High Dose Vitamin C for Multiple Myeloma

Overseen By Aaron Holley

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Arkansas

Must not be taking: Coumadin

Disqualifiers: HIV, CNS myeloma, Insulin-dependent diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 9

Duration: 6 weeks

18 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using warfarin and insulin-dependent diabetics. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug High Dose Ascorbic Acid (HDAA) for treating multiple myeloma?

Research shows that high-dose ascorbic acid can help kill multiple myeloma tumor cells by creating reactive oxygen species that lead to cell death. It has been effective in combination with other treatments, like melphalan, in reducing tumor growth in mice and has shown promising results in patients with relapsed or resistant multiple myeloma. ^{1 2 3 4 5}

Is high-dose vitamin C safe for humans?

High-dose vitamin C, when used with other treatments, has been studied in patients with multiple myeloma and other conditions. It was generally well-tolerated, with some reports of mild side effects like low white blood cell counts, but no severe non-blood-related toxicities were observed. ^{1 2 3 4 5}

How is the drug High Dose Ascorbic Acid (Vitamin C) unique in treating multiple myeloma?

High Dose Ascorbic Acid (Vitamin C) is unique because it selectively kills multiple myeloma tumor cells by generating reactive oxygen species (ROS) that lead to cell death, while sparing normal cells. This approach aims to reduce the toxicity associated with traditional high-dose chemotherapies and can be used alone or in combination with other treatments like melphalan. ^{1 2 4 5 6}

What is the purpose of this trial?

The purpose of this research is to evaluate whether HDAA in combination with a single dose of 100 mg/m2 IV melphalan followed by autologous stem cell transplantation (ASCT) is safe and effective for subjects with relapsed refractory multiple myeloma. The proposed melphalan dose is 50% of the current standard myeloablative dose (200 mg/m2). Based on our preclinical data, the investigator hypothesize that the combination of reduced dose melphalan with IV HDAA will have high efficacy and tolerability Primary Objective To determine tumor response using International Myeloma Working Group (IMWG) criteria (see Appendix B). Secondary Objectives Objectives: 1. Determine the safety and tolerability of HDAA in combination with reduced dose melphalan conditioning and autologous stem cell transplantation (ASCT) in relapsed refractory multiple myeloma subjects. 2. Determine the rate of Minimal Residual Disease (MRD) negativity at time point of response assessment using 8 color flow cytometry on BM sample. Functional imaging, such as positron emission tomography (PET) scan and magnetic resonance imaging (MRI), will also be performed to assess the disease status. 3. Categorize and quantify adverse events compared to historical control. 4. Determine quality of life parameters using standardized health-related quality of life measures 5. Determine oxidative stress parameters in plasma during treatment.

Research Team

Carolina Schinke, MD

Principal Investigator

University of Arkansas

Eligibility Criteria

This trial is for adults over 18 with relapsed refractory multiple myeloma who've had at least three prior treatments and disease progression within the last six months. They must have enough stored stem cells, specific levels of proteins or plasmacytosis indicating active disease, and a stable neutrophil count without growth factor support.

Inclusion Criteria

I have given my consent to participate.

I've had 3+ treatments for my condition and it has worsened in the last 6 months.

I have stored stem cells meeting the required count.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a test dose of HDAA alone at screening, then proceed to either 75, 100, or 125 gm on day -4, HDAA combined with melphalan 100 mg/m2 on day -1, and ASCT on day 0. Four additional HDAA doses will be administered 3 days apart on D+2, D+5, D+8, and D+11, followed by weekly doses for four additional weeks.

6 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including tumor response, quality of life, and adverse events.

24 months

Regular visits (frequency not specified)

Treatment Details

Interventions

• High Dose Ascorbic Acid (HDAA)

Trial Overview The study tests high-dose ascorbic acid (HDAA) combined with a half-standard dose of melphalan chemotherapy followed by autologous stem cell transplantation. It aims to assess safety, effectiveness in tumor response, minimal residual disease rates, side effects compared to past data, quality of life impact, and oxidative stress changes.

Participant Groups

Group I: 75gm HDAA + Melphalan 100mg/m2 Experimental Treatment 1 Intervention

Subjects will receive HDAA alone (75gm) on day -4, HDAA combined with melphalan 100 mg/m2 on day -1, and ASCT on day 0. Four additional HDAA doses (75gm) will then be administered 3 days apart on D+2, D+5, D+8 and D+11, followed by weekly doses of the corresponding dose of HDAA for four additional weeks. On day, D-1, when both drugs are given, melphalan should be given first

Group II: 125gm HDAA + Melphalan 100mg/m2 Experimental Treatment 1 Intervention

Subjects will receive HDAA alone (125gm) on day -4, HDAA combined with melphalan 100 mg/m2 on day -1, and ASCT on day 0. Four additional HDAA doses (125gm) will then be administered 3 days apart on D+2, D+5, D+8 and D+11, followed by weekly doses of the corresponding dose of HDAA for four additional weeks. On day, D-1, when both drugs are given, melphalan should be given first

Group III: 100gm HDAA + Melphalan 100mg/m2 Experimental Treatment 1 Intervention

Subjects will receive HDAA alone (100gm) on day -4, HDAA combined with melphalan 100 mg/m2 on day -1, and ASCT on day 0. Four additional HDAA doses (100gm) will then be administered 3 days apart on D+2, D+5, D+8 and D+11, followed by weekly doses of the corresponding dose of HDAA for four additional weeks. On day, D-1, when both drugs are given, melphalan should be given first

Who Is Running the Clinical Trial?

University of Arkansas

Lead Sponsor

Trials

500

Recruited

153,000+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

Findings from Research

In a small study of 4 relapsed refractory multiple myeloma patients, adding high-dose intravenous ascorbic acid (15 grams/week) to their chemotherapy regimen resulted in one complete response and very good partial responses in the others after 4 cycles.

This suggests that pharmacological doses of ascorbic acid may enhance the effectiveness of conventional chemotherapy in difficult-to-treat multiple myeloma, warranting further clinical studies with larger patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological dose ascorbic acid administration in relapsed refractory multiple myeloma patients. Bolaman, AZ., Turgutkaya, A., Küçükdiler, HE., et al.[2022]

Pharmacologically-dosed ascorbic acid (PAA) can selectively kill multiple myeloma (MM) tumor cells while sparing normal cells, which could help reduce the toxic effects of high-dose chemotherapy.

In both laboratory and animal studies, PAA demonstrated efficacy in inhibiting tumor formation in MM, suggesting it could be a promising treatment option either alone or in combination with traditional drugs like melphalan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic Acid. Xia, J., Xu, H., Zhang, X., et al.[2019]

In a study involving patients with relapsed CD20-positive B-cell non-Hodgkin's lymphoma, intravenous l-ascorbic acid (AA) at a dose of 75 g was found to be safe and successfully achieved the target serum concentration of >15 mM without any observed adverse reactions.

The successful completion of this trial paves the way for a phase II trial to further evaluate the efficacy of intravenous AA in combination with chemotherapy for lymphoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Clinical Trial of Intravenous L-ascorbic Acid Following Salvage Chemotherapy for Relapsed B-cell non-Hodgkin's Lymphoma. Kawada, H., Sawanobori, M., Tsuma-Kaneko, M., et al.[2014]

Vitamin C, when loaded into myeloma cells using dehydroascorbic acid, protects these cells from the cytotoxic effects of arsenic trioxide, suggesting a potential strategy to enhance treatment efficacy.

The study found that while vitamin C can generate harmful reactive oxygen species in certain conditions, loading cells with it in a specific way can actually reduce oxidative stress and improve cell viability against arsenic trioxide treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin C protects HL60 and U266 cells from arsenic toxicity. Karasavvas, N., Cárcamo, JM., Stratis, G., et al.[2021]

The combination of arsenic trioxide (As(2)O(3)) and ascorbic acid (AA) was found to have acceptable toxicity levels in a Phase I trial with six patients, showing that it can be administered safely without significant dose-limiting side effects.

This treatment demonstrated promising activity against relapsed/refractory multiple myeloma, with two patients achieving partial responses and four maintaining stable disease, suggesting potential effectiveness in overcoming chemotherapy resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Bahlis, NJ., McCafferty-Grad, J., Jordan-McMurry, I., et al.[2018]

An international multi-center study investigated the combination of arsenic trioxide, ascorbic acid, and dexamethasone for treating advanced multiple myeloma, suggesting a potential new treatment strategy.

The study highlights that reducing glutathione levels with ascorbic acid may enhance the effectiveness of arsenic trioxide in inducing growth inhibition and apoptosis in multiple myeloma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II multicenter study of arsenic trioxide, ascorbic acid and dexamethasone in patients with relapsed or refractory multiple myeloma. Wu, KL., Beksac, M., van Droogenbroeck, J., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacological dose ascorbic acid administration in relapsed refractory multiple myeloma patients. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic Acid. [2019]

3. Japan pubmed.ncbi.nlm.nih.gov

Phase I Clinical Trial of Intravenous L-ascorbic Acid Following Salvage Chemotherapy for Relapsed B-cell non-Hodgkin's Lymphoma. [2014]

4. United States pubmed.ncbi.nlm.nih.gov

Vitamin C protects HL60 and U266 cells from arsenic toxicity. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. [2018]

6. Italy pubmed.ncbi.nlm.nih.gov

Phase II multicenter study of arsenic trioxide, ascorbic acid and dexamethasone in patients with relapsed or refractory multiple myeloma. [2018]