Gemcitabine + Ascorbate for Sarcoma

Not currently recruiting at 2 trial locations

Overseen By Mohammed Milhem, MBBS

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Iowa

Must not be taking: Flecainide, Methadone, Amphetamines, others

Disqualifiers: G6PD deficiency, Heart failure, Stroke, others

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of gemcitabine and high-dose ascorbate (vitamin C) for treating advanced soft tissue or bone sarcomas that cannot be surgically removed or have metastasized. The goal is to determine if this combination can slow or halt tumor growth. It targets patients who have previously tried other treatments without success. Patients diagnosed with locally advanced, inoperable, or metastatic soft tissue or bone sarcoma and who have undergone at least one chemotherapy regimen may be suitable for this trial. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering patients a chance to be among the first to receive this novel combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are on certain drugs like flecainide, methadone, amphetamines, quinidine, and chlorpropamide, unless you can switch to a different medication. Also, you must not have received chemotherapy or any investigational drug within 2 weeks prior to starting the study drug.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that patients on certain drugs like warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide may need substitutions. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that taking high doses of Vitamin C with the drug gemcitabine is usually safe. In studies where these were used together, most participants did not experience serious problems. Some might have mild side effects, but major issues are uncommon. Early results suggest this combination does not cause significant harm, making it a potentially safe option for further testing. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the treatment using Gemcitabine combined with high-dose ascorbate for sarcoma because it introduces a novel approach by leveraging vitamin C's potential effects in cancer therapy. Unlike standard treatments such as doxorubicin or ifosfamide, which primarily target cancer cells through straightforward chemical mechanisms, this combination aims to enhance the efficacy of gemcitabine by using ascorbate to potentially increase oxidative stress within cancer cells, making them more vulnerable to chemotherapy. This dual approach could offer a more effective treatment option with potentially less toxicity than traditional chemotherapy regimens.

What evidence suggests that Gemcitabine + Ascorbate could be an effective treatment for sarcoma?

This trial will evaluate the combination of high-dose Vitamin C (ascorbate) with gemcitabine for treating sarcomas. Research has shown that high doses of Vitamin C, when combined with gemcitabine, a chemotherapy drug, may help treat certain cancers. Early results indicate that patients tolerate this combination well. Evidence suggests it might improve survival rates. Specifically, patients with advanced pancreatic cancer who received both treatments lived an average of 16 months, compared to 8 months for those who didn't receive Vitamin C. While this study focused on pancreatic cancer, these findings suggest potential benefits for other hard-to-treat cancers like sarcomas. ^{1 2 3 6 7}

Who Is on the Research Team?

John Rieth, MD

Principal Investigator

University of Iowa Hospitals & Clinics

Are You a Good Fit for This Trial?

Adults aged 18+ with advanced, inoperable or metastatic soft tissue or bone sarcoma (excluding GIST and Kaposi's) who have tried at least one chemotherapy regimen. Participants must be physically capable of tolerating a high-dose vitamin C infusion and not have certain heart conditions, uncontrolled medical issues, recent major surgeries, HIV, or severe kidney stones.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

I have advanced sarcoma, have had chemotherapy, and my tumor is at least 1cm big.

I have treated brain metastases with no current signs of worsening and don't need steroids.

Exclusion Criteria

Serum bilirubin >1.5 x ULN

Serum sodium < 130

Pregnancy (positive pregnancy test) or lactation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive gemcitabine and high-dose ascorbate. Ascorbate is administered on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Gemcitabine is administered on Days 1, 8, and 15, after the infusion of ascorbate. Treatment continues for 6 cycles.

24 weeks

Visits on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment. Disease progression is assessed by CT or MRI every 2 cycles.

12 weeks

Every 2 cycles

Extension

Participants whose disease has not progressed and who are tolerating therapy may continue treatment beyond 6 cycles at the discretion of the investigator.

Indefinite, based on disease progression

What Are the Treatments Tested in This Trial?

Interventions

• Ascorbate

Trial Overview The trial is testing the effectiveness of combining Gemcitabine (a chemotherapy drug) with Ascorbate (high-dose vitamin C) to treat various types of sarcomas. The study aims to see if this combination can help control the disease better than existing treatments.

How Is the Trial Designed?

Group I: Gemcitabine + High-Dose Ascorbate Experimental Treatment 1 Intervention

Ascorabte is administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Treatment will be terminated with progression of disease. Disease will be assessed by CT of the chest, abdomen and pelvis or MRI of the lesion every 2 cycles for progression.

Ascorbate is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as Ascorbic Acid for:

• Scurvy
• Dietary supplement

Approved in European Union as Vitamin C for:

• Scurvy
• Dietary supplement

Approved in Canada as Ascorbate for:

• Scurvy
• Dietary supplement

Approved in Japan as Ascorbic Acid for:

• Scurvy
• Dietary supplement

Approved in China as Vitamin C for:

• Scurvy
• Dietary supplement

Approved in Switzerland as Ascorbate for:

• Scurvy
• Dietary supplement

Who Is Running the Clinical Trial?

University of Iowa

Lead Sponsor

Trials

486

Recruited

934,000+

Mohammed Milhem

Lead Sponsor

Trials

9

Recruited

240+

Varun Monga, MD

Lead Sponsor

Trials

7

Recruited

130+

Mohammed Milhem, MBBS

Collaborator

Trials

2

Recruited

40+

University of Iowa Adolescent and Young Adult (AYA) Cancer Program

Collaborator

Trials

2

Recruited

40+

St. Baldrick's Foundation

Collaborator

Trials

19

Recruited

9,100+

Published Research Related to This Trial

Magnesium ascorbyl-2-phosphate is as effective as ascorbic acid in stimulating collagen synthesis in dermal fibroblasts, making it a suitable alternative for experiments requiring stable conditions.

The sodium salt of ascorbyl-2-phosphate is less effective, needing a tenfold higher concentration to match the collagen synthesis stimulation of ascorbic acid, highlighting the importance of choosing the right form for research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulation of collagen synthesis in human dermal fibroblasts by the sodium and magnesium salts of ascorbyl-2-phosphate. Geesin, JC., Gordon, JS., Berg, RA.[2019]

Palmitoyl ascorbate liposomes (PAL) demonstrated significantly greater anticancer effects compared to free ascorbic acid (AA) in both in vitro and in vivo studies, particularly in slowing tumor growth in mice with mammary carcinoma.

The mechanism of action for PAL involves the production of extracellular reactive oxygen species and the involvement of intracellular transition metals, indicating a novel approach to inducing cancer cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Palmitoyl ascorbate liposomes and free ascorbic acid: comparison of anticancer therapeutic effects upon parenteral administration. Sawant, RR., Vaze, OS., Wang, T., et al.[2021]

Intravenous ascorbate (vitamin C) can reach high concentrations in the blood and tissues, effectively killing cancer cells through pro-oxidant effects without harming normal tissues, unlike oral ascorbate which was ineffective in previous trials.

In mouse models, intravenous ascorbate combined with standard chemotherapy drugs like carboplatin and paclitaxel not only inhibited ovarian cancer growth but also reduced the toxicity associated with chemotherapy, suggesting a promising avenue for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Ma, Y., Chapman, J., Levine, M., et al.[2015]

Ascorbate (vitamin C) is essential for human health and acts as a cofactor for various metabolic enzymes, highlighting its importance beyond just being a vitamin.

The review discusses the controversial role of ascorbate as an anticancer agent, summarizing both its potential antitumor effects and the limitations that have been reported in previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The prospects of vitamin C in cancer therapy. Lee, WJ.[2021]

Vitamin C (VC) significantly prevented the induction of malignant sarcomas in mice when administered in drinking water, demonstrating its potential as a prophylactic treatment against cancer.

However, VC did not significantly reduce the size or weight of existing tumors, indicating that while it may help prevent cancer development, it is not effective as a therapeutic intervention once tumors have formed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive effect of vitamin C (L-ascorbic acid) on methylcholanthrene-induced soft tissue sarcomas in mice. Abdel-Galil, AM.[2018]

Ascorbic acid and its derivatives, such as sodium L-ascorbate, were found to induce apoptosis in human promyelocytic leukemic HL-60 cells, characterized by cell shrinkage and DNA fragmentation, at concentrations of 1-10 mM.

The study suggests that the ascorbyl radical produced during the degradation of these compounds plays a key role in triggering apoptosis, as indicated by the elevation of intracellular calcium levels, while certain derivatives did not induce these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between ascorbyl radical intensity and apoptosis-inducing activity. Sakagami, H., Satoh, K., Ohata, H., et al.[2017]

Pharmacological ascorbate (high-dose vitamin C) shows potential as an effective addition to standard treatments for soft tissue sarcomas, specifically fibrosarcoma and liposarcoma, based on preclinical studies in both lab and animal models.

The effectiveness of ascorbate is linked to its ability to induce toxicity and DNA damage in cancer cells through mechanisms involving hydrogen peroxide and intracellular labile iron, suggesting it could be a safe and non-toxic complement to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models. Schoenfeld, JD., Sibenaller, ZA., Mapuskar, KA., et al.[2022]

A case study suggests that mega ascorbic acid therapy may have been effective in treating reticulum cell sarcoma, indicating potential therapeutic benefits of high-dose vitamin C in cancer treatment.

Despite the initial success with ascorbic acid, the patient later developed papillary thyroid carcinoma, raising questions about the long-term efficacy and role of ascorbic acid in cancer prevention and body resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a papillary thyroid carcinoma in a patient while on high dosage ascorbic acid therapy. Campbell, A.[2019]

Intravenous administration of ascorbate (vitamin C) can achieve much higher plasma concentrations compared to oral intake, which is limited by absorption and excretion processes.

High concentrations of ascorbate have shown potential cell toxicity in laboratory studies, suggesting that the method of administration may significantly impact its effectiveness in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ascorbate induces autophagy in pancreatic cancer. Cullen, JJ.[2021]

In a phase I clinical trial involving 9 patients with stage IV pancreatic adenocarcinoma, pharmacological ascorbate (vitamin C) combined with gemcitabine was found to be well tolerated, with few adverse effects reported.

The treatment resulted in significantly higher plasma ascorbate levels and a mean survival of 13 months for patients who completed at least two cycles, suggesting potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Welsh, JL., Wagner, BA., van't Erve, TJ., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04877587

Gemcitabine With Ascorbate Including Adolescents The purpose of this research study is to see if a high dose of ascorbate (Vitamin C), in combination with the chemotherapy drug gemcitabine, ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23381814/

results from a phase I clinical trial - PubMed - NIH Conclusions: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2213231724003537

A randomized trial of pharmacological ascorbate ... The average overall survival (OS) at 5 years is currently 12 %, with an abysmal 3 % for those diagnosed with distant disease [5]. Despite promising results with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3482496/

Pharmacologic ascorbate synergizes with gemcitabine in ... The prognosis is poor, with estimated 5-year survival rates of less than 5% [1]. In addition to late detection and fulminant disease course, the high mortality ...

5. medicine.uiowa.edu medicine.uiowa.edu/news/2024/11/high-dose-iv-vitamin-c-plus-chemotherapy-doubles-survival-advanced-pancreatic-cancer

High-dose IV vitamin C plus chemotherapy doubles survival in ... The results showed that average overall survival was 16 months for the patients receiving the chemotherapy plus vitamin C, compared to eight ...

6. ados-oncologia.org ados-oncologia.org/files/Pharmacological-Ascorbate-with-Gemcitabine-for-the-Control-of.pdf

NIH Public Access Our phase I trial was designed to determine the effect of escalating doses of ascorbate when combined with gemcitabine in stage IV pancreatic cancer patients.

7. pure.psu.edu pure.psu.edu/en/publications/pharmacological-ascorbate-with-gemcitabine-for-the-control-of-met

Pharmacological ascorbate with gemcitabine for the control ... Conclusions: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest ...