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Vitamin C

Vitamin C (ascorbic acid) 500 mg/capsule. Ingestion of 2 capsules (1000 mg) daily for 12 months.

Placebo capsule. Ingestion of 2 capsules daily for 12 months. Placebo will be prepared as capsules that look and taste identical to the vitamin C supplement capsules. The content of the placebo is lactose, potato starch, gelatin, magnesium stearate, and talc.

Monotherapy with oral vitamin C supplementation to elevate plasma vitamin C level to the upper end of the physiological range.

Vitamin C (ascorbic acid)

Placebo

Kirsten Grønbæk, Professor

The primary purpose of this multi-centre, randomized, placebo-controlled, double-blind phase II study is to investigate if oral vitamin C may change the biology of low-risk myeloid malignancies; i.e., clonal cytopenia of undetermined significance (CCUS), low-risk myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML)-0/1 by reversing the epigenetic changes characteristic of these disease entities. The epigenetic regulator TET2 is the gene most often affected in CCUS. Preclinical studies have shown that active demethylation by the TET enzymes is dependent on vitamin C, and the investigators and collaborators have shown that plasma vitamin C levels are exceedingly low in hematological cancer patients but are easily corrected by oral vitamin C. This study is part of an array of EVITA studies aimed at clarifying whether the standard of care of patients with myeloid malignancies should be changed and oral vitamin C supplement added to the treatment recommendations.

BACKGROUND Recent investigations have shown that mutations in epigenetic regulators are common, both in the apparently normal hematopoiesis of the elderly and in patients (pts) with myeloid cancers. It was long anticipated that DNA methylation was a permanent silencing mark, but with the discovery of the ten eleven translocation (TET) enzymes it became clear that active demethylation occurs. The initial steps in this process are catalyzed by TET enzymes, which are, however, frequently mutated and methylated in hematological cancers. The Jumonji enzymes, which catalyze histone demethylation, are also aberrantly regulated in hematological cancers.

Vitamin C (VitC) was identified in the 1930'ies as the necessary micronutrient in the prevention of scurvy. Unlike plants and most animals, humans are unable to synthesize vitC from glucose due to lack of the required enzyme, L-gulonolactone oxidase. Therefore, vitC must be provided through the diet. Recent studies recognize vitC as an important cofactor for the Fe(II)- and 2-oxoglutarate dioxygenase family. These include the TET enzymes, which are involved in the conversion of 5-methylcytosine (5-mC) to its oxidized derivatives 5-hydroxymethylcytosine (5-hmC), 5-carboxyl cytosine (5-caC), and 5-formylcytosine (5-fC), and the Jumonji enzymes that are involved in histone demethylation. Accordingly, vitC may potentially play an important role in the regulation of DNA and histone demethylation. However, \> 80 percentage of hematological cancer pts were found to be severely vitC deficient. Interestingly, analyses of 20 participants included in the investigators' recently conducted randomized, placebo-controlled pilot study (NCT02877277) show that the level of vitC in MDS and CMML pts undergoing treatment with azacitidine, is easily elevated to the normal range by oral vitC supplement (unpublished data). When pts that were already taking vitC supplements were switched to placebo, the vitC levels quickly dropped below the normal range.

It has also been shown that the formation of 5-hmC and its derivatives may be compromised in healthy individuals and pts with TET mutations. However, since many of these mutations are heterozygous, and since the three TET enzymes (TET1, TET2, and TET3) may have some redundancy, restoration of vitC to physiological levels might have an impact on the level of 5-hmC/5-mC in individuals with TET mutant clonal hematopoiesis or hematological cancer.

Analyses of 5-hmC/5-mC levels in peripheral blood (PB) mononuclear cells (MNCs) from the participants in the pilot study also showed a clear trend toward increased 5-hmC in the vitC arm, however, after designing the trial the investigators realized that 5-hmC/5-mC levels are better measured in hematopoietic stem cells in the bone marrow (BM) where the levels are 10-20 fold higher. Thus, the pilot study will be followed-up with a randomized placebo-controlled trial of oral vitC in individuals with low-risk myeloid malignancies; i.e., CCUS or low-risk MDS/CMML, to investigate if oral vitC can change the biology of these disease entities and ultimately prevent progression.

Hypotheses:

1. The investigators and collaborators have previously shown that cancer pts are vitC deficient, and individuals with CCUS, which represents pre-MDS, might also be vitC deficient. The hypothesis is that this may lead to reduced levels of 5-hmC/5-mC in vivo in both cancer pts and individuals with CCUS
2. Elevating serum vitC levels to the normal range in CCUS and low-risk MDS/CMML pts by oral supplementation with vitC may

   * reduce the malignant clone,
   * increase the 5-hmC/5-mC ratio,
   * change the plasma cytokine profile towards a less inflammatory, less tumorigenic profile,
   * change gene expression

Aims:

To determine if restoring vitC to the normal range in CCUS and low-risk MDS/CMML pts can:

1. reduce the malignant clone,
2. increase the 5-hmC/5-mC ratio in CCUS and low-risk MDS/CMML pts
3. reduce accumulation of 5-mC at promoters/enhancers/long terminal repeats (LTRs), or at other regulatory genomic regions of tumor suppressors/methylated driver genes/genes involved in hematopoietic development,
4. upregulate the expression of these genes,
5. change the plasma cytokine profile,
6. alter intestinal permeability (measured by concentration of bacterial DNA in peripheral blood) and/or composition of gut microbiota,
7. entail any safety risks.

RESEARCH PLAN A total of 100 patients is planned for enrolment. Individuals with CCUS, low-risk MDS, or CMML-0 or -1 will be included from Rigshospitalet, Herlev University Hospital, Odense University Hospital, Aalborg University Hospital or Keck Hospital of University of Southern California between November 2017-December 2021.

The participants will enter block randomization with a ratio of 1:1; vitC 1000 mg/day p.o. versus placebo for one year.

Up to 30 healthy elderly volunteers are planned for enrolment. Amount and type of bacterial DNA in PB will be determined and serve as controls.

MATERIAL AND MEASUREMENTS PB: PB samples (45 mL) will be taken at study entry and every 3 months (or more if required according to physician's choice) during the first year.

Measurements include blood counts including differential count, levels of folic acid, vitamin B12, vitamin D, iron, ferritin, transferrin, transferrin saturation, plasma vitC levels, cytokines, and bacterial DNA content (referenced to bacterial DNA on patient's skin and in feces).

BM: BM samples (18 mL) will be taken at study entry, after 3 months, and after one year.

Levels of vitC and various cytokines will be measured. Mutations in genes frequently involved in myeloid cancer/clonal hematopoiesis, including epigenetic regulators, and variant allele frequencies (VAF) will be investigated by targeted next generation sequencing in sorted BM CD34+ cells (if available) or BM negative fraction of CD34+ sorting at study entry, after 3 months and after one year.

RNA sequencing and total 5-hmC/5-mC assessment will be performed on BM CD34+ hematopoietic stem cells.

Feces: Feces samples (9 mL) will be collected from a subset of patients at study entry, after 3 months, and after one year. Bacterial DNA will be extracted and sequenced.

RESEARCH BIOBANK A research biobank will be established at The Epi-/Genome Laboratory, Rigshospitalet / Biotech Research and Innovation Centre to store the biological samples from the participants. The research biobank is approved by the Regional Science Ethics Committee and the Danish Data Protection Agency in accordance with the Act on Processing of Personal Data (license no. H-16022249 and 04864/RH-2016-259, respectively). Cryopreserved separated MNCs from BM and PB will be stored in addition to granulocyte pellets and plasma. The date for closing the research biobank is 31-12-2030.

For correlative studies, biological samples will be sent to Van Andel Research Institute, Grand Rapids, US, and Imperial College, London, UK (external collaborators), for RNA sequencing and analyses of DNA methylation and hydroxymethylation, respectively. Biological samples will also be sent to Life Science Faculty, University of Copenhagen, and The National Veterinary Institute, Technical University of Denmark (external collaborators) for measurement of serum vitC concentrations and analyses of T cell responses, respectively.

METHODS VitC measurement: Ascorbate and total vitC, i.e., ascorbate + dehydroascorbic acid (the oxidized form of vitC; DHA), are quantified by high-performance liquid chromatography (HPLC) with coulometric detection; DHA is assessed by subtraction of ascorbate from total vitC. Uric acid is used as endogenous internal standard.

Cell sorting: Magnetic-activated cell sorting (MACS, using a EasySep device).

Total 5-hmC/5-mC measurement: Dot blot analysis of 5-hmC. 5-hmC/5-mC measurement by Mass Spectrometry.

Locus specific 5-hmC/5-mC measurement: "EPIC" 850 K BeadChips. 5-hmC/5-mC at selected sites will be measured by pyrosequencing.

Gene expression: Total RNA sequencing and reverse transcriptase-quantitative polymerase chain reaction.

Mutation detection: Targeted next generation sequencing of a panel of genes recurrently mutated in myeloid cancer as described.

STATISTICAL CONSIDERATIONS AND POWER CALCULATION This study is the first study to examine the effects of vitC as monotherapy on 5-hmC/5-mC levels in hematopoietic stem cells in humans in vivo. Therefore, it is not possible to perform a power calculation or a sample size calculation. The number of participants (n=100) is set as an estimate of the number needed to observe a potential significant difference between the groups (vitC vs. placebo) in the primary endpoint; median change in VAF of somatic mutations from baseline to 12 months.

Efficacy analyses are by intention-to-treat. Safety analyses include all participants who receive at least one dose of protocol therapy.

ETHICAL CONSIDERATIONS The study has been approved by the Regional Science Ethics Committee (H-16022249) and the Danish Data Protection Agency (04864/RH-2016-259).

All participants included in the project will be informed orally and in writing. Participation will only be accepted after written consent. Participants will be informed that they can at any time for any reason withdraw from the study without it affecting their treatment in the health care system.

Using the targeted DNA sequencing approach described, there is a small risk of detecting a germline mutation in the participants related to myeloid malignancy. The participants will be asked to state in the informed consent if they do not want to receive any further relevant health-related information that may appear during the project analyses. Unless the participant explicitly states that he or she does not want to be informed of any potential health-related random findings in the study, the participant will be informed and offered further investigations and genetic counseling at the local hospital in case of random findings.

Patient disadvantages, side effects, risks, and complications Blood sampling is associated with brief discomfort and/or pain. No significant risks are associated with the blood sampling. Local bleeding can occur, which in rare cases can cause discomfort and discoloration for a few days. Rarely, a blood sampling can cause vasovagal reaction leading to a brief loss of consciousness.

BM aspiration is associated with brief pain while the local anesthesia is given. Furthermore, many individuals experience an uncomfortable feeling in the nates and leg while the BM is aspirated. This lasts approximately 30 seconds. Finally, some tenderness can occur for a few days after the procedure. Possible complications to undergoing a BM investigation include bleeding and infection. However, the incidence of these complications is extremely low.

According to the Nordic Nutrition Recommendations there is no evidence that intake of vitC above 1000 mg/day are either carcinogenic or teratogenic. However, high intakes (\> 1000-2000 mg/day) may cause diarrhea and other gastrointestinal disturbances and susceptible individuals may experience kidney stone formation from increased oxalate formation. Since vitC is only given at physiological doses, it is anticipated that the study is safe and will provide no additional risk for the participants; an assumption that is supported by the experience from the pilot study.

Prospective, randomized, placebo-controlled trial.

Randomization performed by the independent provider of study medication (Glostrup Pharmacy).

Epigenetics, Vitamin C, and Abnormal Blood Cell Formation - Vitamin C in Patients With Low-Risk Myeloid Malignancies

Epigenetics, Vitamin C, and Abnormal Hematopoiesis - Role of Vitamin C in Epigenetic Regulation in Hematopoiesis Sub-Study on CCUS, Low-Risk MDS, and CMML-0/1

Median change from baseline to 12 months in mutant allele burden as measured by the variant allele frequency (VAF) and number of mutations in the vitC group vs. the placebo group.

Mean change from baseline to 3 months and 12 months in global 5-hmC/5-mC measured in hematopoietic stem cells is compared between the vitamin C group and the placebo group. In addition, the mean change from baseline in 5-hmC/5-mC at 12 months is compared between participants in the vitamin C arm with baseline plasma vitamin C level in the normal range vs. participants in the vitamin C arm with baseline plasma vitamin C level below the normal range.

Mean change from baseline to 12 months in 5-mC at promoters/enhancers/long terminal repeats, and other regulatory genomic regions of tumor suppressors/methylated driver genes/genes involved in hematopoietic development.

Mean change from baseline to 12 months in methylated histone H3 lysine at position 9 at promoters/enhancers/long terminal repeats, and other regulatory regions of tumor suppressors/methylated driver genes/genes involved in hematopoietic development.

Mean change from baseline to 12 months in plasma cytokine levels (e.g., IL-6, S100A9, etc.).

Mean change from baseline to 12 months in mRNA levels of tumor suppressor genes, oncogenes, epigenetic regulators, cytokines, and genes involved in hematopoietic development.

Mean change from baseline to 3 months in mRNA levels of tumor suppressor genes, oncogenes, epigenetic regulators, cytokines, and genes involved in hematopoietic development.

Number of serious adverse events and treatment-related adverse events as assessed by CTCAE v5.0. Adverse events, that are not considered serious or related to vitamin C intake, will not be recorded.

Percentage of participants with baseline plasma vitamin C level below the normal physiological range.

Change in intestinal permeability and gut microbiota (concentration of bacterial DNA in PB and adscription of bacteria by sequencing)

Van Andel Institute - Stand Up To Cancer Epigenetics Dream Team

University of Southern California

Imperial College London

University of Copenhagen

Odense University Hospital

Technical University of Denmark

Aalborg University Hospital

Rigshospitalet, Denmark

Professor, MD, DMSc

Digestive System Diseases

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Antineoplastic Agents

Hematinics

Anti-Infective Agents

Irinotecan

Gemcitabine

Docetaxel

Leucovorin

Fluorouracil

Oxaliplatin

Mitomycins

Mitomycin

Levoleucovorin

Antimetabolites

Tubulin Modulators

Antimitotic Agents

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antidotes

Folic Acid

Vitamin B Complex

Anti-Bacterial Agents

Antibiotics, Antitubercular

Alkylating Agents

Folinic Acid

Folate

Vitamin B9

G-FLIP in combination with Vitamin C, then G-FLIP-DM in combination with Vitamin C

G-FLIP is a combination of Low Doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, and Oxaliplatin

G-FLIP

G-FLIP-DM is low doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, Oxaliplatin, Docetaxel and Mitomycin C

G-FLIP-DM

High dose of Vitamin C, used in combination with G-FLIP and then G-FLIP-DM

Azriel Hirschfeld, MD

Pancreatic cancer, especially at advanced metastatic stage, is a devastating disease. It is the fourth leading cause of cancer death. Its prognosis is grim - 5-year survival rate being 6%. The current therapies for advanced metastatic pancreatic cancer are very toxic and with limited efficacy. A safer and more effective therapy for this devastating disease is greatly needed.

G-FLIP regimen is a combination of low doses (doses lower than those approved by the FDA and used in the clinic) of several anti-cancer drugs, Gemcitabine, Fluorouracil, Leucovorin, Irinotecan and Oxaliplatin. The efficacy of G-FLIP against cancers (especially pancreatic cancer) is based on laboratory and clinical results, which indicates the synergistic efficacy of these anti-cancer drugs against cancer cells and overcoming tumor drug resistance that cancer cells frequently develop. Also, because of their low doses, this regimen is less toxic than when these drugs are used alone.

Meanwhile, intravenous infusion of high doses (doses significantly higher than the daily nutritional requirements) of Vitamin C (ascorbic acid) has been observed to have anti-cancer activities. This is especially true when Vitamin C is used in combination with other anti-cancer drugs.

STUDY OBJECTIVE

The objective of this study is to evaluate the safety, tolerability and efficacy of G-FLIP (Low Doses of Gemcitabine, Fluorouracil \[5FU\], Leucovorin, Irinotecan, and Oxaliplatin), when used in combination with ascorbic acid (Vitamin C), as first-line therapy in patients with advanced pancreatic cancer. The objective of this study is also to evaluate the safety, tolerability and efficacy of G-FLIP-DM (G-FLIP + Low Doses of Docetaxel and Mitomycin C), when used in combination with ascorbic acid, in patients with advanced pancreatic cancer who develop Disease Progression (DP) with G-FLIP treatment. The primary endpoint is 12-month survival rate. The secondary endpoints include Overall Survival (OS), Quality of Life (QOL), Response Rate (RR), Progression-Free-Survival (PFS), and safety.

STUDY DRUGS

Study drugs include G-FLIP, G-FLIP-DM, and Vitamin C (Ascorbic Acid)

STUDY DESIGN

Sample Size:

There will be 30 "evaluable" study subjects in this study.

Treatments:

G-FLIP: All study subjects are treated with G-FLIP. Each treatment cycle of G-FLIP is 2 weeks, with G-FLIP given on Days 1 and 2 of each cycle. If study subjects exhibit Disease Progression (DP), treatment with G-FLIP will stop, and they will be treated with G-FLIP-DM.

G-FLIP-DM: Study subjects who exhibit DP with G-FLIP treatment will be treated with G-FLIP-DM. Each G-FLIP-DM treatment cycle is 2 weeks, with G-FLIP-DM given on Days 1 and 2 of each cycle.

Ascorbic Acid: Ascorbic acid will be administered twice weekly throughout the study, given on any 2 separate days of the week. Ascorbic acid will be administered throughout the study including during the follow-up period, even if treatment with G-FLIP or G-FLIP-DM has been terminated due to DP. Additionally, in 50% of the study subjects (i.e., 15 evaluable study subjects), treatment with ascorbic acid will begin on the same week when G-FLIP begins. In the other 50% of the study subjects (i.e., the other 15 evaluable study subjects), treatment with ascorbic acid will be delayed by 2 cycles. Results from these 2 groups of study subjects would allow comparison of potential acute safety of ascorbic acid, when used in combination with G-FLIP.

Open-Label: This is an open-label study, where investigators and study subjects are not blinded to the treatment.

Randomization: The assignment of study subjects will be randomized, as long as they meet eligibility criteria of the study.

DOSE DELAY AND DOSE MODIFICATION

In the event of adverse drug reactions, dose delay and dose modification will be dependent on the type of toxicities. The detailed dose modification scheme for G-FLIP, G-FLIP-DM and Ascorbic Acid are outlined in the protocol.

CONCOMITANT MEDICATIONS AND PROPHYLACTIC TREATMENT

Other than G-FLIP, G-FLIP-DM and ascorbic acid, patients cannot receive any other standard or investigational treatment for their cancer, or any study drugs for any non-cancer indications, while on this study. All concomitant medications (including names, dosage and schedule) must be recorded.

Prophylactic treatment for drug-related symptoms can be given according to Package Inserts of the study drugs and clinical practice. Supportive treatment may include anti-emetic, anti-diarrhea, anti-pyretic, anti-allergic, anti-hypertensive, analgesics, antibiotics, allopurinol, and others such as blood products and bone marrow growth factors. Patients may use erythropoietin for anemia. The investigator may utilize erythropoietic factors, or blood or platelet transfusions at their discretion.

DURATION OF TREATMENT AND FOLLOW-UP

At least six months of treatment is recommended for study subjects who have a response from G-FLIP or G-FLIP-DM, unless or until:

* Patients exhibit disease progression in the opinion of the principal investigator
* Unacceptable toxicity from the treatment
* Patient withdrawal of consent (Note: The investigator should make every effort to contact the subject to perform a final evaluation and to determine the reason(s) for withdrawal from the study.)
* Investigator's discretion to withdraw patients from the study because continued participation in the study is not in the patient's best interest.
* Underlying illness: a condition, injury, or disease unrelated to the intended disease which the study is investigating, that renders continuing treatment unsafe or regular follow-up impossible
* General or specific changes in the patient's condition that renders the patient ineligible for further investigational treatment
* Non-compliance with investigational treatment, protocol-required evaluations or follow-up visits

After treatment, study subjects should be followed so that information on survival and post study treatment are available for at least 1 year after the study subjects participate in the trial.

EFFICACY ASSESSMENTS

The efficacy of the study drugs will be assessed according to the following parameters:

Response Criteria of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (Disease Progression or DP) will be derived from CT or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009).

Response Rate (RR) is the number of study subjects, expressed as a percentage of the total number of study subjects participated in the trial, who exhibit PR or CR that has been confirmed from 2 consecutive scans (CT or MRI).

Progression-Free-Survival (PFS) is the length of time when SD (or better) of a study subject is first documented until the time when DP, or death from any cause, occurs.

Overall Survival (OStreatment) is the time from which the study subjects are first treated with G-FLIP to the time when death from any cause occurs. OS, which is the time from which the study subjects are first diagnosed with advanced pancreatic cancer to the time when death from any cause occurs, will also be recorded.

12-Month Survival Rate is the number of study subjects, expressed as a percentage of the total number of study subjects in the trial, who survive for 12 months starting from the time when the study subjects are accrued to the trial. The 12-Month Survival Rate for study subjects who survive for 12 months starting from the time when the study subjects are first diagnosed with advanced pancreatic cancer will also be recorded.

Safety Assessments

The efficacy of the study drugs will be assessed from the first dose to 1 month after last dose of the study drugs. The assessments will be based on the following parameters, performed at baselines and at various times during the study:

* physical exams
* evaluation of symptoms
* vital signs
* ECOG performance status and survival
* clinical pathology (clinical chemistry, renal function \[assessed utilizing the Cockcroft-Gault formula\], hematology, and coagulation)
* urinalysis
* QOL, assessed as described by Aaronson NK, et al. 1993.

Ph 2 Trial of Vitamin C & G-FLIP (Low Doses Gemcitabine, 5FU, Leucovorin, Irinotecan, Oxaliplatin) for Pancreatic Cancer

Ph 2 Trial of G-FLIP (Low Doses Gemcitabine, 5FU, Leucovorin, Irinotecan & Oxaliplatin), Followed by G-FLIP-DM (G-FLIP + Low Doses Docetaxel & MitomycinC), When Used in Combination With Vitamin C, in Patients With Advanced Pancreatic Cancer

Responses to Quality of Life questionnaire over a year since the start of treatment.

The number of study subjects that have a Partial Response (PR) or Complete Response (CR).

The duration of Stable Disease (SD), Partial Response (PR), or Complete Response (CR)

The incidence of adverse events, as measured by blood tests, signs/symptoms, etc.

The number of subjects that survive 12 months after the start of treatment

The number of study subjects survive for 2 years since the start of treatment.

Bruckner Oncology

Heart and Blood Diseases

Immune System Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Melphalan

Bortezomib

Arsenic Trioxide

Antineoplastic Agents, Alkylating

Arm 1: Melphalan 100 mg/m\^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily

Arm 2: Bortezomib (Level 1) 1.0 mg/m\^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m\^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily

Arm 3: Bortezomib (Level 2) 1.5 mg/m\^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily

0.25 mg/kg by vein over 2 hours, once a day for 7 days (Days -9 to -3).

Trisenox (Arsenic Trioxide)

Arm 1 (Level 1):

1.0 mg/m\^2 intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute).

Arm 2 (Level 2):

1.5 mg/m\^2 intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute).

Velcade (Bortezomib)

100 mg/m2 by vein days -4,-3, over 30 minutes

1000 mg once a day through the vein for 7 days.

Vitamin C (Ascorbic Acid)

Muzaffar H. Qazilbash, MD

Primary Objectives:

1. To evaluate the toxicity and safety of a combination of bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan in patients with multiple myeloma
2. To evaluate the efficacy of a combination of bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan in patients with multiple myeloma
3. To determine the effects of bortezomib on melphalan pharmacokinetics

Melphalan is designed to damage the DNA of cells, which may cause cancer cells to die. High-dose melphalan is considered the standard of care for multiple myeloma. Bortezomib is designed to block a protein that plays a role in cell function and growth, which may cause cancer cells to die. Arsenic trioxide may cause cancer cells to die, and researchers want to find out if arsenic trioxide helps melphalan in killing cancer cells. Vitamin C makes arsenic trioxide more available inside the cancer cells, and researchers want to learn if Vitamin C makes arsenic trioxide more effective.

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate). Your complete medical history will be recorded. You will have a dental exam to check for any infected teeth or gums that may flare up after chemotherapy.

You will have a bone marrow aspirate and biopsy. To collect a bone marrow aspirate/biopsy, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. Cytogenetic tests will be performed on the aspirate sample to look for any genetic abnormalities in your DNA. You will have x-rays of your bones taken. The study doctor will look at the x-rays to see if there are any myeloma-related bone changes. You will also have a chest x-ray.

You will have blood (about 2 tablespoons) and urine collected for routine tests. You will have a pulmonary function test, to check if your lungs are strong enough for high-dose chemotherapy. You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). You will also have a MUGA scan to evaluate the function of your heart. Women who are able to have children must have a negative blood pregnancy test. The blood will be drawn as part of the 2 tablespoons drawn at screening.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of dice) to one of 3 treatment groups. There is an equal chance of being assigned to any of the 3 groups. All 3 groups will receive melphalan, arsenic trioxide, and Vitamin C. The second and third groups will also receive bortezomib, but at different dose levels. The first 3 participants assigned to receive bortezomib on this study will receive the lower of 2 bortezomib dose levels.

You will receive arsenic trioxide through a needle in a vein over 2 hours, once a day for 7 days (Days -9 to -3). At the same time, you will receive Vitamin C once a day through the vein for 7 days. After you receive the arsenic trioxide on Days -4 and -3, you will receive melphalan through the vein over 30 minutes.

If you are in Group 2 or 3, you will receive bortezomib by an intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute).

You will receive standard inpatient and outpatient stem cell transplant care and testing. You will have to sign a separate consent form that describes the transplant procedure and its risks. Your stem cells will be reinfused 2 days after the last dose of melphalan. To check for any side effects, you will have an ECG performed 14 days after the transplant.

If intolerable side effects from the chemotherapy occur or there is sign of disease after the transplant, you will be taken off study. If you have already received melphalan and side effects occur, then the transplant will happen. However, if intolerable side effects develop before melphalan, then you may be taken off study without having the transplant. If you are taken off study early, you still may need to return for routine post-transplant follow-up visits, if your transplant physician decides it is necessary.

If there is no sign of disease after the transplant, you will have routine follow-up visits. Blood (about 2 tablespoons) will be drawn for routine tests at least once a week during the first month after the transplant, and then once every month for the next 3 months after that. At about 3, 6, and 12 months after the transplant, you will have bone marrow biopsies and aspirates performed to check the status of the disease. You will have blood (about 2 tablespoons) and urine collected for routine tests. At 12 months after the transplant, you will have x-rays of your bones taken.

One (1) year after the transplant, your participation in this study will be over.

This is an investigational study. Bortezomib, arsenic trioxide, and melphalan are commercially available and FDA-approved for use in patients with myeloma. However, their use in combination with Vitamin C (also commercially available) is investigational. Up to 60 patients will take part in this study. All will be enrolled at M. D. Anderson.

Velcade, Trisenox, Vitamin C and Melphalan for Myeloma Patients

Phase I/II Study of the Combination of Bortezomib With Arsenic Trioxide, Ascorbic Acid and High-Dose Melphalan for Patients With Multiple Myeloma

Number of participants with CR at Day 180 who had maintained CR for at minimum of 4 weeks, and who had: No monoclonal protein in urine/serum when analyzed by immunofixation electrophoresis; bone marrow normal by morphological examination with \<5% plasma cells, \<1% aneuploid light chain restricted population by flow cytometry for DNA/cIg; and, while healing of bony lesion is not required, no new lytic lesion should appear. Further compression fracture of spine not considered progressive disease.

The time to patient toxicity of drug combination bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan defined in days from baseline measure to occurence of adverse events grade 4 (life threatening or disabling) according to National Cancer Institute Common Toxicity Criteria (CTC), version 3.

Cephalon

M.D. Anderson Cancer Center

Melphalan 100 mg/m\^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily

No Bortezomib

Bortezomib (Level 1) 1.0 mg/m\^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m\^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily

Bortezomib 1.0 mg/m^2

Bortezomib (Level 2) 1.5 mg/m\^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily

Bortezomib 1.5 mg/m^2

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Muzaffar H. Qazilbash, MD/Professor, Stem Cell Transplantation

Number of Patients Reaching Complete Response (CR)

Time to Toxicity

Overall Study

Hematologic Neoplasms

ascorbic acid 1.5 g/kg body weight infused over 90 to 120 minutes two or three times weekly concurrent with standard cytotoxic chemotherapy individually selected for each patient by the treating oncologist on the basis of best current clinical practice

vitamin C (ascorbic acid)

Leonard John Hoffer, MD PhD

Concurrent administration of intravenous vitamin C (ascorbic acid, 1.5 g/kg, infused two or three times weekly) together with certain cytotoxic chemotherapy regimens could prove to be an effective treatment for some patients with advanced malignancies for whom existing chemotherapy is usually ineffective. The primary objectives of this study are to identify a tolerable and safe dose of intravenous vitamin C when administered during cytotoxic chemotherapy while attempting to empirically identify specific vitamin C-chemotherapy regimens for which the clinical response is unusually favorable after a minimum of 2 months of therapy, as determined by CT scan and biomarkers, when appropriate.

Cytotoxic chemotherapy is relatively ineffective for a large proportion of common cancers. Combining redox active molecules with certain chemotherapy regimens could increase their anti-cancer activity or protect host tissues from toxicity with no loss of anti-cancer activity. Research in this area has been advocated by cancer organizations, but previous clinical trials of combination chemotherapy and antioxidant therapy been small, poorly designed, and unsystematic. Appropriate study of this treatment concept requires a systematic, meticulous empirical approach similar to the one used in conventional cytotoxic drug discovery. This is a Phase I-II study designed to identify promising chemotherapy-antioxidant protocols and determine their acceptability and limiting toxicity in patients with relentlessly progressive cancers for which conventional chemotherapy is clinically indicated but is known to be minimally or marginally effective.

The tolerable dose of intravenous ascorbic acid (IVAA) for cancer patients with normal renal function not receiving chemotherapy is 1.5 g/kg per 90 to 120 minute infusion (Hoffer et al, Ann Oncol 2008;19:1969-1974). Side effects are minimal to non-existent. In this dose-escalating study the IVAA will be 0.9 g/kg per infusion for the first chemotherapy cycle, increasing to 1.5 g/kg per infusion in subsequent cycles, for the first 3 participants. If well tolerated as expected, the initial dose will be 1.5 g/kg per infusion for subsequent participants. Infusions will take place 2 or 3 times per week, bracketing the days of chemotherapy. Standard tolerance and adverse effect criteria will be used. Therapy will continue for a minimum of 2 months, and continue further in the event of disease stabilization or response, as determined from CT scan and biomarkers, with evaluations continuing every 2 months.

Trial of Chemotherapy Plus Intravenous Vitamin C in Patients With Advanced Cancer for Whom Chemotherapy Alone is Only Marginally Effective

Phase I - II Clinical Trial of Combination Conventional Cytotoxic Chemotherapy and Intravenous Vitamin C in Patients With Advanced Cancer or Hematologic Malignancy for Whom Cytotoxic Chemotherapy Alone is Only Marginally Effective

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Epigenetics, Vitamin C, and Abnormal Blood Cell Formation - Vitamin C in Patients With Low-Risk Myeloid Malignancies	NCT03682029	Myelodysplastic... Chronic Myelomo... Cytopenia	Vitamin C (asco... Placebo	18 Years -	Rigshospitalet, Denmark
Epigenetics, Vitamin C, and Abnormal Blood Cell Formation - Vitamin C in Patients With Low-Risk Myeloid Malignancies	NCT03682029	Myelodysplastic... Chronic Myelomo... Cytopenia	Vitamin C (asco... Placebo	18 Years -	Rigshospitalet, Denmark
Ph 2 Trial of Vitamin C & G-FLIP (Low Doses Gemcitabine, 5FU, Leucovorin, Irinotecan, Oxaliplatin) for Pancreatic Cancer	NCT01905150	Pancreatic Canc...	G-FLIP G-FLIP-DM Vitamin C	18 Years -	Bruckner Oncology
Velcade, Trisenox, Vitamin C and Melphalan for Myeloma Patients	NCT00469209	Myeloma	Trisenox (Arsen... Velcade (Bortez... Melphalan Vitamin C (Asco...	- 75 Years	M.D. Anderson Cancer Center
Ph 2 Trial of Vitamin C & G-FLIP (Low Doses Gemcitabine, 5FU, Leucovorin, Irinotecan, Oxaliplatin) for Pancreatic Cancer	NCT01905150	Pancreatic Canc...	G-FLIP G-FLIP-DM Vitamin C	18 Years -	Bruckner Oncology
Trial of Chemotherapy Plus Intravenous Vitamin C in Patients With Advanced Cancer for Whom Chemotherapy Alone is Only Marginally Effective	NCT01050621	Cancer	vitamin C (asco...	18 Years -	Jewish General Hospital
Epigenetics, Vitamin C, and Abnormal Blood Cell Formation - Vitamin C in Patients With Low-Risk Myeloid Malignancies	NCT03682029	Myelodysplastic... Chronic Myelomo... Cytopenia	Vitamin C (asco... Placebo	18 Years -	Rigshospitalet, Denmark

Spots Global Cancer Trial Database for vitamin c (ascorbic acid)