Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Immunomodulating Agents

Adjuvants, Immunologic

Patients with locally advanced/metastatic disease who are due to receive as a first attempt an immune checkpoint inhibitors immunotherapy-based treatment.

Blood sample collection : One blood draw of 10 mL will be realized before the initiation of immunotherapy. Any adverse event related to the blood draw will be recorded. A follow-up will be performed at 6 months to record the immune-related adverse events, a statement of the disease and any other cancer treatments received. A 24 months long term follow up will be performed to record patient vital status and any date of disease progression.

Patients newly diagnosed and naive of any anticancer treatment who are due to receive a curative surgery of their primitive tumor.

Blood samples collection : Three blood draws of 10 mL will be realized : one before the surgery, one after 3 months and one after 6 months. Any adverse event related to the blood draw will be recorded. A follow-up will be performed at 6 months to record the statement of the disease and any other cancer treatments received. A 24 months long term follow up will be performed to record patient vital status and any date of disease relapse.

One blood sample of 10mL is realized before initiation of immunotherapy

Blood sampling

Three blood samples of 10mL are realized at distinct steps of patients disease management : one before the curative surgery, one after three months and one after six months.

Charles DUMONTET, MD

Angelique STUANI

Michael DURUISSEAUX, MD

Benoit YOU, MD

Stephane DALLE, MD

François GOLFIER, MD

The potential of immunotherapy in the treatment of cancer is now well documented. While excessive activation of the immune system may be associated with severe reactions and/or auto-immune syndromes, it is now clearly established that controlled activation of the adaptive immune system constitutes a major contribution to the treatment of cancer. Antigen-independent activation of the adaptative immune system with " immune checkpoint inhibitors " (ICI) has allowed prolonged survival in a minority of patients with previously intractable disease. However, a variety of tumor indications are still presently inaccessible to immunotherapeutic approaches or poorly responsive to these therapies.

The immune system is a highly reactive complex comprising antigen-specific cells (adaptive immune system) and antigen-agnostic cells (innate immune system) which interact closely in a complex network. The adaptive immune response is mediated by B and T cells upon antigen-specific recognition. The innate response is mediated by macrophages, dendritic cells, Natural Killer cells and assume the immediate defense of the organism against infectious agents. The innate immune system plays a key role in antigen processing and presentation, production of key cytokines and as anti-tumor effector cells. The role of the innate immune system in the control of cancer progression and in cancer therapy is well documented. Natural Killer cells, involved in antibody-dependent cellular cytotoxicity, and cells performing phagocytosis such as macrophages and neutrophils, participate in tumor destruction after intervention of adaptive immune cells and in combination with certain tumor-targeting therapies, such as antibodies recognizing tumor-specific antigens.

The Odyssey project aims to harness the next generation paradigm of cancer immunotherapy : systemic stimulation of the innate immune system.

To achieve this endeavour the investigator will exploit a well-known yet poorly documented phenomenon, i.e. the rare occurrence of cure in cancer patients who have presented a simultaneous severe septic episode at the time of diagnosis.

Several clinical studies have been realized in order to demonstrate the effect of the innate immune response activation by the bacterial LPS (lipopolysaccharides) in cancer therapy. However, severe toxicities have been described even at very low dose of LPS. The LPS-activated immune response is mediated by TLR4 (Toll Like Receptor 4), a transmembrane receptor expressed by several cell types including monocytes and macrophages. The interaction of TLR4 with LPS mainly induces the release of proinflammatory cytokines (so called " canonical pathway "). TLR4-signalling cascade can also induce the release of type I interferon (so called " alternative pathway "), a class of cytokines known to promote antitumoral activity. LPS tolerance is presumed to be rather associated with the activation of the alternative pathway. Therefore, managing this LPS tolerance is a key mechanism that could limit the systemic toxicity of LPS while stimulating the innate immune system.

Héphaïstos-Pharma biotech and the CRCL Onco-Pharmacology lab (Centre de Recherche en Cancérologie de Lyon) have set up a modified formulation of the LPS that improves its pharmacokinetic properties, reduces its toxicity, and preferentially activates TLR4-alternative signalling pathway. Before investigating the effect of this new immunostimulant in a future phase I/II clinical trial, a translational study is required to further characterize the TLR4 positive cells population as well as the innate immune system in patients with solid cancer.

Characterisation of TLR4+ Blood Cells in Patients With Solid Cancer

Cohort 1 : 24M-PFS defined as the time from the date of the first drug administration to the first documented clinical, biological or radiological progression according to investigator assessment during a period of 24 months. Patients who have not progressed at the time of analysis will be censored at the time of the latest date of assessment.

Number of TLR4 positive cells before curative surgery and after 3 and 6 months.

OS defined as the time from the date of the day of the treatment to the date of death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.

Concentration of innate and adaptive immune memory cells in peripheral blood as defined by the expression level of specific immunophenotypic cell surface receptors

LPS-mediated activation of TLR4 positive cells defined as the expression of the membrane marker CD169

Number of high grade (≥3) irAE(s) 6 months after initiation of immunotherapy

24M-RFS defined as the time from the date of the surgery to the first documented clinical, biological or radiological progression according to investigator assessment during a period of 24 months. Patients who have not relapsed at the time of analysis will be censored at the time of the latest date of assessment.

Hospices Civils de Lyon

Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Death

Colonic Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Anti-Infective Agents

Gastrointestinal Agents

Herbal and Botanical

Pembrolizumab

Antibodies

Antibodies, Monoclonal

Poly I-C

Carboxymethylcellulose Sodium

Poly ICLC

Immunoglobulins

Immunologic Factors

Antineoplastic Agents, Immunological

Interferons

Laxatives

Cathartics

Antiviral Agents

Cola

This "Run In" phase is aimed to determine if poly-ICLC can be safely combined with standard dosages of pembrolizumab:

i. Pembrolizumab will be administered 200 mg intravenously (IV) every 3 weeks (q3w)

ii. Poly-ICLC will be administered intramuscularly (IM) twice weekly at one of two dose levels: 1 mg or 2 mg

Each dose level will enroll 3-6 participants, up to 12 participants total, depending on the occurrence of dose limiting toxicities (DLT) at each dosing level.

Participants may receive treatment for 1 year (\~17 cycles).

In Phase 2, all participants will receive the standard pembrolizumab dose (200 mg IV q3w) in addition to the maximum tolerated dose of poly-ICLC (either 1 mg or 2 mg), as determined by the Phase 1 arm.

Up to 30 participants will be treated in Phase 2. Participants may receive treatment for 1 year (\~17 cycles).

200mg pembrolizumab will be given intravenously on Day 1 of each 3-week cycle

pembrolizumab

The maximum tolerated dose of Poly ICLC will be given twice weekly, in each 3-week cycle:

Week 1, Days 1 and 4

Week 2, Days 8 and 11

Week 3, Days 15 and 18

Poly-ICLC

Asha Nayak, MD

Sharad Ghamande, MD

The main purpose of this study is to determine the dose of poly-ICLC that is safe and tolerable when it is combined with pembrolizumab in patients with colon cancer. This study will also evaluate how the combination of pembrolizumab and poly-ICLC activates the immune system in the patient's blood and inside the tumor; how it affects the size and number of tumor(s) in each patient; and how effective the combination is in patients with colon cancer that is unlikely to respond to pembrolizumab alone.

Mismatch repair genes normally serve to fix the small glitches that occur when DNA is copied as cells divide. In 1993, researchers discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer; individuals who are deficient in these mismatch repair genes are at high risk for colorectal cancer. Accumulating evidence has shown that immunotherapy may be most effective against these cancers.

Programmed cell death protein 1, also known as PD-1, functions as an immune checkpoint, down-regulating the immune system by preventing the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. A new class of immunotherapy drugs that block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are therefore used with varying success to treat some types of cancer.

Current clinical trials are showing that patients whose tumors are mismatch repair deficient are more likely to respond to immune-boosting anti-PD-1 drugs-such as pembrolizumab-than those with tumors proficient in mismatch repair. The idea is that the greater the number of DNA glitches in a tumor cell, the more abnormal proteins it will produce-and the more abnormal proteins that are generated, the greater the odds that the body's immune cells will regard the tumor cells as "foreign" and target them for destruction. Thus far, PD-1 inhibitors have shown great promise for mismatch repair deficient cancer patients, but not for mismatch repair proficient (MRP) cancer patients.

In this clinical trial, the investigators hypothesize that treating MRP colon cancer patients with immunostimulating agent poly-ICLC will generate an inflammatory response, increasing epitope recognition and development of tumor reactive T-cells at the tumor site. However, interferon alpha and gamma produced by the poly-ICLC will increase PD-L1 expression and limit new T-cell development. Thus, PD1 blockade will increase the effectiveness of treatment with pembrolizumab.

Pembrolizumab + Poly-ICLC in MRP Colon Cancer

A Phase I/II Trial of Pembrolizumab (MK-3475) and Poly-ICLC in Patients With Metastatic Mismatch Repair-proficient (MRP) Colon Cancer

A minimum of 3 participants will be treated at dose level 1 (1mg).

* If 0 out of 3 participants experience dose limiting toxicities (DLT), then dose escalation will proceed to dose level 2 (2mg).
* If 1 out of 3 participants experience DLT, a cohort of additional 3 participants will be assigned to the same dose level (1mg).
* If 2 or more participants of 3 (or 6) experience DLT at dose level 1, then enrollment of participants will be stopped.

Response rate will be determined using RECIST 1.1 criteria, calculated as the number of participants with complete response (CR) or partial response (PR)

The adverse event profile will be presented by dose level of the combination treatment for the phase I portion

The progression free survival rate for the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated, including the correspondent 95% confidence interval.

The 20-week progression free survival rate for the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated along with the correspondent 95% confidence interval.

The overall survival rate of response to the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated along with the correspondent 95% confidence interval.

The duration of response to the combination of pembrolizumab and poly-ICLC administered at the Recommended Phase 2 Dose (RP2D) will be estimated along with the correspondent 95% confidence interval.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Characterisation of TLR4+ Blood Cells in Patients With Solid Cancer	NCT06131775	All Types of So...	Blood sampling Blood sampling	18 Years -	Hospices Civils de Lyon
Characterisation of TLR4+ Blood Cells in Patients With Solid Cancer	NCT06131775	All Types of So...	Blood sampling Blood sampling	18 Years -	Hospices Civils de Lyon
Pembrolizumab + Poly-ICLC in MRP Colon Cancer	NCT02834052	Metastatic Colo... Solid Tumor	pembrolizumab Poly-ICLC	18 Years -	Augusta University

Spots Global Cancer Trial Database for immunostimulant