Gemcitabine + Ascorbate for Sarcoma

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

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will enroll patients who have a diagnosis of locally advanced, unresectable or metastatic soft tissue or bone sarcoma (except gastrointestinal stromal tumors and Kaposi's sarcoma) from any site.

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.

What data supports the idea that Gemcitabine + Ascorbate for Sarcoma is an effective treatment?

The available research shows that vitamin C (ascorbate) has been studied for its potential in cancer treatment, including sarcoma. In one study, vitamin C was found to prevent the development of sarcomas in mice, although it did not significantly reduce the size or weight of existing tumors. This suggests that vitamin C might help in preventing sarcoma but may not be as effective in treating it once it has developed. There is no direct evidence from the provided research that Gemcitabine + Ascorbate is effective for sarcoma specifically, but vitamin C has shown some preventive effects in animal studies. Additionally, vitamin C combined with another drug, gemcitabine, has been tested for safety in pancreatic cancer, which might suggest potential for use in other cancers, but more specific research would be needed for sarcoma. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Gemcitabine + Ascorbate for Sarcoma?

Research shows that vitamin C (ascorbate) can prevent the development of certain types of sarcomas in mice, suggesting it might help in preventing tumor growth. Additionally, high doses of ascorbate have shown potential antitumor effects in various cancers, including pancreatic cancer, when used with other treatments like gemcitabine. ^{1 2 3 4 5}

What safety data exists for Gemcitabine + Ascorbate treatment in sarcoma?

The safety of pharmacological ascorbate combined with gemcitabine has been evaluated in a phase I clinical trial for pancreatic cancer, which aimed to establish safety and tolerability. While this trial was not specific to sarcoma, it provides some insight into the safety profile of the combination treatment. Additionally, ascorbate (vitamin C) has been studied for its potential anticancer effects, though its role remains controversial. The preventive effect of vitamin C on sarcoma induction in mice has been noted, but it did not achieve significant therapeutic levels. Overall, while some safety data exists, specific safety data for Gemcitabine + Ascorbate in sarcoma is limited. ^{1 3 4 6 7}

Is the combination of Gemcitabine and Ascorbate safe for humans?

A phase I clinical trial found that pharmacological ascorbate (vitamin C) combined with gemcitabine was safe and tolerable in patients with advanced pancreatic cancer, suggesting it may be generally safe for human use. ^{1 3 4 6 7}

Is Vitamin C a promising treatment for sarcoma?

Yes, Vitamin C, when used in high doses, shows promise as a treatment for sarcoma. It can be easily added to existing treatments and helps kill cancer cells without harming normal cells. This makes it a potentially effective and safe option to improve current sarcoma therapies. ^{1 4 8 9 10}

What makes the drug Gemcitabine + Ascorbate unique for treating sarcoma?

The combination of Gemcitabine and high-dose intravenous ascorbate (vitamin C) is unique because it leverages ascorbate's ability to produce hydrogen peroxide, which selectively kills cancer cells without harming normal cells. This approach takes advantage of cancer cells' altered oxidative metabolism, potentially enhancing the effectiveness of existing treatments for sarcoma. ^{1 4 8 9 10}

Research Team

John Rieth, MD

Principal Investigator

University of Iowa Hospitals & Clinics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Germany 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. [2022]

2. Ireland pubmed.ncbi.nlm.nih.gov

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

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

4. Korea (South) pubmed.ncbi.nlm.nih.gov

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

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

Ascorbate induces autophagy in pancreatic cancer. [2021]

6. Greece pubmed.ncbi.nlm.nih.gov

Relationship between ascorbyl radical intensity and apoptosis-inducing activity. [2017]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Regulation of collagen synthesis in human dermal fibroblasts by the sodium and magnesium salts of ascorbyl-2-phosphate. [2019]

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

Palmitoyl ascorbate liposomes and free ascorbic acid: comparison of anticancer therapeutic effects upon parenteral administration. [2021]

9. Netherlands 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. [2022]

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

High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. [2015]