This study is open to patients with a type of cancer called melanoma. Patients can join the study if their tumor cannot be removed by surgery or has spread to other organs, and are planned to receive immunotherapy as treatment for their cancer. This study is looking at whether taking calcium pantothenate supplement (a type of Vitamin B5) can increase its levels in the blood and have an effect in the immune system, when its used in combination with the immunotherapy.
This single-center, single-cohort study aims to investigate the effectiveness of oral calcium pantothenate (C-PAN) in raising plasma pantothenic acid levels in melanoma patients. Conducted at Princess Margaret Cancer Centre, the study will enroll 12 eligible subjects with locally unresectable or metastatic melanoma undergoing first-line standard of care (SOC) with combined immune checkpoint inhibitor (ICI) therapy, Nivolumab and Ipilimumab. Additionally, the study will explore changes in immune cell subsets, metabolomics, and gut microbiome to understand the impact of pantothenate/CoA pathway manipulation on ICI efficacy and immune-mediated colitis prevention. Patients will initially receive a run-in period of C-PAN at a dose of 2000 mg daily for 3 to 7 days, alongside approved SOC drugs. Subsequently, patients will continue with the maintenance dose of 2000 mg daily, starting on the same day as the first cycle of combined ICI. This maintenance dose will be continued until the occurrence of unacceptable toxicity, disease progression by iRECIST criteria, or for a maximum duration of 1 year, whichever comes first, unless there are specific criteria indicating the discontinuation of C-PAN. For all subjects, radiologic imaging to assess response to treatment will be performed as per standard practice (ideally every 8 to 12 weeks, with first assessment at week 9). Fecal samples will be collected from all subjects at baseline (1st sample), at week 9 following the start of ICI, and at study completion or discontinuation. An additional fecal sample will be collected in case of development of immune-related colitis or immune-related diarrhea. Standard laboratory investigations for immunotherapy will be collected as per institutional practice. Blood samples for biomarkers will be collected at various time points.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
C-PAN is an essential nutrient as it is required for the synthesis of CoA, a key cofactor in the tricarboxylic acid cycle and fatty acid metabolism, as well as for the synthesis of acyl carrier protein. Pantothenate appears to be safe in humans with studies describing the administration of doses up to 10 grams per day over prolonged periods of time; hence, no upper limit for tolerability has been established. In this study, oral supplement consisting of 2000 mg daily of C-PAN will be administered to a single cohort of patients.
Nivolumab is an ICI, a type of immunotherapy. It is a monoclonal antibody that binds to the protein PD-1 on the surface of immune cells called T cells. Nivolumab 1 mg/kg every 3 weeks for up to 4 cycles (upon patient´s tolerability) followed by maintenance Nivolumab 3 mg/kg (or fixed dose 240 mg) every 2 weeks or Nivolumab 6 mg/kg (or fixed dose 480 mg) every 4 weeks.
University Health Network- Princess Margaret Cancer Centre
Toronto, Ontario, Canada
RECRUITINGTo determine if the dose of 2000 mg daily of pantothenic acid achieves an increase in plasmatic concentration of pantothenic acid by at least a 50% between baseline and week 9, in 9 or more of the patients treated with combined ICI.
Blood samples will be collected at baseline, and at week 9 to evaluate level in plasmatic pantothenic acid level, measured in mcMol/L.
Time frame: 9 weeks
Evaluate the overall response rate (ORR) of the enrolled cohort.
ORR by RECIST V1.1 and iRECIST.
Time frame: 1 year
Evaluate the progression free survival (PFS) of the enrolled cohort.
Measured by RECIST v1.1 and iRECIST.
Time frame: 1 year
Incidence of immune-related colitis.
Immune-related colitis will be assessed by CTCAE version 5.
Time frame: 1 year
Correlation between baseline intestinal microbiome composition to the development of immune-related colitis.
Correlation between bacteria taxa composition obtained through 16S rRNA sequencing and immune-related colitis.
Time frame: 1 year
Correlation between the early changes in composition of intestinal microbiome and the development of immune-related colitis.
Correlate changes in bacteria taxa composition obtained through 16S rRNA sequencing from baseline samples to early time-point (week 9), with the development of immune-related colitis..
Time frame: 1 year
The incidence of treatment-related adverse events.
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TREATMENT
Masking
NONE
Enrollment
12
Ipilimumab is an ICI, a type of immunotherapy. It is a monoclonal antibody that binds to the protein CTLA-4 on immune cells called T cells. Ipilimumab 3 mg/kg every 3 weeks for up to 4 cycles.
All adverse events that are related to C-PAN and/or in the investigator's opinion is related to immunotherapy will be recorded, and graded as per CTCAE version 5.
Time frame: 1 year
The incidence of treatment-related adverse events
Correlation between baseline pantothenic acid plasmatic level in mcMol/L and ORR by RECIST and iRECIST.
Time frame: 1 year
Correlation between change in plasmatic pantothenic acid level between baseline and at first day of ICI, and ORR.
Correlation between change in pantothenic acid plasmatic level in mcMol/L between baseline and first day of ICI, and ORR by RECIST and iRECIST.
Time frame: 1 year