Clinical trial NCT02516670
Conditions: Hormone-Resistant Prostate Cancer Metastatic Prostate Carcinoma Stage IV Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2016-06-20; Completion date: 2021-10-14
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well docetaxel works when given with or without ascorbic acid in treating patients with prostate cancer that has spread to other places in the body. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ascorbic acid (vitamin C) is a water-soluble vitamin that may help inhibit the growth of cancer cells. It is not yet known whether docetaxel works better when given with or without ascorbic acid in treating prostate cancer.

Detailed description:

Arms: arm 1: Patients receive docetaxel IV on day 1 and ascorbic acid IV twice weekly. The first ascorbic acid treatment will be given on day 1 (same day as docetaxel). Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive docetaxel IV on day 1 and placebo IV twice weekly.The first placebo treatment will be given on day 1 (same day as docetaxel). Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ascorbic Acid intervention 2: Docetaxel intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacological Study intervention 5: Placebo intervention 6: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Correlative studies intervention 5: Given IV intervention 6: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
A Randomized Phase 2 Trial of Ascorbic Acid in Combination with Docetaxel in Men with 
Metastatic Prostate Cancer 
 
Protocol ID:  
 
 
 
 
 
J15106, IRB00070691 NCT02516670 
 
 
 
 
Principal Investigator: 
Channing Paller, MD 
 
 
Johns Hopkins University School of Medicine 
Sidney Kimmel Comprehensive Cancer Center 
201 N. Broadway, Viragh 9162  
Baltimore, MD 21287     
Phone: (410) 955-8239 (Office) or 202-660-6322 (Clinic)   
Fax: 410-614-8397  
Email:  cpaller1@jhmi.edu  
 
 
Statistician: 
 
Lead Study Coordinator: 
Marianna Zahurak, MS 
Elisabeth Prophet  
410-955-4219 
eprophe1@jhmi.edu  
zahurma@jhmi.edu  
 
 
Responsible Research Nurse: 
Responsible Regulatory Manager: 
Kathleen Schultz, MS 
Jennifer Durham, PhD 
410-614-9482 
410-502-3038/ (F) 410-614-8216 
kschult3@jhmi.edu  
juram1@jhmi.edu  
 
Coordinating Center: 
Johns Hopkins University School of Medicine 
Sidney Kimmel Comprehensive Cancer Center 
201 N. Broadway, Viragh Floor 9 
Baltimore, MD 21287 
crocc@jhmi.edu  
 
 


 
 
 
ii
IND Sponsor:  
 
Channing Paller, MD 
 
IND:  
 
 
 
IND 126543 
 
 
Investigational Agent:  
Ascorbic Acid (McGuff Pharmaceuticals Inc.)  
 
Commercial Agent:  
Docetaxel 
 
Participating Sites: 
 Barbara Ann Karmanos Cancer Institute 
Site PI: Elisabeth I. Heath, MD FACP 
Professor of Oncology and Medicine 
Director, Prostate Cancer Research 
Karmanos Cancer Institute 
Wayne State University School of Medicine 
4100 John R, HW04H0 
Detroit, MI 48201 
Office: 313-576-8715 
Fax: 313-576-8767 
Email: heathe@karmanos.org 
 
 Thomas Jefferson University 
Site PI: William K. Kelly, DO  
Thomas Jefferson University 
925 Chestnut St. Suite 320A 
Philadelphia, PA 19107 
Office: 215-503-4490 
Fax: 215-503-3408 
Email: William.Kelly@jefferson.edu 
 
 University Hospitals of Cleveland 
      Seidman Cancer Center 
      PI: Prateek Mendiratta, MD 
      University Hospitals of Cleveland 
      11100 Euclid Ave 
      Cleveland, OH 44106 
      Office: 216-844-6031 
  
      Fax: 216-844-1721 
      Email: Prateek.mendiratta@uhhospitals.org  
  
 
 Anne Arundel Health System, Research Institute 
PI: Imad Tabbara, MD 


 
 
 
iii 
2003 Medical Parkway, Wayson Pavilion Ste. 210 
Annapolis, MD 21401 
Office: 443-481-4884 
Fax: 443-481-4893 
Email: itabbara@aahs.org 
 
Protocol Type / Version # / Version Date: 
Original/Version 1.0/ April 30, 2015 
Original/Version 1.1/ May 25, 2015 
Original/Version 1.2/ June 03, 2015 
Original/Version 1.3/ July 06, 2015 
Original/Version 1.4/September 28, 2015  
Protocol Version 2.0/ Date December 21, 2015 
Protocol Version 3.0/Date February 4, 2016 
Protocol Version 4.0/Date May 4, 2016 
Protocol Version 5.0/Date August 12, 2016 
Protocol Version 6.0/Date September 1, 2016 
Protocol Version 7.0/Date March 3, 2017 
Protocol Version 8.0/Date May 10, 2017 
Protocol Version 9.0/Date July 27, 2017 
Protocol Version 10.0/Date: August 31, 2017 
Protocol Version 11.0/Date: November 3, 2017 
Protocol Version 12.0/Date: January 30, 2018 
Protocol Version 13.0/Date: June 11, 2019 
Protocol Version 14.0/Date: October 9, 2019 
Protocol Version 15.0/Date: July 1, 2020 
Protocol Version 16.0/Date: Sept. 17, 2020 
Protocol Version 17.0/Date: Nov. 17, 2020 
Protocol Version 18.0/Date: Oct. 19, 2021 
 
 


 
 
 
iv
SCHEMA 
 
 
   
Randomize  
Arm A, n=42 
Docetaxel (75 mg/m2, Q3 weeks) and IV Ascorbic 
acid (1g/kg, 2 times per week) 
(First three doses (over 1.5 weeks): titrate 0.25 g/kg, 
0.5 g/kg, and 0.75 mg/kg.  Starting with Cycle 1 Week 
2, the dose of Ascorbate will be 1 g/kg as long as this 
dose is tolerated.) 
 
 
 
Arm B, n=21 
Docetaxel (75 mg/m2, Q3 weeks) and Placebo (2 
times per week) 
 
 
 
Visits and labs on 
Day 1 of 8 Cycles  
(Cycle length is 21 
days) 
Bone and CT scans at 
Baseline, every 12 
weeks and at the end 
of study  


 
 
 
v
TABLE OF CONTENTS 
 
Page 
SCHEMA ...................................................................................................................................... iv 
1. 
OBJECTIVES ....................................................................................................................1 
1.1 
Primary Objectives...................................................................................................1 
1.2 
Secondary Objectives...............................................................................................1 
1.3  
Exploratory Objectives ............................................................................................1 
1.4  
Study Design ............................................................................................................1 
2. 
BACKGROUND ................................................................................................................2 
2.1  
Prostate cancer .........................................................................................................2 
2.2  
Docetaxel (Taxotere) in Prostate Cancer .................................................................2 
2.3  
Clinical Efficacy and Safety of I.V. Ascorbic Acid In Cancer Patients ..................3 
2.4  
Ascorbic Acid Mechanism of Action in Prostate Cancer ........................................4 
2.5  
Rationale for Combination Therapy With Ascorbic Acid and 
Chemotherapy ..........................................................................................................5 
2.6  
Justification for Using IV Ascorbic Acid with Docetaxel Prostate Cancer 
at Johns Hopkins ......................................................................................................5 
3. 
PATIENT SELECTION ...................................................................................................6 
3.1 
Eligibility Criteria ....................................................................................................6 
3.2 
Exclusion Criteria ....................................................................................................7 
4.  
 REGISTRATION PROCEDURES .................................................................................8 
4.1  
General Guidelines...................................................................................................8 
4.2 
Registration Process .................................................................................................8 
4.3 
Multicenter Guidelines.............................................................................................9 
5. 
TREATMENT PLAN ......................................................................................................10 
5.1 
Agent Administration.............................................................................................10 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................11 
5.4  
Expected Adverse Events ......................................................................................11 
5.5 
Duration of Therapy and Criteria for Removal from Study ..................................12 
5.6  
Duration of Follow Up ...........................................................................................14 
6. 
 DOSING DELAYS/DOSE MODIFICATIONS ...........................................................14 
6.1 
Dosing Delays ........................................................................................................14 
6.2 
Dose Modifications ................................................................................................16 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................16 
7.1  
Definitions..............................................................................................................17 
7.2  
Relationship ...........................................................................................................18 
7.3  
Expectedness ..........................................................................................................18 
7.4  
Handling of Expedited Safety Reports ..................................................................19 
7.5  
Reporting................................................................................................................19 
8. 
PHARMACEUTICAL INFORMATION ......................................................................21 
8.1  
Ascorbic acid .........................................................................................................21 


 
 
 
vi
8.2  
Docetaxel (Taxotere) .............................................................................................23 
9. 
CORRELATIVE/SPECIAL STUDIES .........................................................................25 
9.1  
Plasma Samples (Optional) ....................................................................................25 
9.2  
Serum Samples.......................................................................................................28 
10. 
STUDY CALENDAR ......................................................................................................29 
11. 
 DATA REPORTING / REGULATORY REQUIREMENTS ....................................32 
11.1  Data Management ..................................................................................................32 
11.2  Safety Meetings .....................................................................................................32 
11.3  Monitoring .............................................................................................................32 
12. 
STATISTICAL CONSIDERATIONS ...........................................................................33 
12.1 
Study Design ..........................................................................................................33 
12.2 
Sample Size/Accrual Rate ......................................................................................34 
12.3  Monitoring Plan .....................................................................................................35 
12.4 
Analysis Plans ........................................................................................................36 
12.5 
Expected accrual rate, accrual duration, and total study duration .........................38 
REFERENCES .............................................................................................................................39 
APPENDIX A: Performance Status Criteria ............................................................................41 
APPENDIX B: FACT-P Questionnaire (Version 4) .................................................................42 
APPENDIX C: Serious Adverse Event Reporting Form .........................................................43 
 


J15106/ Protocol Version 18.0 19-Oct-2021 
 
1
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1. To compare the proportion of metastatic prostate cancer patients with a PSA decline of ≥50% 
over 8 cycles of docetaxel with ascorbic acid (Arm A) versus docetaxel with placebo (Arm B). 
 
2. To compare the proportion of adverse events (fatigue, nausea, bone pain, and anorexia) 
experienced by metastatic prostate cancer patients receiving either docetaxel with ascorbic acid 
(Arm A) versus docetaxel with placebo (Arm B). 
 
1.2 
Secondary Objectives 
 
1. To assess radiographic progression free survival (rPFS) in patients with metastatic prostate 
cancer and compare between treatment arms. 
 
2. To assess the proportion of high grade serious adverse events (fatigue, nausea, bone pain, and 
anorexia) in patients with metastatic prostate cancer and compare between treatment arms 
during 8 cycles of treatment. 
 
3. To assess the proportion of high grade serious adverse events (all types) in patients with 
metastatic prostate cancer and compare between treatment arms during 8 cycles of treatment. 
 
4. To assess changes in quality of life measures as assessed by the FACT-P questionnaire. 
 
5. To assess the proportion of metastatic prostate cancer patients requiring docetaxel dose 
reductions and compare between treatment arms during 8 cycles of treatment. 
 
6. To assess overall survival (OS) in patients with metastatic prostate cancer and compare 
between treatment arms. 
 
1.3  
Exploratory Objectives 
 
 
1. To determine whether ascorbic acid alters docetaxel exposure and compare between treatment 
arms.  To correlate docetaxel exposure with clinical outcomes.  
 
2. To determine peak and trough ascorbic acid levels 
 
3. As a pharmacodynamic measure of oxidant injury in vivo, measure F2-isoprostanes 
 
1.4  
Study Design 
 
This is a double-blinded, placebo-controlled, randomized, phase 2 trial of docetaxel with and 
without I.V. ascorbic acid with the co-primary endpoints of reducing quality-of-life-related-
toxicity (fatigue, anorexia, etc.) and improved PSA response. As a secondary endpoint we will 
monitor radiographic progression free survival, all adverse events, and other measures of quality 
of life. Sixty-three chemo-naïve men with metastatic castration resistant prostate cancer will be 
randomized 2:1 to docetaxel with ascorbic acid (Arm A, n=42) or docetaxel with placebo (Arm B, 
n=21). To allow for 10% drop out rate and 63 evaluable patients, we will accrue up to 69 patients.   


J15106/ Protocol Version 18.0 19-Oct-2021 
 
2
 
The study will consist of a screening period (within 28 days of first dose, inclusive of a 
randomization period of up to 7 days of first dose), a treatment period (8 Cycles total), and a 
follow-up period.  Dose reductions are allowed per Section 6.  Enrollment will continue until 63 
subjects have received at least one dose of study treatment.  Docetaxel will be provided as standard 
of care while ascorbic acid will be provided by the trial sponsor. Blinding will be utilized in this 
study to minimize bias. At randomization, the assignment of ascorbic acid versus placebo will be 
blinded to the patients and the investigator. 
 
All subjects may continue in the treatment period until discontinuation due to unacceptable 
toxicity, lack of clinical benefit as determined by the investigator, or termination of the study by 
the sponsor. After a patient is discontinued from treatment, a mandatory Off-Study/Safety Follow-
Up Visit should be performed approximately 30 days after the last dose of study medication (or 
within seven days prior to initiation of a new anti-cancer treatment, whichever comes first).  
Subjects will be considered in the treatment period until 30 days after the last dose of study drug. 
 
All patients who discontinue treatment should be contacted every six months to monitor overall 
survival for 3 years or until study closure. Information of other cancer therapies after 
discontinuation from the study treatment will be collected. 
 
 
2. BACKGROUND 
 
2.1  
Prostate cancer 
 
Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading cause 
of cancer death in men. Radical prostatectomy and radiation therapy are the established definitive 
treatments for clinically localized PC; yet, over 50,000 men each year progress with a biochemical 
relapse while others develop metastatic disease resulting in over 30,000 deaths annually. While 
chemical castration is temporarily effective in many patients, most men eventually progress to 
castrate-resistant prostate cancer (CRPC) and are then treated with docetaxel-based chemotherapy. 
 
2.2  
Docetaxel (Taxotere) in Prostate Cancer 
 
The safety and efficacy of docetaxel in combination with prednisone in patients with androgen 
independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized 
multicenter active control trial1. A total of 1006 patients with Karnofsky Performance Status (KPS) 
≥60 were randomized to the following treatment groups:  
• 
Docetaxel 75 mg/m
2 every 3 weeks for 10 cycles.  
• 
Docetaxel 30 mg/m
2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.  
• 
Mitoxantrone 12 mg/m
2 every 3 weeks for 10 cycles  
 


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2.3  
Clinical Efficacy and Safety of I.V. Ascorbic Acid In Cancer Patients 
 
Multiple phase I trials of IV ascorbic acid safety and phase I/II trials of IV ascorbic acid safety and 
efficacy in cancer patients have been published. In one trial ascorbic acid in elderly patients with 
advanced cancer who had failed all other therapies, 2 patients had unexpectedly stable disease after 
8 weeks of ascorbic acid treatment 2. In a trial of patients with metastatic stage 4 pancreatic cancer 
who received primary therapy with ascorbic acid, gemcitabine, and erlotinib, 8 of 9 patients had 
tumor shrinkage after 8 weeks of therapy as measured by CT imaging 3. A phase I trial in patients 
with metastatic stage 4 pancreatic cancer who were treated with gemcitabine + IV ascorbic acid as 
primary therapy until tumor progression showed few toxicities associated with the treatment. The 
9 patients had a tripling of disease free interval in comparison to literature controls, and doubling 
of survival compared to retrospective controls 4. In a dose escalation study, found no toxicity at 
doses even above 1.5g/kg, the doses used in the other three trials 5.  In addition, a phase I/II trial 
of high-dose, IV ascorbic acid reduced grade 1 and 2 toxicities associated with carboplatin and 
paclitaxel treatment by more than 50% in women with ovarian cancer in a small, randomized 
clinical trial. Patients receiving IV ascorbic acid reported lower levels of low-grade 
gastrointestinal, hepatobiliary, dermatological, immune/infection, pulmonary and renal toxicities 
commonly associated with carboplatin and paclitaxel treatment 6.  A trial enrolling women with 
breast cancer randomized to IV ascorbic acid or placebo, in the first year following surgery, 
showed significant reductions in nausea (p=0.022), loss of appetite (p=0.005), fatigue (p=0.023), 
dizziness (p=0.004) and hemorrhagic diathesis (p=0.032). Reduced toxicities were experienced by 
patients independent of whether they were being treated with chemotherapy 7.  Similarly, a phase 
I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of 


J15106/ Protocol Version 18.0 19-Oct-2021 
 
4
relapsed or refractory multiple myeloma with ascorbic acid IV on days 1, 4, 8, and 11 demonstrated 
a response rate of 27% in a heavily pretreated population.  Ascorbic acid demonstrates activity at 
twice a week dosing.22 
 
Intravenous ascorbic acid is in wide use by practitioners of complementary and alternative 
medicine. Estimates are that in the US approximately 10,000 patients receive IV ascorbic acid each 
year at average doses of 0.5/kg, with average number of doses of twenty per patient. Using multiple 
tracking mechanisms, minimal adverse events were reported in properly screened patients 8.  
 
2.4  
Ascorbic Acid Mechanism of Action in Prostate Cancer 
 
The mechanism of action of ascorbic acid-mediated tumor suppression appears to depend on 
hydrogen peroxide production in extracellular fluid; hydrogen peroxide induces necrosis in tumor 
cells but not in normal cells.9 Ascorbic acid treatment inhibits prostate cancer cell growth through 
three mechanisms: (1) ascorbic acid induces H2O2-dependent cytotoxicity in prostate cancer cells, 
(2) ascorbic acid treatment decreased ATP levels in prostate cancer cells, and (3) ascorbic acid 
treatment induced autophagy in prostate cancer cells.10  Ascorbic acid treatment also suppresses 
metastases in hormone-refractory prostate cancer.11  Cytotoxicity of ascorbic acid requires mM 
concentrations12. The dose response curve for ascorbic acid on DU-15 and PC-3 prostate cancer 
cells, shown below  (Source: Levine, NCI Developmental Therapeutics Program NSC 33832) 
demonstrate that ascorbic acid was more effective for DU 145, with nearly complete kill at 10 
mM, and produced no growth for PC3. 
  
 
 
Bioavailability of ascorbic acid is tightly controlled in response to oral administration and reaches 
only 100 μM with consumption of five servings of fruits and vegetables, which contain 
approximately 250 mg of ascorbic acid. Oral supplementation even at many grams does not 
increase plasma concentrations beyond 250 μM. IV administration bypasses the tight controls 
found with oral administration, and produces pharmacological ascorbic acid concentrations of 25-
30 mM 13.  Pharmacological ascorbic acid concentrations of 10mM can be maintained for 
approximately 4 hours with infusion rates of 0.5 – 1.0 g/kg per minute 2,9. 


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5
2.5  
Rationale for Combination Therapy With Ascorbic Acid and Chemotherapy  
 
Additivity/Synergy: The combination of ascorbic acid and conventional chemotherapeutic agents 
synergistically inhibited ovarian cancer in mouse models. An additive to synergistic effect was 
shown for ascorbic acid and carboplatin in OVCAR5 and SHIN3 cells at all combination ratios, 
and in OVCAR8 cells at a high ascorbic acid ratio. Epithelial cell HIO-80 was sensitive to 
carboplatin treatment but the addition of ascorbic acid induced no more cell death than carboplatin 
alone.6 Clinically, several trials have demonstrated safety of ascorbic acid in combination with 
chemotherapy, including in ovarian cancer, multiple myeloma, and pancreatic cancer. 3, 4, 6, 22 
Drug-Drug Interaction Potential: A drug-drug interaction between ascorbic acid and docetaxel is 
not anticipated based on drug metabolism.  Docetaxel metabolism is primarily mediated by 
CYP3A4/5 and to a much lesser extent CYP2C8 and CYP1B1. Clinical drug-drug interactions 
have been noted with strong CYP3A4 inducers and inhibitors.  Docetaxel disposition is mediated 
by the following drug transporters: ABCB1, ABCC1, ABCC2, ABCG2, SLCO1A2, SLCO1B1, 
and SLCO1B314. Additionally, docetaxel is bound to alpha1-acid glycoprotein levels (AAG), 
which is a stress-reactive protein and has been linked with docetaxel exposure15.  It is not 
anticipated that ascorbic acid alters any of these processes. Therefore, formal docetaxel 
pharmacokinetics will not be collected except in patients willing to undergo optional PK. For those 
patients, sparse sampling for docetaxel exposure data will be collected in Cycle 1 (docetaxel in 
combination with ascorbic acid administration). In addition, sparse sampling for docetaxel 
exposure data will be collected if adverse drug events are more frequent and severe as deemed by 
the treating oncologist and/or principal investigator of the trial.  The collection would occur in the 
subsequent cycle (C2 and beyond) from when the adverse drug events occur. 
 
 
2.6  
Justification for Using IV Ascorbic Acid with Docetaxel Prostate Cancer at Johns 
Hopkins 
 
Many men with late stage prostate cancer are treated with docetaxel and experience significant 
toxicities including fatigue, alopecia, diarrhea, stomatitis, and peripheral edema16.  Given the 
efficacy of IV ascorbic acid in reducing toxicities in other cancers, a rigorous evaluation of IV 
ascorbic acid in reducing toxicities associated with docetaxel treatment in men with metastatic 
prostate cancer is merited.  
 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins has a large population of 
men with metastatic castration resistant prostate cancer who are treated with docetaxel.  
 
We propose to conduct a randomized, controlled phase 2 trial of docetaxel with and without IV 
ascorbic acid with the primary endpoint of reducing toxicity. A secondary endpoint, progression 
free survival will be measured to determine whether the anti-cancer effects of IV ascorbic acid are 
sufficient to merit larger trials. We also plan to measure correlates, including ascorbic acid levels 
in blood and F2-isoprostanes levels indicative of oxidative stress4, to help shed light on the 
mechanism by which IV ascorbic acid reduces toxicities.   
 
 
 
 
 


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6
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
  
[1]  Have metastatic castration-resistant prostate cancer (prostate cancer progressing despite 
castrate levels of testosterone [< 50 ng/dL] using standard measures of progression 
defined by Prostate Cancer Working Group 217), are chemo-naïve for mCRPC. Patients 
must have symptomatic disease or visceral metastases or otherwise be eligible for 
docetaxel treatment per investigator judgment (e.g. for progression on imaging or rapidly 
rising PSA despite 2nd line hormonal treatment).  
 
Note: Six cycles of prior docetaxel are allowed in hormone-sensitive disease (per ECOG 
3805 data) and have been off of docetaxel for at least 12 months.  
 
[2]  Have a pathological diagnosis of prostate carcinoma  
 
[3]  Patients may be receiving continuous hormonal ablation with surgical or medical 
castration with baseline testosterone <50ng/dL  
 
[4]  Patient may be receiving bone targeted agents. 
 
[5]  Have evaluable disease by RECIST 1.1 and/or PCWG2 criteria. 
 
[6]  Age ≥ 18. 
 
[7]  Have ECOG performance status 0-1 (Appendix A). 
 
[8]  Have estimated life expectancy > 4 months. 
 
[9]  Have normal organ and marrow function as defined below: 
- 
Absolute neutrophil count 
> 1500/mm³ 
- 
Platelets  
 
 
> 100,000/mm³ 
- 
Hemoglobin 
 
 
> 9 g/dL 
- 
Total bilirubin  
 
< 1.0 ULN 
- 
AST(SGOT)/ALT(SGPT) 
< 2.5 x ULN 
- 
Creatinine 
 
 
< 1.6 mg/dl (for patients with >1.6 mg/dl,  
Calculated creatinine clearance must be > 60 
mL/minute (Cockcroft-Gault)). 
 
[10]  Men of reproductive potential and those who are surgically sterilized (i.e., post 
vasectomy) must agree to practice effective barrier contraception that has an expected 
failure rate of < 1% during and for 30 days after discontinuation of study treatment. 
 
 If condoms are used as a barrier contraceptive, a spermicidal agent should be added 
to ensure that pregnancy does not occur.  
 
[11]  Have the ability to understand, and have given written informed consent before 
performance of any study-related procedure not part of normal medical care, with the 


J15106/ Protocol Version 18.0 19-Oct-2021 
 
7
understanding that consent may be withdrawn by the subject at any time without prejudice 
to future medical care. 
 
3.2 
Exclusion Criteria 
 
Patients are ineligible to be included in the study if they: 
 
[1]  Have had known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for CNS involvement for at least one week prior to trial treatment. Patients with 
primary brain tumors are not eligible.  However, as patients are completing abiraterone 
therapy, they will be allowed to continue up to 10 mg/day of prednisone. 
 
[2]  Have had prior chemotherapy for metastatic disease in castration-resistant prostate cancer 
(prior chemotherapy for hormone-sensitive disease, more than twelve months prior to 
registration, is acceptable). 
 
[3]  Have had had surgery within four weeks of dosing of investigational agent, excluding 
minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent 
placement. 
 
[4]  Have had palliative radiation or biological cancer therapy within 2 weeks prior to the first 
dose of study drug. 
 
[5]  Have received other investigational drugs within 28 days prior to enrollment. 
 
[6]  Is expected to require any other form of systemic or localized antineoplastic therapy 
while on study. 
 
[7]  Patients who require frequent (several times a day) monitoring of their blood glucose or 
patients who have recently been hospitalized for glucose control. 
 
[8]  Are being treated with warfarin anticoagulation therapy. 
 
[9]  The subject requires concomitant treatment with the following inhibitors of CYP3A4: 
 Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin 
 Antifungals: 
itraconzaole, 
ketoconazole, 
voriconazole, 
fluconazole, 
posaconazole 
 Antidepressants: nefazodone 
 Antidiuretic: conivaptan 
 Antiretrovirals: delaviridine or protease inhibitors (ritonavir, indinavir, 
lopinavir/ritonavir, saquinavir, nelfinavir) or cobicistat-boosted antiretrovirals.  
 GI: cimetidine, aprepitant 
 Hepatitis C: boceprevir, telaprevir 
 Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or 
pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids).  


J15106/ Protocol Version 18.0 19-Oct-2021 
 
8
 
Because the lists of CYP3A4 inhibitors are constantly changing, it is important to 
regularly 
consult 
a 
frequently-updated 
list 
such 
as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as 
the Physicians’ Desk Reference may also provide this information. As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed 
or if the patient is considering a new over-the-counter medicine or herbal product 
 
[10]  Have uncontrolled intercurrent illness, including but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
[11]  Has glucose-6-phosphate dehydrogenase (G6PD) deficiency (Red blood cell hemolysis 
may occur in people found to be deficient in the G6PD enzyme). 
 
[12]  Have end stage renal disease 
 
[13]  Has history of calcium oxalate stones  
 
[14]  Has history of iron overload 
 
[15]  Have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).  
 
[16]  Have a known active uncontrolled hepatitis B, or hepatitis C infection. 
 
  
4.   
REGISTRATION PROCEDURES 
 
4.1  
General Guidelines 
 
Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive 
Cancer Center at the Johns Hopkins University by the Lead Study Coordinator.  All sites 
should call/email the coordinating center at crocc@jhmi.edu to verify drug availabilities.  
The Registration Form, and Eligibility Worksheet will be supplied to each participating 
site. 
 
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Coordinating Center should be notified of 
cancellations as soon as possible. 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the Research Nurse 
or Study Coordinator and emailed to crocc@jhmi.edu and Elisabeth Prophet to the 
Coordinating Center: 
 Registration Form 
 Signed patient consent form 


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9
 HIPAA authorization form 
 Eligibility Screening Checklist 
 Copy of required screening tests and scans 
 
The Research Nurse or Study Coordinator at the participating site will then e-mail 
(crocc@jhmi.edu and eprophe1@jhmi.edu) the Coordinating Center (Elisabeth Prophet) to 
verify eligibility.  To complete the registration process, the Coordinating Center will: 
 Assign a patient study number 
 Register the patient on the treatment portion of the study with the Sidney 
Kimmel Comprehensive Cancer Center’s Clinical Research Office 
 Fax or e-mail the patient study number to the participating site 
 Call or e-mail the research nurse or data manager at the participating site and 
verbally confirm registration the last eligible start date for treatment.  
 
4.3 
Multicenter Guidelines 
 
 
 
Protocol Chair 
 
 
The Protocol Chair is responsible for performing the following tasks: 
 Coordinating, developing, submitting, and obtaining approval for the protocol 
as well as its subsequent amendments 
 Assuring that all participating institutions are using the correct version of the 
protocol. 
 Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
 Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
 Reviewing data from all sites 
 
 
 
Coordinating Center 
 
 
The Coordinating Center is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior 
to the first patient registration at that site, and maintaining copies of IRB 
approvals from each site. 
 Managing central patient registration. 
 Collecting and compiling data from each site. 
 Establishing procedures for documentation, reporting, and submitting of AE’s 
and SAE’s to the Protocol Chair, and all applicable parties. 
 Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
 
 
Participating Sites 
 
 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical 
Practice (GCP). 
 Submitting data to the Coordinating Center. 
 Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 
 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the 


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10
protocol. 
 Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center. 
 Collecting and submitting data according to the schedule specified by the 
protocol. 
 
 
5. TREATMENT PLAN 
 
 
 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. At randomization, the assignment of 
ascorbic acid versus placebo will be blinded to the patients and investigators. 
 
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route* 
Schedule 
Cycle 
Length 
Docetaxel 
Decadron 8 mg po 
12 hours, 3 hours 
and 1 hour prior to 
docetaxel 
administration, ; 5-
HT3 antagonist IV 
on Day 1, 5-HT3 
antagonist PRN. 
Prednisone 5mg po 
BID continuously 
75 mg/m2 
IV over 60 
min* 
Q 3 weeks 
(Day 1 of 
each cycle) 
21 days  
(3 weeks) 
for a total 
of 8 cycles 
Ascorbic 
acid 
None 
1g/kg**  
(For first cycle  and 
for first cycle in the 
extension phase 
only: titrate first 3 
doses: 0.25, 0.5, and 
0.75g/kg) in 1000ml 
of water 
(Not to exceed 500 
mL per hour.) 
0.75-1 gram 
per minute 
IV* 
2 times per 
week*** First 
dose on day 1 
of the cycle 
Placebo 
(Normal 
Saline) 
None 
1000ml of normal 
saline 
0.75-1 gram 
per minute 
IV* 
2 times per 
week***First 
dose on day 1 
of the cycle 
 


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*Infusion times are approximate (± 15 minutes) and may need to be adjusted based on patient 
tolerability. Infusion time is estimated to be between 90-120 minutes. 
**For a subject weighing 75 kg, the goal dose is 75 grams (1 g/kg), then the titrated dose schedule is 
18.75 g, 37.5 g and 56.25g for cycle 1 only.  Rounding the calculated doses to 19 g, 38 g and 56 g is 
acceptable.  Subsequent doses would be 75 g.  The maximum allowed dose for patients weighing over 
100 kg is 100g.  
***The ideal schedule for ascorbic acid is 3-4 days apart for administration.  However, ascorbate can 
be safely administered on consecutive days (at least 24 hours apart).  The day that ascorbate or placebo 
can be administered can be shifted in the event of holidays, inclement weather, and other reasons for 
clinic closure to even three consecutive days.   
 
 
Subsequent ascorbic acid infusions may not be given less than 24 hours apart. 
 
Acute reactions will be managed using standard therapy for acute drug reactions as per institutional 
standard of care. 
 
5.2 
Dosing Criteria 
 
To continue therapy, subjects must meet the following criteria (exceptions should be approved 
by the principal investigator): 
For Docetaxel: 
 Absolute Neutrophil Count 
>1000/mcL 
 Platelets 
 
  
 
 
>80 x 109/L 
 Hemoglobin  
  
 
 
> 8 g/dL 
 Total bilirubin   
 
 
< 1.0 ULN 
AST(SGOT)/ALT(SGPT) 
< 2.5 x ULN  
For Ascorbic acid: Creatinine  
 
 
< 1.6 mg/dl (for patients with >1.6 mg/dl,   
Calculated creatinine clearance must be > 60 
mL/minute (Cockcroft-Gault)). 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
The concurrent use of all other drugs, over-the-counter medications, or alternative therapies must 
be documented.  Supportive care, including but not limited to anti-emetic medications, may be 
administered at the discretion of the Principal Investigator or Co-Investigators. Concurrent 
treatment with bisphosphonates is allowed. All concomitant treatments, including blood and blood 
products, must be reported on the case report form (CRF). Erythropoietin, G-CSF, or Pegfilgrastim 
may be administered at the discretion of the Principal Investigator or Co-Investigators. Warfarin 
anticoagulant therapy is not allowed18,19. Heparin, enoxaparin, aspirin, NSAIDS, or other 
anticoagulant therapies are allowed. 
 
5.4  
Expected Adverse Events 
 
5.4.1 Ascorbic Acid 
 
Too rapid intravenous administration of the solution may cause temporary faintness or 
dizziness.  
 


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12
The most common side effects of ascorbic acid include: nausea, vomiting, diarrhea, dry 
mouth, loss of appetite, muscle weakness, dizziness, headache,  fatigue, flushing,  leakage 
of protein, injection site reaction (including transient pain, swelling at the site), fever, 
chills. 
 
Less common side effects of ascorbic acid include: kidney stone, renal failure, 
hypernatremia, hypoalbuminemia, hyperglycemia, hypokalemia increase in blood 
pressure, severe headache, sclerosing at the injection site and phlebitis.  
 
Rare side effects of Ascorbic Acid include: respiratory and cutaneous allergies to Ascorbic 
Acid 
 
Of note, it has been reported that patients with a history of glucose 6 phosphate 
dehydrogenase deficiency experienced hemolysis.  
 
Deep-vein thrombosis has been reported after large doses of ascorbic acid. 
 
Rarely, decreased blood pH leading to sickle-cell crisis has been reported in patients with 
sickle cell disease. 
 
At doses of greater than 600 mg, ascorbic acid has been reported to have a diuretic action. 
 
High doses can increase serum cholesterol in atherosclerotic patients. 
 
 
5.4.2 Docetaxel 
 
Most common adverse reactions across all docetaxel indications are infections, 
neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, 
neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, 
asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia. 
 
Other potential adverse reactions include: epistaxis, allergic reactions, rash/desquamation, 
stomatitis/pharyngitis, cough, dyspnea, cardiac left ventricular function, fatigue, tearing, 
arthralgia, and kidney failure.  
  
5.5 
Duration of Therapy and Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in apply.  The reason for 
study removal and the date the patient was removed must be documented in the Case Report 
Form. 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 8 cycles 
or until one of the following criteria applies: 
 
 
Disease progression by RECIST or bone progression per PCWG2 (see below), 
 
 
Intercurrent illness that prevents further administration of treatment, 
 


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 
Unacceptable adverse event(s): toxicity (defined in Section 6.1) that has not recovered 
in 2 weeks or if the same toxicity recurs at the decreased dose (unless there is strong 
evidence of clinical benefit to justify continuation of dosing with study treatment, and 
the investigator must discuss the rationale with the Sponsor before a decision is taken), 
 
 
> Grade 3 hypersensitivity to docetaxel or ascorbic acid 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
An Open Label Extension Phase will be permitted to those patients that have completed the study 
treatment (cycles 1-8), or for patients removed due to protocol defined progression by RECIST. 
The decision to continue treatment beyond initial progression must be documented in the study 
records. Patients can continue on docetaxel standard of care and ascorbic acid or ascorbic acid 
alone. Ascorbic acid will be available twice a week until progression.  Patients will be required to 
get safety labs (CBC and CMP weekly for ascorbic acid), and be assessed for progression per 
investigator judgment and at least every 12 weeks by PSA, CMP, CBC, bone scan, CT scan, and 
H&P. The History & Physical can be performed on Day 1 of each cycle during the Open Label 
Extension Phase (as it is during cycles 1-8), however it is only required to be performed every 12 
weeks, unless clinically indicated and at the investigators discretion. Research bloods and the 
FACT-P Questionnaire will not be collected during the Open Label Extension Phase.  
 
When subjects come off treatment in the Open Label Extension Phase and move to Follow-up, the 
serum samples will need to be collected during the 30 Day Follow-up visit. A CT scan and bone 
scan should also be completed at the 30 Day Follow-up visit unless the scans have already been 
completed within the past 6 weeks. The site study team must inform the site pharmacy when 
subjects will be switching over to the Open Label Extension Phase.  
 
Criteria for Removal from Study  
 
Disease Progression 
Progression will be evaluated on the basis of biochemical, radiographic, or symptomatic 
progression based on modified PCWG2 criteria. Determinations of disease progression will be 
made by the investigator. 
 
Progression will be defined as follows: 
  
1. Radiographic progression defined by at least one of the following: 
 Soft tissue disease progression by modified RECIST criteria v.1.1 (baseline LN size 
must be ≥ 2.0 cm to be considered target or evaluable lesion) 
 Development of two or more new bone lesions not consistent with tumor flare per 
PCWG2. 
2.  Symptomatic or clinical progression defined by one of the following: 
 Development of a skeletal related event (SRE) defined as pathologic fracture, spinal 
cord or nerve root compression, palliative radiation to bone, or surgery to bone 
 Worsening pain due to CRPC unable to be controlled by non-narcotic or narcotic 
medications 


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14
 Sustained worsening of ECOG status resulting from CRPC (e.g., 2 to 3)  
 Treating physician decides to initiate new systemic anti-cancer therapy  
 
We will encourage investigators to continue study treatment until radiographically confirmed 
disease progression requires initiation of new systemic antineoplastic therapy.  In addition we 
will measure PSA levels but do not plan to use PSA progression as a reason for cessation of 
treatment. 
 
5.6  
Duration of Follow Up 
 
Subjects will be followed for adverse events for a minimum of 30 days after the last dose of study 
drug or death, whichever occurs first. Survival status will be collected every 6 months (+/- 4 weeks) 
by phone or chart review for 3 years or until study closure. Subsequent therapies and responses 
may be collected.  Subjects removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event or death. 
 
 
6.  
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dosing Delays 
 
All scheduled cycles occur over a 21-day period. If necessary, treatment may be delayed for up to 
two weeks. If treatment is delayed more than two weeks, the Sponsor must be contacted for further 
instructions on continued treatment. Additional delays or modifications to the treatment schedule 
must be approved by the IND Sponsor. When the delay is due to toxicity, then the next cycle may 
begin with a dose reduction.  If docetaxel needs to be delayed for any reason, ascorbic acid/placebo 
will also need to be delayed and started back up at the same time as docetaxel.  
 
Docetaxel will be withheld for the following drug-related toxicities: 
 Absolute neutrophil count (ANC) <500/uL for longer than seven days 
 
 ANC <1000/uL with a single temperature of >101oF/38.3oC or a sustained temperature of 
>100.4oF/38oC for more than one hour  
 
 Platelet count < 80 x 103/uL  
 
 Hemoglobin < 8 g/dL  
 
 Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non-
hematologic toxicity (for example, including gastrointestinal toxicity) excluding 
asymptomatic electrolyte aberrations.  
 
Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the investigator, 
warrants delaying the dose of study medication. Ascorbic acid will be withheld for the following 
drug-related toxicities: 
 
 Creatinine > 1.6 mg/dl (for patients with >1.6 mg/dl, calculated creatinine clearance must 
be < 60 mL/minute (Cockcroft-Gault)). 
 


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15
 Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non-
hematologic toxicity (for example, including gastrointestinal toxicity) excluding 
asymptomatic electrolyte aberrations. 
 
 Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication 
 
Management of gastrointestinal toxicity: 
 
 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated per Section 6.2. 
Recommended management:  antiemetics. 
 
 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated per Section 6.2. 
Recommended management:  antiemetics. 
 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until < Grade 2.  Resume at one dose level lower, if 
indicated per Section 6.2. 
Recommended management:  Loperamide anti-diarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion 
until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Management of peripheral neuropathy: 
 
Event Name 
Peripheral Neuropathy 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
Resume at one dose level lower if symptoms interfering with 
instrumental ADL 
Grade 3-4 
Discontinue docetaxel 
Recommended management: consider medications for neuropathy. 
 


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16
In case toxicity does not resolve to Grade 0-2 within two weeks after the last dose (except 
creatinine that must resolve to dosing criteria listed in Section 5.2), trial treatment should be 
discontinued after consultation with the Sponsor (with the exception of alopecia, fatigue, skin rash, 
nausea, vomiting, constipation, or diarrhea that can be controlled with treatment) unless there is 
strong evidence of clinical benefit to justify continuation of dosing with study treatment, and the 
investigator must discuss the rationale with the Sponsor before a decision is taken. 
 
Altering the ascorbate/placebo or docetaxel schedule due to scheduling and holidays is permitted. 
For ascorbate/placebo, it is preferred that 2 doses are administered per week. Ascorbic acid 
infusions may not be given less than 24 hours apart. If warranted, the correlative study assessments 
for ascorbic acid should be adjusted to the adjusted infusion days.   
 
6.2 
Dose Modifications    
 
Patients who experience grade 3 or 4 toxicities (individually defined in Section 6.1) that are 
eligible for retreatment will be dose reduced. After a two-week dose delay, if the grade 3 or 4 
toxicity resolves to grades 0-2 (grade 2 peripheral neuropathy must resolve to grade 1 if interfering 
with instrumental ADL), then the following dose reductions are to be applied: 
 
 One dose modification of ascorbic acid is allowed to 0.75g/kg (if two dose reductions 
are required, the patient will go off protocol treatment).   
 
 Two dose modifications of docetaxel are allowed to 60 mg/m2 and 50 mg/m2 (if three 
dose reductions are required, the patient may go off protocol treatment at the IND 
Sponsor’s discretion). 
 
Dose reductions for either drug for symptoms other than grade 3 or 4 toxicities should be discussed 
with and approved by the IND sponsor.  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
This study will use the descriptions and grading scales found in the revised CTCAE version 4.0 
for AE reporting that can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed up as appropriate.  
 
All AEs and SAEs experienced by subjects will be collected and reported from the first dose of 
the investigational agent, throughout the study, and will only be followed for four weeks unless 
related to the investigational agent.  All SAEs will be collected for four weeks after the last dose 
of the investigational agent. Although this responsibility is usually shared among the PI, research 
nurse, and data manager, the PI is ultimately responsible for grading and attribution of all events. 
 
Subjects who have an ongoing AE related to the study procedures and/or medication(s) may 
continue to be periodically contacted by a member of the study staff until the event is resolved or 
determined to be irreversible by the investigator. 
 


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17
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be recorded 
as pre-treatment signs and symptoms. After study treatment administration, all Grade 3 and 4 
clinical laboratory results that represent an increase in severity from baseline will be reported as 
AEs. A Grade 1 or 2 clinical laboratory abnormality should be reported as an AE only if it is 
considered clinically significant by the investigator. 
 
7.1  
Definitions 
 
7.1.1 Adverse Event  
 
An AE is defined as any undesirable sign, symptom, or medical condition occurring after 
starting the study drug (or therapy), even if the event is not considered to be related to the 
study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered AEs if they worsen after starting the study 
treatment (any procedures specified in the protocol). AEs occurring before starting the 
study treatment but after signing the informed consent form will not be recorded. Abnormal 
laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms or require therapy. 
 
7.1.2 Serious Adverse Event  
 
A SAE is an undesirable sign, symptom, or medical condition that:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe)  
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Supplemental Form)  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above). Examples of such events include but are 
not limited to intensive treatment in an emergency room or at home for allergic 
bronchospasm; and blood dyscrasias or convulsions that do not result in 
hospitalization. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
 
Events not considered to be SAEs are hospitalizations for:  
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  


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18
• 
Medical/surgical admission for purpose other than remedying ill health state and 
that was planned prior to entry into the study. Appropriate documentation is 
required in these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
• 
Admissions for monitoring of treatment-related infusion reactions that do not 
otherwise meet the criteria for a SAE. 
 
7.2  
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
 No (unrelated, not related, no relation):  The time course between the administration of the 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship, and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
 Yes (related): The time course between the administration of the study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
 The temporal sequence from study drug administration: The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have.  
 Concomitant medication: The other medications the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them might be recognized 
to cause the event in question.  
 Known response pattern for this class of study drug: Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event.  
 The pharmacology and pharmacokinetics of the study drug: The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should 
be considered.  
 
7.3  
Expectedness 
 
Unexpected adverse event: An AE that varies in nature, intensity, or frequency from information 
on the investigational drug/agent provided in the product IB, package insert, or safety reports. Any 
AE that is not included in the IB consent is considered “unexpected.”  
 
Expected (known) adverse event: An AE that has been reported in the IB. An AE is considered 
“expected” only if it is included in the IB document as a risk. 


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19
 
7.4  
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor will notify investigators of all SAEs that 
are unexpected (i.e., not previously described in the IB), and related to the investigational agent. 
This notification will be in the form of an expedited safety report (ESR) that is to be faxed to the 
investigators and the study coordinators. Upon receiving such notices, the investigator must review 
and retain the notice with the IB and, where required by local regulations, submit the ESR to the 
appropriate IRB. The investigator and IRB will determine if the informed consent requires 
revision. The investigator should also comply with IRB procedures for reporting any other safety 
information.  
 
 
 
 
7.5  
Reporting 
 
7.5.1 General 
 
All AEs (both expected and unexpected) will be captured on the appropriate study-specific 
CRFs.  
 
In addition, all SAEs, regardless of causality to study drug and/or administration device, 
will be reported promptly to the IND sponsor (fax: 410-502-9933; e-mail: crocc@jhmi.edu 
and eprophe1@jhmi.edu), within 24 hours of recognition of the event (Appendix C).  If 
this falls on a weekend or holiday, an email notification is acceptable but must be followed 
by an SAE reporting form on the next business day. 
 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance of 
documentation of adverse events and is responsible for submitting adverse event reports to 
the Protocol Chair promptly.  The Coordinating Center will maintain documentation of all 
adverse event reports for each participating site.  Adverse event reports submitted to the 
Coordinating Center must be signed and dated by the participating site’s Principal 
Investigator.  The Coordinating Center will provide appropriate forms to be used by all 
participating sites for reporting adverse events.  Information to be provided must include: 
 Subject ID number, and initials 
 Date of the event 
 Description of the event 
 Description of site's response to the event 
 Assessment of the subject's condition 
 Subject's status on the study (on study, off study, etc.) 
 Attribution of event to study drug 
 
Participating Sites 
Participating sites are responsible for reporting adverse events to their IRB according to its 
specific requirements and to the Coordinating Center as follows: 
 
Fatal Events whether anticipated or unanticipated, and whether or not related to the study 


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20
must be reported to the Coordinating Center within 24 hours of the participating site 
Principal Investigator's learning of the event. 
 
Serious and Unanticipated Adverse Events as defined above must be reported to the 
Coordinating Center within 24 hours of the participating site Principal Investigator's 
learning of the event.  
 
Other Serious Adverse Events which may result in a change to the protocol, informed 
consent, or risk to subjects as specified in the protocol must be reported within three (3) 
working days of the participating site Principal Investigator's learning of the event.  
 
Adverse Events which result in no change to protocol, informed consent, or risk to subjects 
must be reported to the Coordinating Center on a monthly basis.  
 
Adverse event reports are to be faxed to the Coordinating Center at SKCCC. Follow-up 
reports are faxed, mailed, or sent electronically to the Coordinating Center as necessary. 
The investigator must also report follow-up information about SAEs within the same time 
frames. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided within the same time frames described above. 
 
All SAEs must be collected whether or not they are considered causally related to the 
investigational product.  Investigators and other site personnel are responsible for reporting 
all casually related SAEs to their IRB and the Protocol Chair. 
 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report the pregnancy of a male patient’s female partner 
within 4 weeks days of completing the trial. All pregnancies of female partners of patients 
must be followed to the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage, and stillbirth must be reported as SAEs (Important 
Medical Events).  If the pregnancy continues to term, the outcome (health of infant) must 
also be reported to the IND sponsor and Lilly. 
7.5.2 Institutional Review Board  
 
All SAEs will be reported to the IRB per institutional standards within three business days 
of recognition of the AE if the event is related and expected, related and unexpected, or 
related and fatal or life-threatening due to administration of the investigational product. If 
the SAE is unrelated to administration of the investigational agents, then it should be 
reported to the IRB per institutional guidelines. Follow-up information will be submitted 
to the IRB as soon as relevant information is available. 
7.5.3 Food and Drug Administration  
 
All reporting to the Food and Drug Administration (FDA) will be completed by the IND 
Sponsor. 
 
7.5.3.1 Expedited IND Safety Reports: 


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21
 
Seven Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be telephoned or faxed (301-827-9796) to 
the FDA within seven calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected and 
related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with 
the IND concerning similar events should be analyzed.  The new report should 
contain comments on the significance of the new event in light of the previous related 
reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA within 15 calendar days of first learning of the event. Follow-up information 
will be submitted to the FDA as soon as relevant information is available. 
 
7.5.3.2 IND Annual Reports 
 
In accordance with regulation 21 CFR § 312.33, the IND Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
adverse events and progress of the investigation.  Please refer to Code of Federal 
Regulations, 21 CFR § 312.33, for a list of the elements required for the annual report.  
All IND annual reports will be submitted to the FDA by the IND Sponsor. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1  
Ascorbic acid  
8.1.1 Agent Accountability 
 
The sponsor/investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and 
usage of investigational products in accordance with the protocol and any applicable laws 
and regulations.  
8.1.2 Mode of Action 
 
Ascorbic Acid (vitamin C) is a water-soluble vitamin. In humans, an exogenous source of 
ascorbic acid is required for collagen formation and tissue repair. Ascorbic acid is 
reversibly oxidized to dehydroascorbic acid in the body. These two forms of the vitamin 
are believed to be important in oxidation-reduction reactions. The vitamin is involved in 
tyrosine metabolism, conversion of folic acid to folinic acid, carbohydrate metabolism, 


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22
synthesis of lipids and proteins, iron metabolism, resistance to infections, and cellular 
respiration. 
8.1.3 Description 
 
Ascor L 500® (Ascorbic Acid Injection, USP) 500mg/mL, is available in a 50-mL sterile 
dispensing vial. Ascorbic Acid injection is a clear, colorless to slightly yellow sterile, 
solution of Ascorbic Acid in Water for Injection. 
8.1.4 Preparation 
 
When dispensing vials, use aseptic technique. Dispense entire contents in aliquots under a 
laminar flow hood without delay. Prepare stoppers with a suitable antiseptic solution. Do 
not use unless solution is clear and seal is intact. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration, 
whenever the solution and container permit. Ascorbic acid should be diluted in sterile water 
for injection (final volume of 1000ml). 
 
The ascorbic acid or placebo for ascorbic acid infusions will be prepared by the pharmacy.  
The calculated dose of ascorbic acid will be diluted in Sterile Water for Injection USP.   
Normal saline will be used for the placebo infusion.  To maintain the blind for the study, 
the infusion bags will be covered with opaque bags and tubing will be covered with an 
opaque tubing cover or amber tape.   
 
A study-specific worksheet will be completed when preparing ascorbic acid infusions.  The 
worksheet will document the dose prepared and calculations for dose preparation.   
8.1.5 Storage 
 
Store between 2°- 8°C. Do not freeze. 
8.1.6 Stability 
 
The administration of ascorbic acid infusion must be completed within 72 hours of 
preparation. If not used immediately, the infusion solution must be refrigerated while also 
protected from light to keep the product stable. The maximum 72 hour period under 
refrigeration and protected light conditions includes the product administration period. 
8.1.7 Route of Administration 
 
Ascorbic acid should be administered by intravenous infusion. For intravenous injection, 
dilution into a large volume parenteral of water is recommended to minimize the adverse 
reactions associated with intravenous injection. Infusion will be administered at 0.75-1 
gram per minute not to exceed 500 mL per hour.  Ports are recommended but not mandatory 
due to frequency of infusion. 
 
Treatment will be administered on an outpatient basis with the option of home infusions 
starting week 2 of the cycle.  If home infusions are administered, then institutional 
guidelines must be followed.  Docetaxel infusions and week 1 of every cycle must be 
administered on an outpatient basis with the exception of the week 1 day 4 ascorbic 
acid/placebo infusion, which can be given at home when clinically appropriate. Reported 


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23
adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat 
the patient's malignancy.  At randomization, the assignment of ascorbic acid versus 
placebo will be blinded to the patients and investigators. 
8.1.8 Patient Care Implications 
 
Too rapid intravenous administration of the solution may cause temporary faintness or 
dizziness. 
 
Diabetics, patients prone to recurrent renal calculi, those undergoing stool occult blood 
tests, and those on sodium-restricted diets or warfarin anticoagulant therapy18,19 should not 
take excessive doses of ascorbic acid over an extended period of time. Diabetics taking 
more than 500 mg of ascorbic acid daily may obtain false readings of their urinary glucose 
test. No exogenous ascorbic acid should be ingested for 48 to 72 hours before amine 
dependent stool occult blood tests are conducted because possible false-negative results 
may occur. Heparin, enoxaparin, aspirin, NSAIDS, or other anticoagulant therapies are 
allowed. 
 
Ascorbic acid at pharmacologic doses can give false positive results for blood glucose with 
some commercial point of care glucometers (glucose meters), although this has not seen 
with clinical chemistry laboratory autoanalyzers. Glucometers should not be used to 
measure blood glucose during and up to 10 hours after intravenous ascorbate 
administration20,21.  Patients should be counseled that correction of falsely high blood 
glucose levels with excess insulin may cause hypoglycemia and death, that some strips 
provide false readings while others, such as Bayer Contour are less likely to do so.  They 
should also be counseled that if they do see high blood glucose readings following IV 
ascorbic acid, they should not increase their insulin unless the high glucose reading is 
confirmed at least 10 hours after IV AA administration. 
8.1.9 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to and returned by the patients, and the amount remaining at the 
conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational products will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
8.2  
Docetaxel (Taxotere) 
8.2.1 Agent Accountability 
 
The sponsor/investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and 


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24
usage of investigational product in accordance with the protocol and any applicable laws 
and regulations. Docetaxel is commercially supplied. 
8.2.2 Mode of Action 
 
Docetaxel is an antineoplastic agent (belonging to the taxoid family) that acts by disrupting 
the microtubular network in cells that is essential for mitotic and interphase cellular 
functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable 
microtubules while simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to the stabilization of 
microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to 
microtubules does not alter the number of protofilaments in the bound microtubules, a 
feature which differs from most spindle poisons currently in clinical use.  
8.2.3 Description 
 
Docetaxel Injection Concentrate is a clear yellow to brownish-yellow viscous solution. 
Docetaxel is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg 
(1 mL) or 80 mg (4 mL) Docetaxel (anhydrous). Each mL contains 20 mg Docetaxel 
(anhydrous) in 0.54 grams polysorbate 80 and 0.395 grams dehydrated alcohol solution. 
 
The Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, 
nonaqueous, viscous solution with an accompanying sterile, nonpyrogenic, diluent (13% 
ethanol in Water for Injection) vial. 
8.2.4 Preparation 
 
Docetaxel should be reconstituted according to the manufacturer’s recommendation. 
8.2.5 Storage 
 
Docetaxel should be stored between 2 and 25°C (36-77°F) in a secure and dry place. Retain 
in the original package to protect from bright light. Freezing does not adversely affect the 
product. 
8.2.6 Stability 
 
Taxotere infusion solution, if stored between 2 and 25°C (35.6 and 77°F) is stable for 4 
hours. Fully prepared Taxotere infusion solution (in either 0.9% Sodium Chloride solution 
or 5% Dextrose solution) should be used within 4 hours (including the administration). 
8.2.7 Route of Administration 
 
Docetaxel should be administered by intravenous infusion. 
8.2.8 Patient Care Implications 
 
The most common adverse reactions across all TAXOTERE indications are infections, 
neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, 
dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, 
nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence 
varies depending on the indication.  


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25
 
Drug interactions:  Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter 
docetaxel metabolism. 
 
8.2.9 Returns and Reconciliation 
 
Not applicable. 
 
9. CORRELATIVE/SPECIAL STUDIES 
 
9.1  
Plasma Samples (Optional) 
 
In patients willing to undergo an optional PK collection, we will determine whether ascorbic acid 
alters docetaxel exposure and compare between treatment arms, pharmacokinetics samples will be 
collected prior to, during, and after docetaxel infusions on Cycle 1 Day 1 (docetaxel in combination 
with ascorbic acid administration).  PK samples should be collected from a separate site from 
where the drug is being infused, such as a contralateral arm or either arm if using a port. If there 
are severe adverse events that are greater than what is expected by the treating physician and 
thought to be related to study drug, PKsare strongly recommended to help determine etiology of 
AEs. NOTE: If PKs are collected for AEs, the collection will start on the next dose in the 
subsequent cycle.    
 
9.1.1 Docetaxel Pharmacokinetics Samples (Optional)  
 
Blood samples will be collected for docetaxel pharmacokinetics on Cycle 1 Day 1 
(docetaxel after ascorbic acid administration) at the following time points: 
 
PK for patients consenting to the optional PK. 
Day 1 of Cycle 1:  
Prior to docetaxel administration 
Document the start of infusion time 
30 minutes after the start of the docetaxel infusion  
55 minutes after the start of the docetaxel infusion and prior to end of infusion 
Document the end of infusion time 
2 hours post- end of infusion docetaxel infusion (~3 hours) 
5 hours post- end of infusion docetaxel infusion (~6 hours) 
 
Day 2 of Cycle 1:  
Approximately 24 hours post-docetaxel infusion 
 
PK for patients who had more frequent or severe toxicities. 
Day 1 of the next Cycle (Cycle >2):  
Prior to docetaxel administration 
Document the start of infusion time 
30 minutes after the start of the docetaxel infusion  
55 minutes after the start of the docetaxel infusion and prior to end of infusion 
Document the end of infusion time 
2 hours post- end of infusion docetaxel infusion (~3 hours) 
5 hours post- end of infusion docetaxel infusion (~6 hours) 
 


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26
Day 2 of the next Cycle (Cycle >2):  
Approximately 24 hours post-docetaxel infusion 
 
Docetaxel pharmacokinetics samples will be measured using a validated liquid 
chromatography/tandem mass spectrometric (LC/MS/MS) method in the Sidney Kimmel 
Comprehensive Cancer Center Analytical Pharmacology Core (APC) Laboratory. If 
clinically significant differences in efficacy or toxicity are noted between treatment arms, 
then unbound docetaxel exposure and alpha-1-acid glycoprotein will be assessed for a 
comprehensive assessment of docetaxel pharmacology. Unbound docetaxel will be 
determined using equilibrium dialysis methods using a radiolabeled docetaxel or 
LC/MS/MS.  Alpha-1-acid glycoprotein will be determined utilizing a Radial 
Immunodiffusion Plates from Kent Diagnostics. 
 
Relevant individual PK parameters will be estimated using a compartmental PK method 
with the software WinNonlin. The pharmacokinetic variables will be tabulated and 
descriptive statistics (e.g., geometric means and coefficients of variation) calculated for 
each treatment arm.  If clinically significant differences in efficacy or toxicity are noted 
between treatment arms, the unbound concentrations and alpha-1-acid glycoprotein will be 
incorporated into a population PK method with NONMEM or PKBugs to ascertain the 
differences between arms.  Pharmacokinetic parameters (i.e., Cmax, AUC T½, and Cl) will 
be compared across treatment using nonparametric statistical testing techniques. 
Correlations with toxicity and efficacy will be explored using nonparametric statistical 
testing techniques. Significance for comparisons will be at the p<0.05 level. 
 
Refer to the study lab manual for processing and shipping instructions.  
 
9.1.2 Ascorbic Acid Pharmacokinetics Samples (Optional) 
 
PK for patients consenting to the optional PK. 
Blood samples will be collected for ascorbic acid pharmacokinetics on Cycles 1, 2, 3, 4, 
and 6 at the following time points: 
 
First ascorbate administration of the cycle of Cycles 1, 2, 3, 4, and 6:  
pre-ascorbic acid infusion 
immediately after the end of the ascorbic acid infusion 
60 minutes after the completion of the ascorbic acid infusion 
 
Day 19 (or same day as last ascorbate administration of the cycle) of Cycles 1, 2, 3, 4, 
and 6:  
pre-ascorbic acid infusion 
immediately after the end of the ascorbic acid infusion 
60 minutes after the completion of the ascorbic acid infusion 
 
PK for patients who had more frequent or severe toxicities. 
Blood samples will be collected for ascorbic acid pharmacokinetics on the next Cycle 
(Cycle >2) after the adverse drug event occurs at the following time points: 
 
First ascorbate administration of the next cycle:  
pre-ascorbic acid infusion 
immediately after the end of the ascorbic acid infusion 


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60 minutes after the completion of the ascorbic acid infusion 
 
Day 19 (or same day as last ascorbate administration of the next cycle):  
pre-ascorbic acid infusion 
immediately after the end of the ascorbic acid infusion 
60 minutes after the completion of the ascorbic acid infusion 
 
Ascorbic acid in plasma and in red blood cells will be measured by HPLC coupled to 
coulometric electrochemical detection using a validated method. 
 
Refer to the study lab manual for processing and shipping instructions.  
 
 
9.1.4 F2-isoprostanes 
 
Blood samples will be collected for F2-isoprostanes at baseline (any time prior to first dose 
of docetaxel administration) and on Cycles 4 and 6 at the following time points: 
 
Baseline (pre-treatment) sample: 
Any time prior to first dose of docetaxel treatment 
 
First ascorbate administration of the cycle of Cycles 4 and 6:  
pre-ascorbic acid infusion 
immediately after the end of the ascorbic acid infusion 
60 minutes after the completion of the ascorbic acid infusion 
 
Correlative analyses will assess the association between ascorbic acid and lipid 
peroxidation (F2-isoprostanes) in the two study arms, globally, and over time.  F2-
isoprostanes are a reliable marker of oxidative stress recommended for assessing oxidant 
injuries in humans. We hypothesize that higher levels of ascorbic acid in the blood will be 
associated with reduced toxicity and that the mechanism of action is through the reduction 
of F2-isoprostanes.  For each patient, we will divide each follow-up laboratory data value 
of ascorbic acid and F2-isoprostanes by its baseline value and perform a log transformation 
if necessary to symmetrize the data.   Initially these data will be summarized graphically 
by study arm and time point using scatterplots and boxplots with data points superimposed.   
 
 
Two types of analyses of the correlates will be done.  In the first, repeated measurements 
of toxicity and the correlates will be averaged over time points and analyses done at the 
patient level.  Analysis of covariance models (ANCOVA) will be used to relate toxicity 
with ascorbic acid and F2-isoprostanes, allowing for differences in the two treatment arms. 
   
The second type of analysis will be based on the repeated measures data. Comparisons of 
ascorbic acid and F2-isoprostanes by study arm at Cycle 4 and Cycle 6, accounting for 
baseline measures obtained from the same patient, will be made by taking differences 
between post baseline and baseline values and comparing these differences between arms 
of the study with t-tests.  This comparison of differences may be adjusted for the presence 
of toxicity using a regression model.  Regression will also be used to assess the association 
between F2-isoprostane and ascorbic acid at Cycle 4 and Cycle 6, adjusting for study arm 
and toxicity.  
 


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Plasma F2-Isoprostanes will be measured by a validated LC/MS method. 
 
Refer to the study lab manual for processing and shipping instructions.  
 
 
9.2  
Serum Samples 
 
Blood will be collected at Day 1 of each cycle (must be pre-treatment on Cycle 1 Day 1), and at 
study completion (30-day follow-up visit) to identify potential therapeutic targets, biomarkers, 
and predictors of response through proteomic approaches. Refer to the study lab manual for 
processing and shipping instructions.  
 
 
 


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10. STUDY CALENDAR 
Required Studies 
Pre-study  
R 
Cycles 1-8 (1 cycle = 21 days) 
30-day FU17 
Long 
FU7 
 
 
 
Day 1 
Day 2 
Day 4 
Day 8 
Day 12 
Day 15 
Day 19 
 
 
Visit Windows (days)1 
-21 to -7 
-7 to 0 
 
 
 
 
 
 
 
+ 7 
+ 28 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
Docetaxel  
 
 
X 
 
 
 
 
 
 
 
 
Ascorbic acid/Placebo2,3 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
ELIGIBILITY 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion review 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
Medical and Cancer History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam and ECOG 4  
X 
 
X4 
 
 
 
 
 
 
X 
 
Vital Signs, Weight5 
X 
 
X5 
 
 
X 
 
X 
 
X 
 
AE/Toxicity Notation 
 
 
X4 
 
X 
X 
X 
X 
X 
X 
 
Concurrent meds 
X 
 
X4 
 
 
X 
 
X 
 
X 
 
FACT-P Questionnaire6 
X 
 
X6 
 
 
 
 
 
 
 
 
Long term follow-up7 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
Chemistry8,9,10 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Hematology8,9,10 
X 
 
X 
 
 
 
 
 
 
X 
 
PSA9 
X 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
G6PD11 
X 
 
 
 
 
 
 
 
 
 
 
CORRELATIVE18  
 
 
 
 
 
 
 
 
 
 
 
Docetaxel PK Samples12 
 
 
X12 
X12 
 
 
 
 
 
 
 
Ascorbic Acid PK Samples13 
 
 
X13 
 
 
 
 
 
X13 
 
 
Plasma samples for F2-isoprostanes14 
X14 
 
X14 
 
 
 
 
 
 
 
 
Serum Samples15 
 
 
X 
 
 
 
 
 
 
X 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
 
 
Radiologic Evaluation/ RECIST 1.11, 16  or 
PCWG2 
X1 
 
X16 
 
 
 
 
 
 
X16 
 
 
 
1  
Longer delays to be approved by the study sponsor. IRB approval is required for all eligibility waivers prior to randomization. The window for the 


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30
baseline Radiologic Evaluation/RECIST 1.1 is 4 weeks.  
2  
Each treatment cycle is 3 weeks (21 days). Ascorbic Acid/Placebo dosing should be 2 times per week on day 1 of each cycle and any day as long as it is 
at least 24 hours from the prior infusion.  
3  
Ports are recommended but not mandatory due to the frequency of infusion.  
4  
After screening, physical exams may be limited as indicated by symptoms. ECOG – Eastern Cooperative Oncology Group performance status. Physical 
exam, ECOG status, AE/Toxicity notation and concurrent medication review have a -4 day window of day 1 of the cycle. 
5  
Vital signs include temperature, blood pressure, respiration rate, heart rate, and weight. Height is collected pre-study only study. There is a -4 day window 
of day 1 of the cycle that the vital signs can be collected within.  
6  
To assess changes in quality of life measures, the FACT-P questionnaire will be given at baseline (Pre-Study or Cycle 1 Day 1), Cycle 4 Day 1, Cycle 
6 Day 1; and Cycle 8 Day 1. There is a -4 day window of day 1 of the cycle that the FACT-P questionnaire can be completed within.  
7  
Survival status and subsequent therapies will be collected during long term follow-up (LTFU) every 6 months (+/- 4 weeks), by phone or chart review, 
for 3 years or until study closure. Gather date of death, date of radiographic and/or PSA progression, start and stop dates for subsequent therapies.   
8  
Clinical Hematology: CBC with differential ANC, ALC, AEC, and platelet count; Serum Chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, calcium.  
9  
Safety labs may be collected within a window of up to five days prior to scheduled visit/dosing. 
10  Labs should be reassessed approximately once per week for hold parameters. Only labs required for ascorbic hold parameters will be required on weeks 
2 and 3. A CBC does not need to be drawn unless clinically indicated and would not alter dosing with placebo/ascorbic acid. 
11  G6PD testing: Red blood cell hemolysis may occur in people found to be deficient in the G6PD enzyme. 
12  PK is optional.  If there are severe adverse events that are greater than what is expected by the treating physician and thought to be related to study drug, 
PKs are strongly recommended to help determine etiology of AEs. For docetaxel PK samples, blood should be drawn during Day 1 of Cycle 1 at the 
following time points: prior to docetaxel administration, 30 and 55 minutes after the start of the docetaxel infusion, and 2 and 5 hours post-docetaxel 
infusion; Day 2: approximately 24 hours post-docetaxel infusion. See protocol Section 9.1.1 for details. 
13  PK is optional.  If there are severe adverse events that are greater than what is expected by the treating physician and thought to be related to study drug, 
PKs are strongly recommended to help determine etiology of AEs. For ascorbic acid correlative analysis, approximately 5 mL of whole blood will be 
collected for plasma and RBC isolation at each time point. Blood should be drawn during Cycles 1, 2, 3, 4, and 6 at the following time points: first 
ascorbate administration of the cycle: Pre-ascorbic acid infusion, immediately after the ascorbic acid infusion, 60 minutes after the completion of the 
ascorbic acid infusion, and last ascorbate administration of the cycle: pre-ascorbic acid infusion, immediately after the ascorbic acid infusion, and 60 
minutes after the completion of the ascorbic acid infusion. In addition when feasible, samples will be requested from the patient in the event of DLT or 
other persistent and severe toxicity during any cycle of therapy. See protocol Section 9.1.2 and 9.1.3 for details. 
14  For F2-isoprostanes correlative samples, approximately 10 mL of whole blood will be collected for plasma isolation at each time point.  Blood should 
be drawn at baseline (1 sample, any time prior to first dose of docetaxel administration) and on the first ascorbate administration of the cycle of Cycles 
4 and 6 at the following time points: Pre-ascorbic acid infusion, immediately after the ascorbic acid infusion, and 60 minutes after the completion of the 
ascorbic acid infusion.  See protocol Section 9.1.4 for details. 
15  Approximately 10mL of whole blood will be collected for serum isolation at each time point. See protocol Section 9.2 for details. 
16  CT scan (chest/abdomen/pelvis or MRI if patient has contrast allergy) and bone scan to be assessed at baseline and every 12 weeks (+/- 1 week), and at 
the 30-day follow-up visit (scans do not need to be repeated if one has not been done within the past 6 weeks). 


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17  30 days after their last dose of study drug. Ascorbic acid will be available twice a week until progression.  Patients will be required to get safety labs 
(CBC and CMP weekly for ascorbic acid), and be assessed for progression per investigator judgment and at least every 12 weeks by PSA, CMP, CBC, 
bone scan, CT scan, and H&P.  
18 Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. 
 
 
NOTE: In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person 
clinical trial visits or portions of clinical trial visits where determined to be appropriate and where determined by the 
investigator not to increase the participants risks. Prior to initiating telemedicine for study visits the study team will 
explain to the participant, what a telemedicine visit entails and confirm that the study participant is in agreement 
and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will 
proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved by the 
Health System and within licensing restrictions.  
 
 
 


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32
11.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
11.1  Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study staff. These 
data will be reviewed for completeness and accuracy by the Principal Investigator.  
 
Data and/or completed case report forms must be transmitted by fax or e-mail to the Coordinating 
Center following the completion of each cycle as detailed in Section 10. Case report forms will be 
provided to participating sites by the Coordinating Center. 
 
11.2  Safety Meetings 
 
Scheduled meetings will take place weekly, biweekly or monthly depending on patient 
enrollement, and will include the protocol principal investigator, study coordinator(s), data 
manager(s), sub-investigators (as appropriate), collaborators (as appropriate), and biostatisticians 
(as appropriate) involved with the conduct of the protocol. During these meetings matters related 
to the following will be discussed: safety of protocol participants, validity and integrity of the data, 
enrollment rate relative to expectation, characteristics of participants, retention of participants, 
adherence to protocol (potential or real protocol violations), data completeness, and progress of 
data for objectives. 
 
11.3  Monitoring 
 
The SKCCC Compliance Monitoring Program will provide external monitoring for JHU-
affiliated sites in accordance with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC 
Subcommittee will determine the level of patient safety risk and level/frequency of monitoring.  
Dr. Channing Paller will be holding the IND for this study.  She will comply with all regulated 
reporting requirements to the FDA. 
 
Authorized representatives of the Coordinating Center may visit participating sites to perform 
audits or inspections, including source data verification.  The purpose of these audits or inspections 
is to systematically and independently examine all trial related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), and any applicable 
regulatory requirements. 
 
Interim analysis of toxicity, outcome and ongoing scientific investigations will be performed 
every 6 months by the Sidney Kimmel Comprehensive Cancer Center Data Safety Monitoring 
Board (SKCCC DSMB). The SKCCC DSMB will review aspects of this trial that are outlined in 
the responsibilities section of the Data and Safety Monitoring Board (DSMB) Guidance. If the 
committee decides that amendments should be made to this trial, recommendations will be made 
in writing to the Study Principal Investigator. The study team will submit modifications to the 
IRB within 60 days of receipt from the DSMB. The Associate Director of Clinical Research, will 
arbitrate any disagreements between the DSMB and the study Principal Investigator. These 


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33
changes may include early termination of accrual if deemed appropriate.  
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design 
 
The hypotheses of this study are that I.V. ascorbic acid may increase PSA responses over the 24 
weeks of treatment and/or mitigate toxicities over this same time period.  This study will have 
toxicity and PSA response as co-primary endpoints.  PSA response will be defined as achieving at 
least a 50% decline in PSA from baseline (day 1, prior to treatment initiation) at any time during 
the 24 weeks of treatment.  Toxicity will be measured as the worst grade of four specific adverse 
events (AEs) over the 24 weeks of treatment.  The specific toxicities for this endpoint are fatigue, 
nausea, bone pain, and anorexia.  Data from the TAX 327 study, which enrolled similar patients, 
show a PSA response rate of 45% and an overall grade 3-4 AE rate of 45.8% (all toxicity types).  
It is expected for the current trial that docetaxel with I.V. ascorbic acid will improve the PSA 
response rate to 80%.  While we do not have preliminary data for the toxicity endpoint as defined 
for this study, we include simulation results that illustrate the probability the study will detect a 
significant difference between the two treatment arms. Scenarios for these simulations are based 
on the TAX 327 study.  
 
Primary objective:  Determine if the proportion of patients with ≥50% decline in PSA over the 8 
cycles of therapy is higher in the docetaxel with I.V. ascorbic acid arm and determine if the 
proportions of AEs of fatigue, nausea, bone pain, and anorexia reported in the docetaxel+ I.V. 
ascorbic acid arm are lower compared to the docetaxel and placebo arm. 
 
Co-Primary endpoints:  
1. The occurrence of a ≥50% decline in PSA from baseline at any time during the 24 weeks 
of treatment. 
2. The proportions of worst grade AEs among those specified (fatigue, nausea, bone pain, and 
anorexia) in the categories: no toxicities, grade 1-2, and grade 3-4 in the two arms of the 
study. 
   
Secondary objectives:   
 
1. Compare radiographic progression free survival (rPFS). 
2. Compare the proportions of maximum grade serious adverse events (SAE) of fatigue, 
nausea, bone pain, and anorexia during the 24 weeks of treatment. 
3. Compare the proportions of maximum grade SAE of all types.  
4. Compare QoL as measured by the FACT-P questionnaire. 
5. Compare docetaxel dose reductions. 
6. Compare overall survival between arms of the study. 
 
Correlative objectives: 
1. To determine whether ascorbic acid alters docetaxel exposure and compare between 
treatment arms.  To correlate docetaxel exposure with clinical outcomes. 
2. To determine peak and trough ascorbic acid levels 
3. As a pharmacodynamic measure of oxidant injury in vivo, measure F2-isoprostanes  
 


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34
 
12.2 
Sample Size/Accrual Rate 
 
PSA response and toxicity are co-primary endpoints of this study.  To preserve the study 
significance level at 15%, the significance level is set at 5% for PSA response and 10% for toxicity.  
The TAX 327 PSA response rate used as the reference for this study is 45%.  A one-sided 0.05 
Fisher’s exact test with the sample size 63, 21 patients on the docetaxel+placebo arm and 42 
patients on the docetaxel with I.V. ascorbic acid arm, has 80% power to detect an improvement in 
the PSA response rate to 80%.   
 
Sample size implications for the toxicity endpoint are summarized below.  Power determination is 
based on simulated clinical studies in which the analysis is the Cochran-Armitage test for trend 
comparing two groups in observed proportions scored by toxicity grade (i.e., categorized as grade 
0, grades 1-2, and grades 3-4).  All scenarios assume that, on average, 16% of patients on the 
docetaxel+placebo arm experience a grade 3-4 toxicity of one of the specified types.  This estimate 
was obtained as the sum of grade 3-4 AEs for fatigue, nausea, bone pain, and anorexia reported 
for the every-3-week docetaxel arm in the Tannock study16. 
 
Scenario 1: Substantial decreases in both high and medium grade toxicities:   
After 5000 simulations at the 0.1-alpha level with probabilities 
 
Grade 0 
Grade 1-2 
Grade 3-4 
P0 standard 
0.10 
0.74 
0.16 
P1 Vit C 
0.45 
0.50 
0.05 
Rejected 4654 times (93.1%) 
 
Scenario 2: Smaller decreases in high and medium grade toxicities:   
After 5000 simulations at the 0.1-alpha level with probabilities 
 
Grade 0 
Grade 1-2 
Grade 3-4 
P0 standard 
0.10 
0.74 
0.16 
P1 Vit C 
0.30 
0.60 
0.10 
Rejected 2629 times (52.6%) 
 
Scenario 3: No decrease in high grade toxicities, but large decrease in medium grade toxicity: 
After 5000 simulations at the 0.1-alpha level with probabilities 
 
Grade 0 
Grade 1-2 
Grade 3-4 
P0 standard 
0.10 
0.74 
0.16 
P1 Vit C 
0.50 
0.34 
0.16 
Rejected 3711 times (74.2%) 
 
Scenario 4: No decrease in high grade toxicity, but some decrease in medium grade toxicity: 
After 5000 simulations at the 0.1-alpha level with probabilities 
 
Grade 0 
Grade 1-2 
Grade 3-4 
P0 standard 
0.10 
0.74 
0.16 
P1 Vit C 
0.34 
0.50 
0.16 
Rejected 1971 times (39.4%) 
 
 
 


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35
Scenario 5: No change in toxicity at any level: 
After 5000 simulations at the 0.1-alpha level with probabilities 
 
Grade 0 
Grade 1-2 
Grade 3-4 
P0 standard 
0.10 
0.74 
0.16 
P1 Vit C 
0.10 
0.74 
0.16 
Rejected 497 times (9.9%) 
 
12.3  Monitoring Plan 
 
We will monitor the PSA response endpoint for futility midway through the trial.  The PSA 
endpoint will be monitored using a predictive probability approach.  This monitoring plan is based 
on calculations of the predicted probability of a significant result if the trial were to continue to 
the end.  At the time the trial is monitored, 500 simulations of the future results of the trial are 
generated and analyzed.  If the probability is too low (i.e., less than 0.05) that the trial would end 
with a significant result, the study may be stopped for futility.  The study will be monitored after 
30 patients, 10 patients in the docetaxel+placebo arm and 20 patients in the docetaxel with I.V. 
ascorbic acid arm.  The predictive distributions of the number of events in future patients are 
generated using a beta-binomial distribution with α and β parameters based on the data observed 
in the trial up to that point.   
 
The table below gives the operating characteristics of the monitoring plan based on 1000 
simulations for different combinations of p0 and p1.  The first row shows results using the 
hypothesized proportions used for the study design (p0=0.45) and (p1=0.80).  Other combinations 
for p0 and p1 are simulated to demonstrate the stopping rule if the difference in these proportions 
is smaller than hypothesized.    
 
Table 1.  Operating characteristics of monitoring rule for PSA response 
 
p0 vs p1 
Prob stop for 
futility 
Avg N/group 
(Control, Trt) 
Prob H0 
rejected 
(power) 
0.45 vs 0.80 
3.2% 
20.6, 41.3 
79.6% 
0.45 vs 0.76 
5.9% 
20.4, 40.7 
66.8% 
0.45 vs 0.70 
12.2% 
19.7, 39.3 
51.6% 
0.45 vs 0.60 
27.4% 
18.0, 36.0 
22.4% 
0.45 vs 0.45 
53.9% 
15.1, 30.1 
3.3% 
 
 
Safety monitoring and early stopping rule for safety:   
A central hypothesis of this study is that I.V. ascorbate will help alleviate pain and reduce treatment 
related toxicities.  Since we also do not anticipate overlapping toxicities of I.V. ascorbate and 
docetaxel, we will monitor the study arm for two types of toxicities that, if observed, would likely 
to be attributable to the addition of I.V.  This includes sclerosis preventing infusion and kidney 
stones requiring cessation of treatment.  Safety will be monitored after every patient in the 


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36
docetaxel+I.V, ascorbate study arm using 33% as the target limit on these adverse events.  This 
monitoring rule will halt enrollment if the posterior probability of these events exceeding 0.33 is 
70% or higher.  The prior probability for this toxicity monitoring rule will be a Beta distribution 
with parameters of 2 and 4.  This distribution corresponds to assuming a 2 in 5 chance that the risk 
of DLT is 33% or higher and 90% certainty that the risk is between 7.6% and 65.7%.  The 
monitoring rule applies this prior distribution to the observed number of patients experiencing 
events and computes the resulting posterior probability that the rate is too high.  If the posterior 
certainty that the rate is too high based on these assumptions is 70% or higher, the study should 
stop.  The following table shows the resulting guideline. 
 
Study paused if:  
2 AEs 
3 AEs 
4 AEs 
5 AEs 
6 AEs 
7 AEs 
And patients between: 
2-3 
4-6 
7-8 
9-11 
12-14 
15-17 
 
Study paused if:  
8 AEs 
9 AEs 
10 AEs 
11 AEs 
12 AEs 
13 AEs 
And patients between: 
18-20 
21-22 
23-25 
26-28 
29-31 
32-34 
 
Study paused if:  
14 AEs 
15 AEs 
16 AEs 
And patients between: 
35-37 
38-40 
41-42 
 
For example, the rule will call for stopping the study if 4 out of the first 7 patients experience these 
AEs.  The next table shows the percent of the time that the stopping rule will terminate the study 
under different hypothetical risks of AEs, along with the average sample size (based on 5000 
simulations).  
 
Risk of AE 
0.10 
0.20 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
% of Time Study Stops 
4.2% 
19.5% 
34.6% 
50.9% 
71.1% 
86.3% 
95.2% 
98.7% 
Expected Sample Size 
40.4 
35.0 
30.2 
25.5 
19.4 
14.1 
10.1 
7.5 
 
 
12.4 
Analysis Plans 
 
 
 
 
Co-Primary endpoints:   
The primary analysis for the PSA response outcome will be a one-sided 0.05 alpha level Fisher’s 
exact test.  The primary analysis for the toxicity endpoint will be a one-sided 0.10 Cochran-
Armitage test for trend.  
 
Secondary endpoints: 
1. For each treatment arm, the median rPFS and a 2-sided 95% confidence interval will be 
provided.  Estimates of the time-to-event curves from the Kaplan-Meier method will be 
provided and compared using the log-rank statistic.  
2. The proportions of patients experiencing grade 3 or higher (maximum grade) serious 
adverse events (SAEs) of fatigue, nausea, bone pain, and/or anorexia during the 24 weeks 
of treatment will be compared between arms of the study with the Cochran-Armitage test 
for trend. 
3. Proportions of maximum grade SAE of all types will also be compared using the Cochran-


J15106/ Protocol Version 18.0 19-Oct-2021 
 
37
Armitage test for trend.  
4. The FACT-P questionnaire will be given at baseline and once prior to cycles 4, 6 and 8 of 
therapy.  FACT-P scores will be compared at each cycle between arms of the study with 
an analysis of covariance using the baseline QoL score as a covariate.   
5. The number of dose reductions and total number of completed cycles will be summarized 
by study arm. 
6. For each treatment arm, the median OS and a 2-sided 95% confidence interval will be 
provided.  Estimates of the time-to-event curves from the Kaplan-Meier method will be 
provided and compared using the log-rank statistic. 
 
Correlative Analyses: 
Correlative analyses will assess the association between ascorbic acid and lipid peroxidation (F2-
isoprostanes) in the two study arms, globally, and over time.  F2-isoprostanes are a reliable marker 
of oxidative stress recommended for assessing oxidant injuries in humans.  We hypothesize that 
higher levels of ascorbic acid in the blood will be associated with reduced toxicity and that the 
mechanism of action may be coupled to reductions of F2-isoprostanes.  For each patient, we will 
divide each follow-up laboratory data value of ascorbic acid and F2-isoprostanes by its baseline 
value and perform a log transformation if necessary to symmetrize the data.   Initially these data 
will be summarized graphically by study arm and time point using scatterplots and boxplots with 
data points superimposed.   
 
Two types of analyses of the correlates will be done.  In the first, repeated measurements of toxicity 
and the correlates will be averaged over time points and analyses done at the patient level.  Analysis 
of covariance models (ANCOVA) will be used to relate toxicity with ascorbic acid and F2-
isoprostanes, allowing for differences in the two treatment arms. 
   
The second type of analysis will be based on the repeated measures data.  Comparisons of ascorbic 
acid and F2-isoprostanes by study arm at cycle 4 and cycle 6, accounting for baseline measures 
obtained from the same patient, will be made by taking differences between post baseline and 
baseline values and comparing these differences between arms of the study with t-tests.  This 
comparison of differences may be adjusted for the presence of toxicity using a regression model.  
Regression will also be used to assess the association between F2-isoprostane and ascorbic acid at 
cycle 4 and at cycle 6, adjusting for study arm and toxicity.  
 
Relevant individual PK parameters will be estimated using a compartmental PK method with the 
software WinNonlin. The pharmacokinetic variables will be tabulated and descriptive statistics 
(e.g., geometric means and coefficients of variation) calculated for each treatment arm.  If 
clinically significant differences in efficacy or toxicity are noted between treatment arms, the 
unbound concentrations and alpha-1-acid glycoprotein will be incorporated into a population PK 
method with NONMEM or PKBugs to ascertain the differences between arms.  Pharmacokinetic 
parameters (i.e., Cmax, AUC T½, and Cl) will be compared across treatment using nonparametric 
statistical testing techniques. Correlations with toxicity and efficacy will be explored using 
nonparametric statistical testing techniques. Significance for comparisons will be at the p<0.05 
level. 
 
 
 


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38
12.5 
Expected accrual rate, accrual duration, and total study duration 
 
We plan to open the study at four institutions: Johns Hopkins Hospital/Sibley Memorial Hospital, 
Karmanos, Jefferson, University Hospitals of Cleveland Seidman Cancer Center and Inova.  The 
accrual rate is expected to be one to two patients per month at each institution, with the completion 
of accrual expected within 18 months.  Total accrual at Johns Hopkins/Sibley is expected to be 25 
patients, with 13 from each of the other institutions. 


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39
REFERENCES 
 
1 
Dagher, R. et al. Approval summary: Docetaxel in combination with prednisone for the 
treatment of androgen-independent hormone-refractory prostate cancer. Clinical cancer 
research : an official journal of the American Association for Cancer Research 10, 8147-8151, 
doi:10.1158/1078-0432.CCR-04-1402 (2004). 
2 
Hoffer, L. J. et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Annals of 
oncology : official journal of the European Society for Medical Oncology / ESMO 19, 1969-1974, 
doi:10.1093/annonc/mdn377 (2008). 
3 
Monti, D. A. et al. Phase I evaluation of intravenous ascorbic acid in combination with 
gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PloS one 7, e29794, 
doi:10.1371/journal.pone.0029794 (2012). 
4 
Welsh, J. L. et al. Pharmacological ascorbate with gemcitabine for the control of metastatic and 
node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer 
chemotherapy and pharmacology 71, 765-775, doi:10.1007/s00280-013-2070-8 (2013). 
5 
Stephenson, C. M., Levin, R. D., Spector, T. & Lis, C. G. Phase I clinical trial to evaluate the safety, 
tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with 
advanced cancer. Cancer chemotherapy and pharmacology 72, 139-146, doi:10.1007/s00280-
013-2179-9 (2013). 
6 
Ma, Y. et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and 
reduced toxicity of chemotherapy. Science translational medicine 6, 222ra218, 
doi:10.1126/scitranslmed.3007154 (2014). 
7 
Vollbracht, C. et al. Intravenous vitamin C administration improves quality of life in breast cancer 
patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, 
epidemiological cohort study in Germany. In vivo 25, 983-990 (2011). 
8 
Padayatty, S. J. et al. Vitamin C: intravenous use by complementary and alternative medicine 
practitioners and adverse effects. PloS one 5, e11414, doi:10.1371/journal.pone.0011414 
(2010). 
9 
Chen, Q. et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as 
a pro-drug to deliver hydrogen peroxide to tissues. Proceedings of the National Academy of 
Sciences of the United States of America 102, 13604-13609, doi:10.1073/pnas.0506390102 
(2005). 
10 
Chen, P. et al. Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through 
ATP depletion and induction of autophagy. Anti-cancer drugs 23, 437-444, 
doi:10.1097/CAD.0b013e32834fd01f (2012). 
11 
Pollard, H. B., Levine, M. A., Eidelman, O. & Pollard, M. Pharmacological ascorbic acid suppresses 
syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In vivo 24, 249-
255 (2010). 
12 
Parrow, N. L., Leshin, J. A. & Levine, M. Parenteral ascorbate as a cancer therapeutic: a 
reassessment based on pharmacokinetics. Antioxidants & redox signaling 19, 2141-2156, 
doi:10.1089/ars.2013.5372 (2013). 
13 
Levine, M., Padayatty, S. J. & Espey, M. G. Vitamin C: a concentration-function approach yields 
pharmacology and therapeutic discoveries. Advances in nutrition 2, 78-88, 
doi:10.3945/an.110.000109 (2011). 
14 
de Weger, V. A., Beijnen, J. H. & Schellens, J. H. Cellular and clinical pharmacology of the taxanes 
docetaxel and paclitaxel--a review. Anti-cancer drugs 25, 488-494, 
doi:10.1097/CAD.0000000000000093 (2014). 
15 
Puisset, F. et al. Clinical pharmacodynamic factors in docetaxel toxicity. British journal of cancer 
97, 290-296, doi:10.1038/sj.bjc.6603872 (2007). 


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40
16 
Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced 
prostate cancer. The New England journal of medicine 351, 1502-1512, 
doi:10.1056/NEJMoa040720 (2004). 
17 
Scher, H. I. et al. Design and end points of clinical trials for patients with progressive prostate 
cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical 
Trials Working Group. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 26, 1148-1159, doi:10.1200/JCO.2007.12.4487 (2008). 
18 
Feetam, C. L., Leach, R. H. & Meynell, M. J. Lack of a clinically important interaction between 
warfarin and ascorbic acid. Toxicology and applied pharmacology 31, 544-547 (1975). 
19 
Sattar, A., Willman, J. E. & Kolluri, R. Possible warfarin resistance due to interaction with 
ascorbic acid: case report and literature review. American journal of health-system pharmacy : 
AJHP : official journal of the American Society of Health-System Pharmacists 70, 782-786, 
doi:10.2146/ajhp110704 (2013). 
20 
Dimeski, G., Jones, B. W., Tilley, V., Greenslade, M. N. & Russell, A. W. Glucose meters: 
evaluation of the new formulation measuring strips from Roche (Accu-Chek) and Abbott 
(MediSense). Annals of clinical biochemistry 47, 358-365, doi:10.1258/acb.2010.009291 (2010). 
21 
Vasudevan, S. & Hirsch, I. B. Interference of intravenous vitamin C with blood glucose testing. 
Diabetes care 37, e93-94, doi:10.2337/dc13-2452 (2014). 
22           Berenson, J.R., Matous, J., Swift R.A., Mapes, R., Morrison, B. & Yeh, H.S., et al. A phase I/II 
study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of 
relapsed or refractory multiple myeloma. DOI:10.1158/1078-0432.CCR-06-1812 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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APPENDIX B: FACT-P Questionnaire (Version 4) 
 
 
 


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43
APPENDIX C: Serious Adverse Event Reporting Form 
 
Please notify IND Sponsor, Channing Paller, MD within 24 hours (Fax: 410-614-8397, Email:  
cpaller1@jhmi.edu) 
 
Protocol Title: 
 
 
A Randomized Phase 2 Trial of Ascorbic Acid in Combination with 
Docetaxel in Men with Metastatic Prostate Cancer 
 
Protocol 
Number: 
J15106 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Date: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all 
that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Persistent or Significant Disability 
 Congenital Anomaly 
 Other Important Medical Event 
 Cancer 
 Overdose 
 
Hospital Admission 
Date:  
 
 
 
Hospital Discharge 
Date: 
Date Event 
Discovered: 
Section A: Subject Information 
Subject ID: 
Subject Initial: 
 
Subject Gender: 
Male 
Female 
 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Date of First Dose: 
 
Action taken with the study drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Date of Last Dose prior to 
Event: 
 
Number of Total Doses: 
 
Event Onset Date: 
Event End Date: 


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44
Relationship to: 
Ascorbic acid/Placebo Docetaxel  
Underlying Disease 
Unrelated 
                                   
 
 
Related 
                                   
 
 
Section C: Brief Description of the Event: 
 
 
 
 
 
 
 
Section D: Relevant Medical History 
 
 
 
 
Section E: Concomitant Drug (Not related to Serious Adverse Event) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify