months) from date of randomization to progressive disease (PD) or death, whichever comes first, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan: Progressive Disease (PD), >= 20% increase in sum of target lesions' diameters, compared to smallest sum on study (including baseline sum, if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of new lesions.

    Measured: approximately 3 years 8 months

  7. Efficacy as Assessed by Disease Control Rate (DCR)

    The number of subjects who have at least one scan with best overall response (BOR) of confirmed complete response (CR), partial response (PR), or stable disease (SD), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions as assessed by CT scan: Best Overall Response (BOR), best response (CR, PR, or SD) 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; Stable Disease (SD), <20% increase, <30% decrease in the sum of the longest diameter of target lesions, no measurable increase in non-target lesions, and no new lesions.

    Measured: approximately 3 years 8 months

  8. Efficacy as Assessed by Duration of Response (DOR)

    Time (months) from best overall response (BOR) of complete response (CR) or partial response (PR) to progressive disease (PD), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions by CT scan: Best Overall Response (BOR), best response (CR, PR, or SD) 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; Progressive Disease (PD), >= 20% increase in sum of target lesions' diameters, compared to smallest sum on study (including baseline sum, if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of new lesions.

    Measured: approximately 3 years 8 months

  9. Efficacy as Assessed by Overall Survival (OS)

    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

    Measured: approximately 3 years 8 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Feb 2018
  2. Study start9 Mar 2018
  3. Primary completion24 Nov 2021
  4. Study completion24 Nov 2021

Why it stopped: Loss of funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03420521
Sponsor's protocol ID
J17156
Other IDs
IRB00151698
Status last verified
Dec 2023
First submitted
30 Nov 2017
Last updated
9 Jan 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab and Ipilimumab in people with Neuroendocrine Tumors and Carcinoid Tumor, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response Rate (ORR) of Neuroendocrine Tumor (NET) of the Lung, Pancreas, and Gastrointestinal (GI) Tract (time frame: up to 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03420521.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2024.

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