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Advanced Solid TumorsPhase 2NIMBLeNCT03461952

Nivolumab Ipilimumab in Patients With hyperMutated Cancers Detected in Blood (NIMBLe)

A Phase 2 study testing Nivolumab and Ipilimumab in people with Advanced Solid Tumors, run by Canadian Cancer Trials Group at 6 sites in 2 countries.

Terminated

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

Official record
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Trial summary

The purpose of this study is to determine the safety and effectiveness of nivolumab alone or in combination with ipilimumab in patients with metastatic or unresectable tumors harbouring mutations in genes, POLE and POLD1. These mutations will be determined by plasma cfDNA. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Solid Tumors
What is being tested?
Nivolumab and Ipilimumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
6 sitesin 2 countries
Study dates
11 Mar 2019to 9 Feb 2022
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 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have histologically confirmed advanced (metastatic or unresectable) solid tumors.
  • Patients must have received at least 1 standard cancer therapy for their tumor type and progressed on their most recent regimen; patients may be treatment naïve if they refuse standard treatment or there is no standard treatment for their cancer.
  • Prior adjuvant/neoadjuvant therapy with curative intent is considered a prior therapy if disease recurrence occurs within at least 6 months.
  • Patients may not have received prior immunotherapy
  • Patients must consent to blood collection for testing after registration by a central reference laboratory.
  • Patients must have clinically and/or radiologically documented disease with at least one lesion measurable as defined by RECIST 1.1.
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  • Patients must be ≥ 18 years of age.
  • ECOG performance status 0 or 1.
  • Patients must have adequate hematology and organ function
  • Patient consent for screening must be appropriately obtained in accordance with applicable local and regulatory requirements.
  • Patients must have solid tumors that demonstrate POLE or POLD1 mutations identified at study entry via plasma cfDNA testing or tumor tissue testing for POLE and POLD1 mutations. A CLIA-certified testing of tumor tissue demonstrating POLE or POLD1 mutation can qualify for eligibility and randomization, however, plasma will be submitted for central cfDNA testing. In the event of discordance between tissue and central laboratory testing, the patient will continue in study but will not be included in the primary analysis. These patients will however be included in the secondary analysis.
  • Patients must have recovered to ≤ grade 1 from all reversible toxicity related prior systemic or radiation therapy and have a 2 weeks washout.
  • Previous major surgery is permitted provided that it has been at least 28 days prior to patient registration and that wound healing has occurred.
  • White Blood Cells ≥ 2.0 x 109/L (2000/µL)
  • Absolute neutrophils ≥ 1.5 x 109/L (1500/µL)
  • Platelets ≥ 100 x 10^9/L (100 x103/µL)
  • Hemoglobin ≥80 g/L* (8.0 g/dL)
  • Bilirubin ≤ 1.5 x ULN (upper limit of normal)**
  • AST and/or ALT ≤ 3 x ULN
  • Serum creatinine ≤ 1.5 x ULN or: Creatinine clearance ≥40 mL/min
  • Patients must be willing to consent to provision of archival tissue
  • Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements
  • Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the trial.
  • In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient randomization.
  • Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must have agreed to use a highly effective contraceptive method

Who cannot join

  • Patients with a history of other untreated malignancies or malignancies, which required therapy within the past 2 years. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be eligible after consultation with the CCTG.
  • Patients with primary CNS tumors are not eligible.
  • Patients with active brain metastases or leptomeningeal metastases are not eligible. Patients with brain metastases are eligible if these have been treated and clinically stable. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents). Physiologic replacement doses of systemic corticoidsteroids are permitted, even if >10mg/day prednisone equivalents
  • History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 14 days of study drug administration*
  • Active or prior documented autoimmune or inflammatory disorders. Including, inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions considered to be of low risk for recurrence are permitted to enroll.
  • History of hypersensitivity to nivolumab or ipilimumab or any excipient.
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  • Any previous treatment with a PD-1 or anti-PD-L1, anti-PD-L2 inhibitor, including nivolumab or an anti-CTLA4, including ipilimumab, or drug specifically targeting T-cell stimulation or immune checkpoint pathways.
  • Patients with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol (including corticosteroid administration), or would put the patient at risk. This includes but is not limited to:
  • History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements.
  • Active infection requiring systemic therapy; (including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or tuberculosis or any infection requiring systemic therapy).
  • Active peptic ulcer disease or gastritis
  • Active pneumonitis.
  • Patients receiving concurrent treatment with other anti-cancer therapy or other investigational anti-cancer agents.
  • Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects).
  • Pregnant or lactating women.
  • Men who are sexually active with women of childbearing potential and women of childbearing potential must agree to use adequate contraception.

Trial locations and contacts

6 sites in 2 countries.

6 sites in 2 countries

Canada5 sites

  • Tom Baker Cancer Centre

    Calgary, Alberta, T2N 4N2

  • Juravinski Cancer Centre at Hamilton Health Sciences

    Hamilton, Ontario, L8V 5C2

  • Ottawa Hospital Research Institute

    Ottawa, Ontario, K1H 8L6

  • University Health Network

    Toronto, Ontario, M5G 2M9

  • BCCA - Vancouver Cancer Centre

    Vancouver, British Columbia, V5Z 4E6

Other trials in Canada

United States1 site

  • Columbia University Medical Center

    New York, New York, 10032

Other trials in United States

About this study

Official title: A Phase II Open Label, Randomized Non-Comparative Trial of Nivolumab Alone or in Combination With Ipilimumab for the Treatment of Patients With Advanced Hypermutated Solid Tumors Detected by a Blood Based Assay

The purpose of this study is to determine the safety and effectiveness of nivolumab alone or in combination with ipilimumab in patients with metastatic or unresectable tumors harbouring mutations in genes, POLE and POLD1. These mutations will be determined by plasma cfDNA. Nivolumab and ipilimumab have been given to patients across multiple types of cancer, and safe doses and schedules have been determined.

Read the detailed description

Participants in this study have been diagnosed with metastatic or unresectable solid tumors that have a mutation in POLE and/or POLD1. Nivolumab alone or in conjunction with ipilimumab is predicted to be effective against tumors with POLE and/or POLD1 mutations as these genetic changes cause increased rates of mutations in the DNA of tumor cells. These high mutation rates have been associated with response to immunotherapy agents such as nivolumab and ipilimumab.

Being tested
Nivolumab, Ipilimumab

What participants receive

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

Study groups in NCT03461952
Study groupRoleWhat they receive
NivolumabExperimental240mg Q2W
Receives: Drug: Nivolumab
Nivolumab + IpilimumabExperimentalNivolumab 240mg Q2Wk + Ipilimumab 1mg/kg 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 by RECIST 1.1

    Objective Response Rate by RECIST 1.1: CR, PR, SD, or PD

    Measured: 36 months

Secondary outcomes (5)

  1. Efficacy as Measured by Objective Response Rate

    Will be reported using percentages over all randomized patients with 90% exact confidence intervals

    Measured: 36 months

  2. Duration of Response

    Response rates will be reported using percentages over all patients who have received at least one dose of treatment with 90% exact CI of each arm in a non-comparative analysis

    Measured: 36 months

  3. Number and Severity of Adverse Events Using CTCAE 5.0

    AE rates will be reported using percentages with 90% exact CI

    Measured: 36 months

  4. Correlation Between POLE or POLD1 Mutations in Tumor and POLE or POLD1 Mutations in Blood

    Correlation between POLE or POLD1 mutations in tumor and POLE or POLD1 mutations in blood: Will be assessed by Fischer's exact test in each arm

    Measured: 36 months

  5. To Evaluate Response by iRECIST

    iRECIST: iCR, iPR, iSD, iUPD, iUPD/PD

    Measured: 36 months

Timeline

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

  1. First posted12 Mar 2018
  2. Study start11 Mar 2019
  3. Primary completion1 Jun 2021
  4. Study completion9 Feb 2022

Why it stopped: cfDNA screening data found that the prevalence of POLE/POLD1 mutations was lower than expected. It was determined that there are no feasible options to amend this study in a fashion that would not be duplicative of other currently accruing trials.

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
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03461952
Sponsor's protocol ID
I235
Other IDs
0001
Acronym
NIMBLe
Status last verified
Feb 2024
First submitted
5 Mar 2018
Last updated
22 Feb 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 Advanced Solid Tumors, run by Canadian Cancer Trials Group at 6 sites in 2 countries.

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 25 inclusion and 16 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 22 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in Canada, 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 22 Feb 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 by RECIST 1.1 (time frame: 36 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 NCT03461952.

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 22 Feb 2024.

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