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Table 2 16 published clinical studies using medium-to-high dose IVC as anti-cancer therapy

From: High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer

Cancer type (s) Allocation/Phase Interventions VitC IV dosea VitC dosage and injection scheme No. patients Results Conclusions/Comment Ref.
IVC monotherapy
 Advanced cancers Single group, Phase 1 IVC monotherapy high 30–110 g/m2 (0.8–3.0 g/kg), 4x/week, 4 weeks
(both consecutive), rate of 1 g/min
17 All doses were well tolerated. Doses of 70, 90, and 110 g/m2 maintained levels at or above 10–20 mM for 5–6 h (Cmax 49 mM). No objective antitumor response Recommended dose for future studies is 70–80 g/m2 (= 1.9–2.2 g/kg) based on Cmax [13, 125]
Single group, Phase 1 IVC monotherapy high 0.4–1.5 g/kg, 3x/week, 4 week treatment cycles; oral dose of 500 mg twice daily on non-infusion days 24 Well tolerated, without significant toxicity; dose of 1.5 g/kg sustains plasma ascorbic acid concentrations > 10 mM for > 4 h (Cmax 26 mM); 2 patients with unexpected stable disease The recommended phase 2 dose is 1.5 g/kg; ascorbate may need to be combined with cytotoxic or other redoxactive molecules to be an efficacious treatment [12], no ClinicalTrial.gov Identifier
Single group, Phase n.s. IVC monotherapy medium 0.15–0.71 g/kg/day, continuous infusion for up to 8 weeks 24 IVC therapy relatively safe, only few and minor adverse events observed; plasma ascorbate concentrations in the order of 1 mM attained Further clinical studies with high dose IVC are warranted [65], no ClinicalTrial.gov Identifier
 Prostate Phase 2 IVC monotherapy medium 5 g week 1, 30 g week 2 and 60 g weeks 3–12; daily oral dose of 500 mg starting after first infusion for 26 weeks 23 No patient achieved the primary endpoint of 50% PSA reduction; instead, a median increase in PSA of 17 μg/L was recorded at week 12; no signs of disease remission were observed; target dose of 60 g AA IV produced a peak plasma AA concentration of 20.3 mM [126] This study does not support the use of intravenous AA outside clinical trials [66, 126, 127]
IVC combination therapy - Chemotherapy and radiation therapy
 Advanced cancers Single group, Phase 1/2 IVC + standard care cytotoxic chemotherapy high 1.5 g/kg, 2 or 3x per week 14 IVC-chemotherapy is non-toxic and generally well tolerated; individual highly favourable responses found in biliary tract, cervix and head and neck cancer patients, colorectal cancer patients without benefit Neither proves nor disproves IVC’s value in cancer therapy; illustrates potential for “discovery in clinical practice” [83, 128]
 Glioblastoma Single group, Phase 1 IVC + RT + temozolomide (TMZ) high Radiation phase: 15–125 g, 3x weekly, 7 weeks; Adjuvant phase: dose-escalation until plasma level of 20 mM was achieved, 2x weekly, 28 weeks 13 Safe and well tolerated; targeted ascorbate plasma levels of 20 mmol/L achieved in the 87.5 g cohort; favourable OS and PFS compared to historical controls (RT + TMZ only) Phase 2 clinical trial initiated (NCT02344355), currently active, not recruiting [16, 129, 130]
 NSCLC Single group, Phase 2 IVC + carboplatin + paclitaxel high 75 g, 2x weekly 14 Increased disease control and objective response rates Still recruiting (NCT02420314), see Table 3 [16, 133]
 Ovarian Phase 1/2a, randomized Arm 1: IVC + carboplatin + paclitaxel
Arm 2: carboplatin + paclitaxel only
high Dose escalation up to 75 or 100 g, with target peak plasma concentration of 350 to 400 mg/dl (20 to 23 mM), 2x/week, for 12 months (of which the first 6 months in conjunction with chemotherapy) 25 Longer PFS and substantially decreased toxicities compared to control arm w/o Vit C; trend toward improved median OS Study not powered
for detection of efficacy, larger
clinical trials warranted
[63, 145]
 Pancreatic Single group, Phase 1/2a IVC + gemcitabine high 25–100 g dose escalation in phase I, 75–100 g in phase II, 3x weekly, for 4 weeks 14 Well tolerated, no clinically significant influence on gemcitabine pharmacokinetics Phase 2/3 trial needed to detect
efficacy and benefit of IVC
[14, 146]
Single group, Phase 1 IVC + RT + gemcitabine high 50–100 g daily during RT, 6 weeks 16 Safe and well tolerated with suggestions of efficacy; increased OS and PFS compared to institutional average; 100 g determined to be MTD, 75 g selected as a recommended phase II dose Phase 2 trial is indicated [110, 147]
Phase 2, randomized Arm 1: IVC + G-FLIP/G-FLIP-DM
Arm 2: G-FLIP/G-FLIP-DM only
high 75–100 g, 1–2x per week, with GFLIP every every 2 weeks until progression 26 Safe and well tolerated. May avoid standard 20–40% rates of severe toxicities Abstract only, no data shown [148, 149]
Single group, Phase 1 IVC + gemcitabine high 50–125 g, 2x weekly to achieve target plasma level of ≥350 mg/dL (≥20 mM) 9 Well-tolerated with suggestion of some efficacy; plasma levels of 20–30 mM were reached with doses ranging from 0.75–1.75 g/kg Phase 2 trial is indicated [82, 150]
IVC combination therapy - Targeted therapy
 Colorectal, Gastric Single group, Phase 1 IVC + mFOLFOX6 or FOLFIRI (part 1);
IVC + mFOLFOX6 ± bevacizumab (part 2)
high Dose escalation phase (part 1): 0.2–1.5 g/kg, once daily, days 1–3, in a 14-day cycle until MTD was reached;
Speed expansion phase (part 2): MTD or at 1.5 g/kg if MTD not reached
36
(30 colorectal,
6 gastric)
MTD not reached; no DLT; favourable safety profile and preliminary efficacy Recommended dose for future studies 1.5 g/kg/day; extended to phase 3 study [151, 152]
 Pancreatic Single group, Phase 1 IVC + gemcitabine + erlotinib high 50–100 g, 3x/week, 8 weeks 9 Tumor shrinkage in 8/9 patients; peak ascorbic acid concentrations as high as 30 mmol/L in the highest dose group Phase 2 trial with longer treatment period 100 g dosage warranted [153, 154]
 B-cell non-Hodgkin’s lymphoma Single group, Phase 1 IVC + CHASER regimen high 75 g or 100 g 5x in 3 weeks 3 Whole body dose of 75 g safe and sufficient to achieve an effective serum concentration (>  15 mM (264 mg/dl) No NCT number; Phase II trial is indicated [155], no ClinicalTrial.gov Identifier
IVC combination therapy - Combinations with emerging non-pharmaceutical therapies
 NSCLC Phase 1/2, randomized Arm 1: IVC + mEHT + BSC
Arm 2: BSC alone
high 1 g/kg, 1.2 g/kg or 1.5 g/kg, 3x/week for 8 weeks (Phase 1); 1 g/kg, 3x/week, 25 treatments in total (Phase 2) 97 IVC treatment concurrent with mEHT is safe and improved the QoL of NSCLC patients (Phase 1, Ou et al., 2017); significantly prolonged PFS, OS and QoL (Phase 2) IVC + mEHT is a feasible treatment in advanced NSCLC [156,157,158]
  1. Shown are the 16 published trials using medium-to-high dose IVC out of a total 34 published trials. All 34 trials, including those using low-dose or oral VitC, are summarized in Fig. 3. Entries are ordered primarily by kind of combination treatment, and secondarily by cancer type
  2. aHigh dose ≥1 g/kg, low dose ≤10 g whole body dose
  3. n.s., not specified; g/kg × 37 = g/m2 (1.5 g/kg = 56 g/m2); G-FLIP/G-FLIP-DM: low dose Gemcitabine, fluorouracil, leucovorin, irinotecan, and oxaliplatin/ G-FLIP + low dose docetaxel and mitomycin C; CHASER regimen: Rituximab, cyclophosphamide, cytarabine, etoposide and dexamethasone; mFOLFOX6/FOLFIRI, oxaliplatin, leucovorin and 5-fluorouracil/irinotecan, leucovorin and 5-fluorouracil