Camu-Camu Prebiotic and Immune Checkpoint Inhibition in Patients With Non-small Cell Lung Cancer and Melanoma
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT05303493|
Recruitment Status : Recruiting
First Posted : March 31, 2022
Last Update Posted : July 20, 2022
|Condition or disease||Intervention/treatment||Phase|
|NSCLC Stage IV Melanoma Stage IV Unresectable Melanoma Advanced Non-Small Cell Lung Cancer||Biological: Camu Camu Capsules (Camu Camu powder encapsulated (500mg each) + ICI||Phase 1|
Immune-checkpoint inhibitors (ICI) now represent the backbone therapy for patients with advanced or unresectable non-small cell lung cancer (NSCLC) and metastatic melanoma. However, only a minority of patients obtain durable complete responses.
In patients with advanced NSCLC with a Programmed Death Ligand-1 (PD-L1) expression level below 50%, the standard-of-care is pembrolizumab plus platinum doublet chemotherapy, with overall survival (OS) at 2 years reaching 46%. In patients with advanced melanoma, combination of anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab) is a key standard-of-care option. In a study in patients with advanced melanoma evaluating the combination regimen of nivolumab plus ipilimumab group, OS at 5 years was 52% in the nivolumab plus ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.
Despite these improvements in outcomes with ICI, these survival and response rates remain suboptimal, and therefore, developing strategies to safely increase ICI efficacy or reverse ICI resistance represents an unmet clinical need. Moreover, there are currently no available options for patients who progress on standard-of-care ICI. Recent pre-clinical studies have demonstrated the role of the gut microbiome in improving ICI efficacy, and therefore, efforts to modulate the gut microbiome is an active area of study. Indeed, two phase I clinical studies evaluating gut microbiome modulation with fecal microbial transplantation (FMT) demonstrated increase in objective response rate compared to historical controls. Moreover, studies in over 8,000 patients (including patients with NSCLC and melanoma) have confirmed the independent and negative role of antibiotics (ATB) in patients receiving ICI, further validating the important role of the gut microbiome.
Therefore, it is clear that modulation of the gut microbiome represents a promising therapeutic strategy in improving ICI efficacy. Other than FMT, prebiotic substances (compounds which positively shift the gut microbiome) are a reliable and safe method of gut microbiome modulation. Data suggest that the berry Camu Camu (CC), also known as Myrciaria dubia has prebiotic potential to enrich Akkermansia muciniphila, a bacterium shown to alleviate metabolic disorders and improve ICI efficacy in preclinical models. Our preclinical work showed that CC oral supplementation significantly decreased tumor size and had an additive effect in combination with anti-PD-1 in two murine tumor models, MCA-205 (anti-PD-1 sensitive) and E0771 (anti-PD-1 resistant). Flow cytometry and RNA seq analysis of the tumor microenvironment (TME) and T cell depletion showed that CC's anti-tumor effect was dependent on CD8+ T cells. Moreover, CC supplementation was able to transform an anti-PD-1-resistant tumor into an anti-PD-1-sensitive tumor. ATB administration inhibited CC activity, proving that the activity of CC was dependent on the gut microbiome. The 16S rRNA profiling of murine fecal samples showed that CC increased bacterial diversity and enrichment of beneficial bacteria.
CC is available over the counter as a natural prebiotic and has been approved for human clinical trials in obesity (NCT04130321) and HIV (NCT04058392).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||
Cohort 1. For patients with advanced NSCLC, treatment will consist of ICI in combination with CamuCamu.
Cohort 2. For patients with advanced cutaneous melanoma, treatment will consist of single-agent anti-PD-1 either nivolumab or pembrolizumab at the discretion of the treating physician in combination with investigational CC capsules Cohort 3. For patients with advanced melanoma receiving standard-of-care ICI who exhibit either an ORR of SD or PD during the first 3 months of ICI initiation, their current regimen will continue unchanged and they will receive Camu C and will be continued for 18 weeks or upon progression.
|Masking:||None (Open Label)|
|Official Title:||Phase I Trial of Camu Camu Prebiotic and Immune Checkpoint Inhibition in Patients With Non-Small Cell Lung Cancer and Melanoma|
|Actual Study Start Date :||June 29, 2022|
|Estimated Primary Completion Date :||April 15, 2024|
|Estimated Study Completion Date :||April 15, 2027|
Experimental: Camu-camu (intervention) in addition to standard-of-care ICI
Camu-camu (intervention) will be added to standard-of-care ICI in:
Cohort 1. For patients with advanced NSCLC, treatment will consist of single-agent pembrolizumab in combination with physician's choice platinum-doublet chemotherapy in combination with CC.
Cohort 2. For patients with advanced cutaneous melanoma, treatment will consist of single-agent anti-PD-1 either nivolumab or pembrolizumab at the discretion of the treating physician.
Cohort 3. For patients with advanced melanoma receiving standard-of-care ICI (either single-agent anti-PD-1 or combination anti-CTLA-4 plus anti-PD-1) who experience progressive disease (PD), their current regimen will continue unchanged and they will receive CC at 1500 mg for 3 months or until confirmed progression if progression occurs earlier.
Biological: Camu Camu Capsules (Camu Camu powder encapsulated (500mg each) + ICI
Evaluate the safety and tolerability of CC prebiotic in addition to ICI in patients with NSCLC and melanoma
- Incidence of treatment-related adverse events (safety and tolerability) in patients with NSCLC and melanoma [ Time Frame: At the end of every cycle (each cycle is 21 or 28 days, depending of the ICI treatment) until disease progression, then, every 3 months thereafter (for up to a total of 2 years) ]
Safety of administration of CamuCamu in the Safety Analysis Dataset. The assessment of safety will be based on the incidence of AEs, SAEs, AEs leading to discontinuation, and deaths in the Safety Analysis dataset.
Treatment-related adverse events will be graded according to the NCI CTCAE v5.0. of CC prebiotic in addition to ICI in patients with NSCLC and melanoma on the basis of the following endpoints:
- Incidence and severity of AEs, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)
- Change from baseline in targeted vital signs
- Change from baseline in targeted clinical laboratory test results
- Objective response rate in the NSCLC and melanoma cohort by RECIST criteria. [ Time Frame: At 3 and 6 months, then at 12 months and up to 2 years ]
To evaluate the preliminary activity of CC in combination with single-agent anti-PD-1 in patients with melanoma, and in combination with anti-PD-1 and chemotherapy in patients with advanced NSCLC as measured by ORR (ORR; the rate of complete response plus partial response, as per the iRECIST and RECIST criteria).
Objective Response Rate (ORR) as defined by the proportion of patients with NSCLC and melanoma whose Best Overall Response (BOR) is either a complete response (CR) or partial response (PR) as assessed by iRECIST, based on RECIST v1.1. BOR is defined as the best response designation over the study as a whole, recorded between the dates of first dose until the last tumor assessment prior to subsequent therapy. CR or PR determinations included in the BOR assessment must be confirmed by a second scan performed no less than 4 weeks after the criteria for response are first met.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05303493
|Contact: Wiam Belkaid, PhDfirstname.lastname@example.org|
|Contact: Arielle Elkrief, MDemail@example.com|
|Centre hospitalier de l'Université de Montréal (CHUM)||Recruiting|
|Montréal, Quebec, Canada, H2X 3E4|
|Contact: Wiam Belkaid, PhD 514-836-3273 firstname.lastname@example.org|
|Contact: Arielle Elkrief, MD 514-890-8000 email@example.com|
|Principal Investigator: Bertrand Routy, MD, PhD|
|Principal Investigator:||Bertrand Routy, MD, PhD||Centre hospitalier de l'Université de Montréal (CHUM)|