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

NCT03982121 | Withdrawn Phase 1

• 2 other identifiers: 2017-005020-142017/2630
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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 colorectal LM (CRLM) in combination with intravenous (i.v.) administration of anti-PD-1 antibody (nivolumab) and chemotherapy (FOLFOX regimen).

Conditions

Colorectal Cancer Metastatic

Outcome Measures

Primary Outcomes (2)

• 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.

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

• Recommanded phase 2 dose (RP2D)

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

  RP2D will be assessed on 8 weeks

Study Arms (6)

A

EXPERIMENTAL

FOLFOX IV + NIVOLUMAB IV

Drug: FOLFOX regimen; Drug: Nivolumab

B

EXPERIMENTAL

FOLFOX IV + GLA IT

Drug: FOLFOX regimen; Drug: GLA-SE

C

EXPERIMENTAL

FOLFOX IV + IPILIMUMAB IT

Drug: FOLFOX regimen; Drug: Ipilimumab

D

EXPERIMENTAL

FOLFOX IV + NIVOLUMAB IV + GLA IT

Drug: FOLFOX regimen; Drug: Nivolumab; Drug: GLA-SE

E

EXPERIMENTAL

FOLFOX IV + NIVOLUMAB IV + IPILIMUMAB IT

Drug: FOLFOX regimen; Drug: Nivolumab; Drug: Ipilimumab

F

EXPERIMENTAL

LFOX IV + NIVOLUMAB IV + GLA IT + IPILIMUMAB IT

Drug: FOLFOX regimen; Drug: Nivolumab; Drug: Ipilimumab; Drug: GLA-SE

Interventions

FOLFOX regimen DRUG

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

A; B; C; D; E; F

Nivolumab DRUG

Nivolumab 240 mg

A; D; E; F

Ipilimumab DRUG

Ipilimumab 5 or 10 or 25 mg

C; E; F

GLA-SE DRUG

GLA-SE 1 or 2 or 5 or 10 or 20 μg

B; D; F

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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,
• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Gustave Roussy, Cancer Campus, Grand Paris: lead

Study Sites (1)

Gustave Roussy

Villejuif, Val De Marne, 94805, France

Location

MeSH Terms

Interventions

Folfox protocol; Nivolumab; Ipilimumab; glucopyranosyl lipid-A

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, open-label, dose-escalation combination phase 1 study

Study Record Dates

• First Submitted: June 7, 2019
• First Posted: June 11, 2019
• Study Start: June 4, 2019
• Primary Completion: February 12, 2020
• Study Completion: February 12, 2020
• Last Updated: February 17, 2020

Record last verified: 2020-02

Locations

FR (1)