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Colorectal Cancer MetastaticPhase 1ISILINCT03982121

Study of Intratumoral Ipilimumab and TLR4 Agonist GLA-SE in Combination With Systemic Nivolumab and Chemotherapy

A Phase 1 study testing FOLFOX regimen, Nivolumab and Ipilimumab in people with Colorectal Cancer Metastatic, run by Gustave Roussy, Cancer Campus, Grand Paris at 1 site in France.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

To determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the toxicity profile (NCI CTCAE v5.0 and immune related adverse events) of i.t. administration of anti-CTLA4 antibody (ipilimumab) and TLR4 agonist (synthetic glucopyranosyl lipid A formulated in a stable emulsion [GLA-SE]) in… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Cancer Metastatic
What is being tested?
FOLFOX regimen, Nivolumab and Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
1 siteFrance
Study dates
4 Jun 2019to 12 Feb 2020
Phase
Phase 1
Are there results?
None posted in the registry

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

  • Histologically confirmed colorectal adenocarcinoma.
  • At least one CRLM
  • measurable according to RECIST 1.1,
  • at least >2 cm in maximal diameter,
  • visible on non-contrast enhanced computerized tomography (CT) scan or ultrasonography,
  • amenable to biopsy,
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  • and amenable to percutaneous i.t. injection.
  • At least one other metastasis (controlateral CRLM or a distant visceral or lymph node metastasis)
  • measurable according to RECIST 1.1,
  • and amenable to biopsy.
  • Tumor lesions located in previously irradiated areas are considered measurable if disease progression has been demonstrated in such lesions.
  • Tumor liver involvement <50% on baseline CT scan.
  • Previous failure of active drug classes in mCRC (fluoropyrimidines, oxaliplatin, irinotecan, EGFR inhibitors [if wild-type RAS mCRC] and antiangiogenics).
  • Representative tumor specimens at the initial diagnosis of CRC (paraffin blocks (preferred) or at least 10 unstained slides), with the corresponding pathology report, if available.
  • Age >/=18 years.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  • Expected life expectancy >3 months (no rapidly progressive disease).
  • Adequate organ functions:
  • Hemoglobin ≥9 g/dL or ≥5.6 mmol/L (blood cell transfusions are allowed), absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥100 x 109/L
  • Serum creatinine ≤1.5 X upper limit of normal (ULN) or creatinine clearance (measured, or calculated per institutional standard) ≥50 mL/min for subject with creatinine levels >1.5 x institutional ULN (glomerular filtration rate can also be used in place of creatinine or creatinine clearance)
  • Serum total bilirubin ≤1.5 ULN or direct (unconjugated) bilirubin ≤ULN for subjects with total bilirubin levels >1.5 ULN
  • AST (SGOT) and ALT (SGPT) ≤5 ULN
  • Albumin >33 g/L
  • International normalized ratio (INR) or prothrombin time (PT) ≤1.5 ULN unless subject is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
  • Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 24 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Female subjects of childbearing potential should be willing to use two validated methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 7 months after the last dose of study medication (Reference Section 5.9.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  • Sexually active male subjects unless surgically sterile, must agree to use condoms as an effective barrier method of contraception or abstain from heterosexual activity for the course of the study through 7 months after the last dose of study medication. It is recommended that their sexual partners use an effective contraceptive during the same period.
  • Signed informed consent.
  • Affiliation to or beneficiary of a social security system.

Who cannot join

  • Allergy or contraindication to oxaliplatin (including peripheral neuropathy [≥ grade 2]), fluorouracil (including known dihydropyrimidine dehydrogenase (DPD) deficiency) or leucovorin or to any other study drug.
  • Prior history of intolerance to full-dose FOLFOX regimen.
  • History of anterior organ transplantation, including allograft stem cell transplantation
  • History of interstitial lung disease
  • Patients eligible for curative-intent local therapies (e.g., surgery or thermablation).
  • Contraindication to percutaneous injection/biopsy (e.g., coagulation disorder, anticoagulant or antiaggregant therapy). Patients treated with low molecular weight heparin (LMWH) are eligible if they can interrupt their treatment for biopsies and i.t. injections.
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  • Concomitant administration of any other anticancer therapy during the trial treatment period.
  • Prior chemotherapy, targeted therapy or radiation therapy within 2 weeks prior to study Day 1 or adverse events due to a previously administered agent that have not recovered (i.e., ≤ Grade 1) at baseline.
  • Immunodeficiency or systemic steroid therapy equivalent to prednisolone >10mg/day or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  • Other malignancy within 2 years prior to enrollment with the exception of curatively treated basal-cell carcinoma of the skin, squamous-cell carcinoma of the skin, and/or curatively resected in situ cervical and/or in situ breast cancers.
  • Symptomatic active central nervous system metastases and/or carcinomatous meningitis.
  • Active automimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or asymptomatic asthma/atopy under topical/aerosol therapies would be an exception to this rule. Subjects who require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with stable hypothyroidism on hormone replacement or Sjogren's syndrome will not be excluded from the study. Patients with controlled type 1diabetes mellitus on a stable insulin regimen may be eligible for this study.
  • Active infection requiring systemic therapy.
  • Pregnancy or breastfeeding, or inadequate contraceptive method, or expectation to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 7 months after the last dose of trial treatment.
  • Prior immunotherapy, including anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • Clinically significant liver disease (i.e., with clinical, biological or morphological signs or symptoms of liver dysfunction, such as jaundice, hepatic encephalopathy, non-malignant ascites, radiological/endoscopic evidence of portal hypertension, biological evidence of liver insufficiency, etc.), including active viral, alcoholic, or other hepatitis, cirrhosis, severe oxaliplatin-induced sinusoidal obstruction syndrome (SOS) and inherited liver disease.
  • Known active Hepatitis B virus infection (e.g., HBsAg reactive) or Hepatitis C virus infection (e.g., HCV RNA [qualitative] is detected) and positive Hepatitis test results.
  • Known history of Human Immunodeficiency Virus (HIV) (HIV 1 and 2 antibodies) and positive HIV test results.
  • Administration of a live vaccine within 30 days prior to the first dose of trial treatment.
  • Any physical, psychological or social condition/reason that would preclude adequate follow-up or hamper patient's safety according to the investigator's opinion.
  • Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent

Trial locations and contacts

1 site in 1 country.

France1 site

  • Gustave Roussy

    Villejuif, Val De Marne, 94805

Other trials in France

About this study

Official title: ISILI (In Situ Immunotherapy of LIver Metastases): An Openlabel, Dose-finding, Phase I Study of Intratumoral Ipilimumab and TLR4 Agonist GLA-SE in Combination With Systemic Nivolumab and Chemotherapy (FOLFOX Regimen) in Patients With Colorectal Liver Metastases.

To determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D) and the toxicity profile (NCI CTCAE v5.0 and immune related adverse events) of i.t. administration of anti-CTLA4 antibody (ipilimumab) and TLR4 agonist (synthetic glucopyranosyl lipid A formulated in a stable emulsion [GLA-SE]) in colorectal LM (CRLM) in combination with intravenous (i.v.) administration of anti-PD-1 antibody (nivolumab) and chemotherapy (FOLFOX regimen).

Being tested
FOLFOX regimen, Nivolumab, Ipilimumab, GLA-SE

What participants receive

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

  • FOLFOX regimenDrug

    Oxaliplatin 85 mg/m² Leucovorin (LV) levogyre form (LLV) 200 mg/m² or dextro-levogyre (DL-LV) racemic mixture 400 mg/m²) Fluorouracil 2400 mg/m²

  • NivolumabDrug

    Nivolumab 240 mg

  • IpilimumabDrug

    Ipilimumab 5 or 10 or 25 mg

  • GLA-SEDrug

    GLA-SE 1 or 2 or 5 or 10 or 20 μg

Study groups in NCT03982121
Study groupRoleWhat they receive
AExperimentalFOLFOX IV + NIVOLUMAB IV
Receives: Drug: FOLFOX regimen; Drug: Nivolumab
BExperimentalFOLFOX IV + GLA IT
Receives: Drug: FOLFOX regimen; Drug: GLA-SE
CExperimentalFOLFOX IV + IPILIMUMAB IT
Receives: Drug: FOLFOX regimen; Drug: Ipilimumab
DExperimentalFOLFOX IV + NIVOLUMAB IV + GLA IT
Receives: Drug: FOLFOX regimen; Drug: Nivolumab; Drug: GLA-SE
EExperimentalFOLFOX IV + NIVOLUMAB IV + IPILIMUMAB IT
Receives: Drug: FOLFOX regimen; Drug: Nivolumab; Drug: Ipilimumab
FExperimentalLFOX IV + NIVOLUMAB IV + GLA IT + IPILIMUMAB IT
Receives: Drug: FOLFOX regimen; Drug: Nivolumab; Drug: Ipilimumab; Drug: GLA-SE

What is being measured

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

  1. Maximum tolerated dose (MTD)

    MTD will be determined based on the DLT definitions and identified as the maximum dose level at which less than 33% of DLT are observed in the evaluable patients.

    Measured: For all the cohorts, the DLT period to determine the MTD will be 28 days

  2. Recommanded phase 2 dose (RP2D)

    RP2D will be determined based on the MTD identified, on analysis of DLT defining events

    Measured: RP2D will be assessed on 8 weeks

Timeline

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

  1. First posted11 Jun 2019
  2. Study start4 Jun 2019
  3. Primary completion12 Feb 2020
  4. Study completion12 Feb 2020

Why it stopped: Study never began because of withdrawal of the industrial partner

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 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Model description
Multicenter, open-label, dose-escalation combination phase 1 study
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03982121
Sponsor's protocol ID
2017-005020-14
Other IDs
2017/2630, 2017
Acronym
ISILI
Status last verified
Feb 2020
First submitted
7 Jun 2019
Last updated
17 Feb 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing FOLFOX regimen, Nivolumab and Ipilimumab in people with Colorectal Cancer Metastatic, run by Gustave Roussy, Cancer Campus, Grand Paris at 1 site in France.

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 29 inclusion and 21 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: withdrawn, as of the sponsor's last update on 17 Feb 2020. 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 France. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

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?

Maximum tolerated dose (MTD) (time frame: For all the cohorts, the DLT period to determine the MTD will be 28 days). The study lists 2 primary outcomes in all. 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 NCT03982121.

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 17 Feb 2020; AzTrials last refreshed its copy on 8 Nov 2026.

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