A Phase II Trial of High-Dose Ascorbate in Stage IV Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Joseph J. Cullen, MD, FACS

A Phase II Trial of High-Dose Ascorbate in Stage IV Non-Small Cell Lung Cancer 
Principal Investigator: 
Muhammad Furqan, M.B., B.S.  
Co-Principal Investigator: 
Bryan Allen, MD, PhD 
IND Sponsor: 
Joseph J. Cullen, MD 
Medical Monitor: 
Daniel Berg, MD 
Sub-Investigators: 
Internal Medicine– Taher Abu Hejleh, M.B., B.S. 
Internal Medicine– Jun Zhang, MD, PhD 
Radiation Oncology—Garry R. Buettner, PhD 
Radiation Oncology—Brett Wagner, PhD 
Radiation Oncology—Zita Sibenaller, PhD 
Surgery—Kalpaj Parekh, MBBS 
Surgery—John Keech, MD 
Consultant: 
Mark Levine, M.D. 
Chief, Molecular and Clinical Nutrition Section 
Digestive Diseases Branch 
National Institutes of Health 
Telephone: (301) 402-5588 Fax: (301) 402-6436 
markl@intra.niddk.nih.gov 
Biostatisticians: 
Sarah Bell, MS 
Brian Smith, PhD 
Research Nurses: 
Kristin Varner, BSN, RN, OCN 
Pam Zehr, RN, CCRC 
Susan Butcher, RN, MSN 
Michelle Arnold, OCN, RN 
Mary Schall, RN, BSN 
Janelle Born, RN, BSN 
IND regulatory manager: 
Kellie Bodeker-Goranson, M.S.H.S., CCRC 
(319) 384-9425 
kellie-bodeker@uiowa.edu 
Protocol Number: 
201412760; NCT02420314 
IND Number: 
105715 [CDER] 
Date: 
07 November 2018 
Version: 
Amendment 7 [07 NOV 2018] 
Amendment 6 [04 JAN 2018] 
Amendment 5 [05 APR 2017] 
Amendment 4 [08 JAN 2017] 
Amendment 3 [08 AUG 2016] 
Amendment 2 [03 MAR 2016] 
Amendment 1 [15 JAN 2016] 
Initial release [04 APR 2015] 
 

 
i 
SUMMARY OF CHANGES 
 
Section 
 
Change 
07 November 2018 
 
 
Cover 
 
Updated date, version 
3.1.2 
 
Clarified patient base for those who have received prior therapy with 
curative intent. 
3.2.2 
 
Clarified PDL-1 expression requirements  
5.1 
 
Inserted, “(except transient increase in blood pressure)” for clarification. 
5.6.2 
 
Change of follow-up from active to passive through chart review and 
following standard-of-care. This is for scheduling convenience for further 
systemic therapy or to release to local care for palliation. 
6.5 
 
Harmonized follow-up requirements to section 5.6.2 for passive follow-up 
through standard of care. 
6.6.2 
 
Inserted, “stable,” for further clarification. 
11 [Study Calendar] 
 
Updated follow-up per sections 5.6.2 and 6.5 
 
 
 
04 January 2018 
 
 
Schema 
 
inserted iron panel and ferritin as baseline assessments 
5.3.6 
 
deleted extra (i.e. empty) bullet-point 
5.3.8 
 
adjusted schedule to ± 7 calendar days to mirror standard of care and 
enable adjustments for clinical scheduling 
6.1 
 
inserted 6.1.13 listing an iron panel (iron, transferrin, TIBC, and % 
saturation) as a baseline lab 
6.1 
 
inserted 6.1.14, listing ferritin as a baseline lab 
6.2 
 
inserted 6.2.14, listing the iron panel and ferritin as required labs for 
cycles 1 and 3 only. 
11 (Study calendar) 
 
inserted iron panel and ferritin line item, inserted footnote s. 
Appendix C 
 
Updated monitoring plan for consistency with data and safety monitoring 
plan approved by NCI for UIOWA’s cancer center. 
Appendix C 
 
Added risk of gout or gout-like symptoms as possible side effect 
04 April 2017 
 
 
Cover 
 
Updated date, version 
7.3.1 
 
Updated to include McGuff Pharmaceuticals, Inc as the preferred supplier 
7.3.2 
 
Inserted text regarding Ascor L-500, renumbered subsequent text 
accordingly. 
 
 
 

 
ii 
January 08, 2017 
 
 
Cover 
 
Updated personnel, date, version 
Schema 
 
Updated information to be consistent with section 3.1 
1.2 
 
Updated secondary objectives to include stage IIIB NSCLC 
3.1.5 
 
Clarified creatinine limit with regard to ULN, for consistency with 
CTCAE v4.03 
3.1.5 
 
Clarified T.Bilirubin limit with regard to ULN, for consistency with 
CTCAE v4.03 
3.1.7 
 
Inserted criterion for patients who have received prior neo-adjuvant, 
adjuvant, chemoradiation, or radiation therapy with curative intent; 
renumbered Inclusion Criteria accordingly. 
3.2.1 
 
Clarified EGFR mutations (i.e., sensitizing) and edited sentence for 
clarity. 
3.2.2 
 
Inserted criterion for PD-L1 expression in response to updated approved 
therapeutic options; renumbered Exclusion Criteria accordingly. 
3.2.9 
 
Clarified other invasive malignancies as excluded if they are active. 
5.3.2 
 
Inserted section on body weight, calling out C1D1 as baseline for 
chemotherapy calculations; change weight if >10% change. Renumbered 
accordingly. 
5.3.3 
 
Inserted section on body height, calling out C1D1 as baseline for 
chemotherapy dose calculations. Renumbered accordingly. 
5.3.5 
 
Inserted reference to sections 5.3.2, 5.3.3 
5.3.6 
 
Inserted reference to sections 5.3.2, 5.3.3 
5.4.10 
 
Inserted section to address palliative radiotherapy, for those patients 
requiring radiation therapy to alleviate pain or secondary symptoms of 
their malignancy. 
5.7 
 
Changed ‘study’ to ‘treatment’ to clarify that those participants who have 
received 2 cycles of therapy will have life-long follow-up. 
12.1 
 
Inserted (Primary End-Point) for clarity. 
Appendix:  
Eligibility checklist 
 
Harmonized with protocol section 3, Eligibility Criteria 
Appendix: 
Monitoring worksheets 
 
Harmonized with protocol 
 
 
 
 
 
 
August 09, 2016 
 
 
Cover 
 
Updated date, version 
Schema 
 
Inserted information regarding health-related quality of life. 
9: Study calendar 
 
Inserted row for health-related quality of life. 

 
iii 
10: Correlative studies 
 
Added health-related quality of life information to establish patient-
reported outcomes for this trial.  
Eligibility checklist 
 
Updated amendment; corrected ‘conception’ to ‘contraception’ 
 
 
 
March 03, 2016 
 
 
Cover 
 
Updated date, version 
5.3.4 
 
Added bullet to address use of current weight for carboplatin dosing 
6.2.7 
 
Deleted ‘dry mouth’ as required assessment; renumbered accordingly 
6.5.1 
 
Inserted, ‘[this sample should be drawn regardless of additional therapy; 
can be drawn subsequent cycles D1 if within window]’ for clarification 
Study calendar:  ROS 
 
Marked ROS as required at follow-up, for consistency with text of 
protocol 
Study calendar: b 
 
updated footnote for consistency with protocol section 5.8 
Study calendar: c 
 
updated footnote for consistency with protocol section 5.6.2 
Study calendar: f 
 
updated footnote for consistency with protocol sections 5.3.3 and 5.3.4 
Appendix C: 
Eligibility checklist 
 
updated to be consistent with protocol section 3 
Appendix D: 
monitoring templates 
 
updated to remove ‘dry mouth’ as evaluated toxicity (C1, C2, C3, C4) 
 
 
 
 
 
 
January 15, 2016 
 
 
Cover 
 
Updated personnel, date, version 
Schema 
 
Added ‘and uric acid within 21 days of D1’ to Baseline assessments. 
3.2.1 
 
Clarified allowance for inadequate tissue sample, inconclusive 
assessment, or tumor not amendable to biopsy as potential for patient 
inclusion. 
3.2.2 
 
Inserted exclusion for warfarin therapy due to its theorized interaction 
with ascorbate; renumbered accordingly. 
5.2.1 
 
Inserted ‘/ infusion for therapy’ for clarity. 
5.3.1 
 
Inserted text to address subjects who fall outside of start window. 
5.3.6 
 
Inserted, “May be adjusted ± 2 days for scheduling.” for consistency with 
UIHC standard practice  
5.4.2 
 
Added ‘(CT)’  and ‘for CT’ for clarification so statement reads, “Imaging 
Contrast (CT). Imaging contrast for CT should not be….” 
5.4.3 
 
Inserted text on Imaging Contrast (MRI) for clarification. Renumbered 
accordingly. 
5.4.5 
 
Inserted text on theorized interaction with warfarin (coumadin).  

 
iv 
5.6.2 
 
Changed follow-up target to 28d from 21d; changed window from ‘+ 10 
calendar days’ to ‘±7 calendar days.’ Changed first follow-up appointment 
from ‘3 months’ to ‘2-4 months’ to accommodate chemotherapy schedules 
post-study.  
5.8.1 
 
Changed follow-up target to 28d from 21d; changed window from ‘+ 10 
calendar days’ to ‘±7 calendar days.’ This is to accommodate standard 
schedules for chemotherapy for scheduling convenience. 
6.5 
 
Changed follow-up target to 28d from 21d; changed window from ‘+ 10 
calendar days’ to ‘±7 calendar days.’ This is to accommodate standard 
schedules for chemotherapy for scheduling convenience. 
7.3.2 
 
Inserted ‘CT’ for clarification regarding imaging contrast 
7.3.4 
 
Inserted ‘CT’ for clarification regarding imaging contrast 
8.1 
 
Corrected ‘administer’ to ‘consider / per physician discretion’ to allow for 
individual medication variance per UIHC standard therapy  
8.4.2, 8.4.3 
 
Moved ‘Dose Delays’ from section 8.4.3 to section 8.4.2. Renumbered 
accordingly. 
8.4.2 
 
Changed text to allow up to a 3 week delay in ascorbate administration. 
Removed qualifiers for dose delay (e.g., holidays, inclement weather). 
11 [study calendar] 
 
Inserted ‘Uric Acid’ and ‘baseline’ (for timeframe), consistent with 
protocol requirements. 
11 [study calendar] 
 
Regarding Footnote ‘n’ – inserted ‘CT’ to clarify contrast contraindication 
Appendix C 
 
Updated eligibility checklist for consistency with section 3.0 
Appendix C 
 
Inserted ‘CT’ in Imaging Contrast for consistency 
Appendix D 
 
Inserted ‘Uric Acid’ into Baseline Assessment worksheet 
Appendix D 
 
Removed ‘Chills’ from worksheets, moved ‘History/Physical’ to open 
space. Chills are not actively captured as an adverse event for this trial. 
April 04, 2015 
 
 
Cover 
 
Updated date, version 
Schema (page) 
 
Added, “blood for research obtained before 15g test” under Baseline 
assessments. 
Schema (page) 
 
Corrected creatinine eligibility to less than or equal to 1.5 mg/dL 
6.1 
 
Clarified window for pre-treatment assessments. 
6.2 
 
Deleted, “On cycle day 1, collect the following information.” Every 
attempt should be made to have these assessments done day 1 but they can 
be performed on another day as decided by the research team. 
6.2 
 
Clarified blood sampling for ascorbate and ROS testing. Added ROS 
testing for cycle day 2. 
6.3 
 
Removed temperature and heart rate as it is no longer required as a routine 
safety assessment per the sponsor and medical monitor. Should be 
captured if indicated clinically. 

 
v 
6.3 
 
Clarified window for pre- and post-infusion BP/HR assessments 
10 
 
Clarified blood sampling schedule for consistency. 
11  
 
Study calendar edited for clarity (screen v. baseline) 
Throughout 
 
Removed space between ‘°’ and ‘F,’ or ‘C’ 
Appendix 
 
Corrected monitoring sheets to be consistent with section 6.3 
 
 
 
January 26, 2015 
 
 
Cover 
 
Updated date, version 
5.3.4 
 
Updated GFR maximum to FDA recommendations of 125 ml/min for all 
patients. 
6.1.9 
 
Added uric acid level at baseline. Renumbered accordingly. 
6.1.10 
 
Added, “Draw in a 4mL green-top Na Heparin tube.” 
8.3.5 
 
Updated GFR maximum to FDA recommendations of 125 ml/min for all 
patients. 
Appendix B 
 
Updated CUP3A4 interaction tables, provided by UIHC drug services 
 
 
 
December 22, 2014 
 
 
Cover 
 
Updated study personnel, date, version 
 
 
 
November 25, 2014 
Cover 
 
Updated study personnel, date, version 
iii 
 
Deleted “uric acid” from the eligibility table 
3.1.5 
 
Removed uric acid from screening labs 
3.2.2 
 
Changed ‘known’ to ‘active’ and added ‘within 1 week of screening’ to 
criterion so that it reads, “Active hemoptysis within 1 week of screening.” 
5.1 
 
Changed “Start up to” to “Can be given any time through” to clarify when 
the ascorbate test dose may be administered. 
5.2.5 
 
Duration corrected in opening sentence to 4 cycles, from 2. Inserted 
‘chemotherapy’ for clarification. 
Table 1 
 
Added “for injection only” to clarify type of sterile water allowed. 
5.3.7 
 
Duration corrected from 2 cycles to 4 cycles. 
5.8 
 
Added, “End-of-Study does not apply to subjects who complete all 4 
cycles of chemotherapy.” 
5.9 
 
Corrected “adjuvant” to “additional” 
6.2.8 
 
Added “(may be done up to 1 week before cycle day 1)” 
6.2.9 
 
Added “may be done up to 1 week before cycle day 1)” 

 
vi 
6.2 
 
Added “Once during the chemotherapy cycle, collect the following 
information:” between sub-section 6.2.9 and 6.2.10 to provide 
clarification that the ascorbate levels should just be drawn once per cycle 
but not necessarily on cycle day 1. 
6.2.12 
 
Added “Test prior to infusion and at the end of infusion (i.e., at the same 
time as the blood draws for ascorbate levels)” to further clarify when these 
tests should be performed. 
6.3 
 
Changed infusion assessments from “each hour” to “in the interim as 
clinically indicated.” 
6.4 
 
Added “CT imaging with contrast cannot be performed on the same day 
as an ascorbate infusion.” 
6.5.2 
 
Inserted “(follow-up #1, only)” because a CBC w/differential will only be 
required for research purposes at the first follow-up visit. 
6.5.3 
 
Inserted “(follow-up #1, only)” because a CBC w/differential will only be 
required for research purposes at the first follow-up visit. 
6.5.5 
 
Added section to specify that labs drawn for standard of care, or other 
purposes, may be reviewed to retrospectively assess long-term treatment 
effects and adverse events. 
6.5.6 
 
Added section to specify that medical information may be reviewed to 
retrospectively assess long-term treatment effects and adverse events. 
Renumbered subsequent sections appropriately. 
9.1.2 
 
Inserted, “Grading may be done by any licensed medical personnel (e.g., 
research nurse, treating physician, etc.) with final determination made by 
the principal investigator” to provide clarification over standard 
procedures. 
9.1.3 
 
Inserted, “grade 3 or greater” for section to read, “Initial attribution of 
ascorbate to a grade 3 or greater event may be assigned by any licensed 
medical personnel…” to clarify that attributions will be made only for 
grade 3 or greater CTCAE events unless lesser events are unexpected. 
9.1.3 
 
Inserted, “CTCAE grade 2 and lesser events do not require attribution 
unless the event is unexpected (i.e., not related to chemotherapy, tumor, or 
previously diagnosed underlying condition).” 
Table 2 
 
Deleted serious adverse event definition as it is listed prior to table 2. 
Section 11: 
Study Calendar 
 
Inserted footnote ‘g’ for comprehensive metabolic panel ‘d1’ and clarified 
that footnote to allow labs drawn up to, and including, a week prior 
Section 11: 
Study Calendar 
 
Inserted footnote ‘c’ for comprehensive metabolic panel ‘F/U’ and 
clarified that footnote to specify labs are only drawn at the first FU 
appointment 
Section 11: 
Study Calendar 
 
Inserted footnote ‘c’ for CBC w/diff ‘F/U’ and clarified that footnote to 
specify labs are only drawn at the first FU appointment 
Section 11: 
Study Calendar 
 
Clarified footnote ‘d’ for history physical that the physical may be done 
up to, and including, 1 week before day 1 of chemotherapy.  

 
vii 
Section 11: 
Study Calendar 
 
Clarified footnote ‘i’ to read blood specimens to be drawn once per cycle, 
and that a finger-stick glucometer will also be used to obtain ascorbate 
levels. 
Section 11: 
Study Calendar 
 
Added to footnote ‘n’ “DO NOT schedule on days with ascorbate 
infusions. Ascorbate and contrast are contraindicated. 
Appendix D:  
recommended 
monitoring worksheets 
 
Updated monitoring worksheets to be consistent with changes to protocol. 
 
 
 
September 2, 2014 
 
 
Section 
 
Change 
N/A 
 
Initial submission received by FDA; pre-release v0.13 
 
 
 

 
viii 
SCHEMA 
 
Screening. Order G6PD post-consent. Subject 
must be able to tolerate one 15g test infusion of 
ascorbate.  
 
Baseline assessments. Fatigue, neuropathy, 
infection, nausea, vomiting, and pain (headache) 
iron panel, ferritin, and uric acid within 21 days of 
D1. Blood for research obtained before 15g test. 
 
Health related quality of life. At baseline, then 
day 1 of cycles 2, 3, & 4, then before the last 
ascorbate infusion. 
 
Adverse events. Screened cycle D1 against case 
report form. Onset and severity of events to be 
quantified. 
 
End of active participation. Active participation 
ends at the CT scan after 4 cycles of therapy. 
 
Follow-up. Minimum 21d post-dose; survival 
through chart review. 
 
Enrollment. Targeted enrollment of 37 
participants for phase II evaluation. 
 
 
 
Selected Patient Eligibility Requirements (Section 3.1) 
• Ability to understand and the willingness to sign a 
written informed consent document 
• Diagnosis of stage IIIB, IV, or recurrent NSCLC 
• Indication for chemotherapy 
• ECOG 0-2 
• No glucose-6-phosphatase dehydrogenase deficiency 
• No known active invasive malignancy 
 
ANC 
≥ 1,500 mm3 
Platelets 
≥ 100,000/mm3 
Hemoglobin 
≥ 8 g/dL 
Bilirubin, total 
≤ 1.5 x ULN 
AST 
≤ 3x ULN 
ALT 
≤ 3x ULN 
Creatinine 
≤ 1.5 x ULN  
 
 
 
 

 
ix 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ........................................................................................................... I 
SCHEMA .................................................................................................................................... VIII 
TABLE OF CONTENTS .............................................................................................................. IX 
1. OBJECTIVES ............................................................................................................................1 
1.1. Primary Objectives ........................................................................................................................... 1 
1.2. Secondary Objectives ....................................................................................................................... 1 
2. BACKGROUND .......................................................................................................................1 
2.1. Stage IV Non-Small Cell Lung Cancer (NSCLC) and its current therapy ....................................... 1 
2.2. Ascorbate Preliminary Data ............................................................................................................. 4 
2.3. Rationale ........................................................................................................................................... 4 
3. SUBJECT SELECTION ............................................................................................................5 
3.1. Eligibility Criteria ............................................................................................................................. 5 
3.2. Exclusion Criteria ............................................................................................................................. 5 
3.3. Inclusion of Women and Minorities ................................................................................................. 6 
4. REGISTRATION PROCEDURES ...........................................................................................6 
5. TREATMENT PLAN ................................................................................................................6 
5.1. Post-consent Screening Procedures .................................................................................................. 6 
5.2. Concomitant Ascorbate (High-dose Ascorbic Acid) Infusions with Carboplatin and Paclitaxel ..... 7 
5.3. Chemotherapy (paclitaxel / carboplatin regimen) ............................................................................ 7 
5.4. General Concomitant Medication and Supportive Care Guidelines ................................................. 8 
5.5. Duration of Therapy ......................................................................................................................... 9 
5.6. Duration of Follow Up ..................................................................................................................... 9 
5.7. Criteria for Removal from Treatment ............................................................................................... 9 
5.8. End of Study Visit (early termination) ............................................................................................. 9 
5.9. Additional Therapy ......................................................................................................................... 11 
6. ASSESSMENTS ......................................................................................................................11 
6.1. Pre-treatment Assessments (baselines) ........................................................................................... 11 
6.2. Assessments During Chemotherapy ............................................................................................... 11 
6.3. Assessments During Ascorbic Acid Infusions ............................................................................... 12 
6.4. Radiologic Assessments (CT imaging) .......................................................................................... 12 
6.5. Follow-up Assessments .................................................................................................................. 12 
6.6. End of Study Assessments.............................................................................................................. 13 
7. DRUG THERAPY ...................................................................................................................13 
7.1. Carboplatin. Please refer to the FDA approved package insert for additional information. .......... 13 
7.2. Paclitaxel. Please refer to the FDA approved package insert for additional information. ............. 14 
7.3. Ascorbic Acid Injection, USP; Ascorbate; NDC 67457-118-50 .................................................... 15 

 
x 
8. DOSE MODIFICATIONS AND DELAYS ............................................................................15 
8.1. Hypersensitivity reactions—Paclitaxel .......................................................................................... 15 
8.2. Hematologic toxicities—paclitaxel and carboplatin ....................................................................... 16 
8.3. Non-Hematologic Toxicity—paclitaxel and carboplatin ............................................................... 16 
8.4. Ascorbate ........................................................................................................................................ 17 
9. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ...................................17 
9.1. Determination of Reporting Requirements..................................................................................... 17 
9.2. Routine Adverse Event Reporting Requirements ........................................................................... 19 
9.3. Expedited Adverse Event Reporting .............................................................................................. 19 
10. CORRELATIVE/SPECIAL STUDIES ...................................................................................20 
10.1. Parameters of Oxidative Stress. ...................................................................................................... 20 
10.2. Patient Reported Outcomes (optional) ........................................................................................... 21 
11. STUDY CALENDAR .............................................................................................................23 
12. MEASUREMENT OF EFECT ................................................................................................24 
12.1. Tumor Response (Primary End-Point) ........................................................................................... 24 
12.2. Progression Free Survival............................................................................................................... 24 
12.3. Overall Survival ............................................................................................................................. 24 
12.4. Toxicity .......................................................................................................................................... 24 
13. STATISTICAL CONSIDERATIONS.....................................................................................24 
13.1. Endpoints ........................................................................................................................................ 24 
13.2. Analysis Plan .................................................................................................................................. 24 
13.3. Accrual Strategy ............................................................................................................................. 24 
13.4. Study Duration ............................................................................................................................... 24 
14. REFERENCES ........................................................................................................................25 
PROTOCOL APPENDIX A : PERFORMANCE STATUS CRITERIA......................................27 
PROTOCOL APPENDIX B: CYP3A4 INTERACTION TABLE ...............................................28 
PROTOCOL APPENDIX C: DATA AND SAFETY MONITORING PLAN .............................31 
PROTOCOL APPENDIX D: RECOMMENDED MONITORING WORKSHEETS ..................40 
 
 
 

 
1 
1. OBJECTIVES 
1.1. 
Primary Objectives 
1.1.1. Determine initial tumor response per RECIST 1.1 criteria. 
1.2. 
Secondary Objectives 
1.2.1. Determine the median time to progression for patients with stage IIIB/IV NSCLC 
treated with high dose ascorbate when administered concurrently with carboplatin and 
paclitaxel. 
1.2.2. Determine the progression free survival and overall survival of patients with stage 
IIIB/IV NSCLC treated with high dose ascorbate when administered concurrently 
with carboplatin and paclitaxel. 
1.2.3. Determine the incidence of toxicity with the 3 drug combination of paclitaxel, 
carboplatin and ascorbate  
2. BACKGROUND 
2.1. 
Stage IV Non-Small Cell Lung Cancer (NSCLC) and its current therapy 
Lung cancer is the number one cause of cancer related mortality worldwide and results in 
approximately 1.2 million deaths per year.1,2 Approximately 75% of all lung cancers are 
classified as non-small cell lung cancer (NSCLC).1 For patients with resectable disease (20% 
of all lung cancers) the cure rates are approximately 40-70%.3,4 Unfortunately, the majority of 
patients with NSCLC, however, present with advanced disease (stage IIIB or IV)5. The 
standard treatment for patients with metastatic lung cancer is chemotherapy. Despite advances 
in new chemotherapy approaches, there has been little improvement in patient outcomes.  
The current standard of care first line chemotherapy treatment of advanced stage NSCLC 
without known activating gene mutation is platinum doublet. In a cornerstone randomized trial 
by Schiller et al,6 the regimen of carboplatin and paclitaxel showed a better toxicity profile and 
was not inferior to the cisplatin containing regimens. However, this trial showed a response 
rate to chemotherapy of only 20% and a median overall survival of 7.9 months. In another trial, 
ECOG 4599,7 adding bevacizumab, a vascular endothelial growth factor inhibitor, to 
carboplatin and paclitaxel improved the median overall survival for advanced stage NSCLC to 
12.3 months, however, this combination resulted in more toxicity, including fatal bleedings. 
The major breakthroughs in NSCLC treatment in the last decade came from developing novel 
therapies that target specific gene alterations in a small subset of NSCLC patients. This include 
EGFR8 and ALK9 tyrosine kinase inhibitors (TKIs) which resulted in dramatic tumor responses 
and significant prolongation of survival. Although targeted therapy had proven to be very 
effective as an initial treatment in the right setting, it is limited by the small frequency of these 
gene abnormalities, the inevitable emergence of cancer resistance to the TKIs and the rapid 
progression upon acquiring resistance. These studies highlight the dismal prognosis of 
patients with advanced stage NSCLC despite undergoing aggressive therapy. Complementary 
approaches that enhance chemotherapy and are well tolerated are urgently needed. One 
promising and innovative approach that exploits the fundamental metabolic differences 
between cancer cells and normal cells is high dose or pharmacological ascorbate.  
2.1.1. Ascorbate as an anti-tumor agent. 
Ascorbate (ascorbic acid, vitamin C, AscH) is one of the early unorthodox therapies for 
cancer, based on two unsupported hypotheses. McCormick postulated that ascorbate protects 
against cancer by increasing collagen synthesis,10,11 while Cameron hypothesized that 

 
2 
ascorbate could have anti-cancer action by inhibiting hyaluronidase and thereby prevent 
cancer spread.12 These hypotheses were subsequently promoted by Cameron and Pauling.13,14 
Cameron and Campbell initially published case reports of 50 patients; some seemed to have 
benefited from high dose ascorbate.15 Cameron and Pauling then published results of 100 
patients with terminal cancer that were given intravenous ascorbate.16 The ascorbate-treated 
patients were compared to 1000 retrospective controls with similar disease. Patients who 
received ascorbate survived on average 300 days longer than controls.14,16 A prospective 
study was then conducted that randomized patients to ascorbate treatment or palliative 
therapy. Treated patients had a median survival of 343 days vs. 180 days for controls.17 
Smaller studies have also reported benefits of ascorbate.18,19 
To test “definitively” whether ascorbate was effective, Moertel conducted two randomized 
placebo-controlled studies randomized to oral ascorbate; neither study showed benefit.20,21 
Subsequently, ascorbate therapy was considered ineffective. However, it was not recognized 
until approximately 15 years later that oral and intravenous ascorbate have strikingly 
different pharmacokinetics.22,23 This difference in the administration route is key. Cameron 
gave patients ascorbate intravenously as well as orally, while Moertel’s patients received 
only oral ascorbate. Thus, the issue of ascorbate in cancer treatment needs to be re-examined.  
The evidence for use of ascorbate in cancer treatment falls into two categories: clinical data 
on dose concentration relationships and laboratory data describing potential cell toxicity with 
high concentrations of ascorbate in vitro. Clinical data show that when ascorbate is given 
orally, fasting plasma concentrations are tightly controlled at < 100 µM.24 As doses exceed 
200 mg, absorption decreases, urine excretion increases and ascorbate bioavailability is 
reduced.22,24 In contrast, when 1.25 grams of ascorbate are administered intravenously, 
concentrations as high as 1 mM are achieved. Some clinicians have infused more than 10 
grams of ascorbate in cancer patients and achieved plasma concentrations of 1 to 5 mM.25 
Thus, it is clear that intravenous administration of ascorbate can yield very high plasma 
levels, while oral treatment does not.  
Figure 1. Pharmacological levels of ascorbate enhance NSCLC cell lines, H292 and H1299, sensitivity 
to chemotherapy. Cell survival was determined using the clonogenic cell survival assay. Cell lines were 
treated with ascorbate (0.5 mM) and carboplatin (10µm) for 1h. Clonogenic cell survival was decreased 
in both cell lines when treated with carboplatin and ascorbate. Means, n = 3.*P < 0.05 vs. carboplatin 
alone.  
H292
H1299
*
*

 
3 
Pharmacologic ascorbate concentrations have 
been shown to selectively kill many cancer cell 
types. Chen et al. measured cell death in 10 
cancer and 4 normal cell types using 1-hour 
exposures 
to 
pharmacological 
ascorbate.26 
Normal cells were unaffected by 20 mM 
ascorbate whereas 5 cancer cell lines had EC50 
values of < 4 mM, a concentration achievable by 
intravenous administration. In addition, cell 
death was independent of metal chelators, but 
dependent on formation of H2O2.27 H2O2 
generation 
was 
dependent 
on 
ascorbate 
concentration, incubation time; [H2O2] displayed 
a linear increase with [AscH] and it increased as 
a quadratic function of ascorbate radical, 
ascorbate being an electron donor to O2 to form 
superoxide and, eventually, H2O2.  
When ascorbate is infused intravenously the 
resulting 
pharmacologic 
concentration 
will 
distribute rapidly into the extracellular water 
space.28 In vivo, Chen and colleagues demonstrated that intravenous injection of ascorbate 
(0.25-0.5 mg/g body weight) increased baseline concentrations of ascorbate in the blood and 
extracellular fluid to > 8 mM as well as increased formation of H2O2.29 More recent studies 
have demonstrated that intraperitoneal doses of 4 g/kg ascorbate resulted in blood 
concentrations of 40 mM; tumor extracellular fluid increased to peaks of 20 mM for up to 3 
hours.24  
Our data demonstrate that pharmacologic doses of ascorbate are cytotoxic to NSCLC cell 
lines and that it enhances chemotherapy sensitivity in vitro (Figure 1). Additionally, 
intraperitoneal administration of high dose ascorbate in combination with carboplatin and 
radiation inhibits orthotopic NSCLC growth and decreases tumor size in mice without causing 
an associated toxicity (Figure 2). Combined, these studies provide a foundation for pursuing 
pharmacologic ascorbate as a prooxidant agent in cancer therapy and specifically in NSCLC 
Ascorbate-mediated cell death has been shown to be due to H2O2 generation, via ascorbate 
radical formation, with ascorbate as the electron donor.26,27,29 When ascorbate is infused 
intravenously the resulting pharmacologic concentration distributes rapidly in the 
extracellular water space.29 Thus, pharmacologic ascorbate concentrations in media, as a 
surrogate for extracellular fluid, should generate ascorbate radical and H2O2. In contrast, the 
same pharmacologic ascorbate concentrations in whole blood generate little detectable 
ascorbate radical and no detectable H2O2.21 This can be accounted for by efficient and 
redundant H2O2 catabolic pathways in whole blood relative to those in media or extracellular 
fluid. Thus, ascorbic acid administered intravenously in pharmacologic concentrations may 
serve as a pro-drug for H2O2 delivery to the extracellular milieu, but without H2O2 
accumulation in blood.  
In a Phase I trial of intravenous ascorbic acid in patients with advanced pancreatic cancer 
conducted at the University of Iowa Hospitals and Clinics, adverse events and toxicity were 
minimal at all dose levels. The high-dose intravenous ascorbic acid was well tolerated when 
administered to patients. Ascorbic acid concentrations reached up to 25 mmol/L in patients 
 
Figure 2. NSCLC H1299 tumor volume 
averages. Tumor volume measurements of 
chemotherapy treated, ascorbate treated, and 
chemotherapy 
+ 
ascorbate 
treated 
mice. 
Pharmacological ascorbate significantly decreased 
tumor growth relative to carboplatin + radiation 
therapy. p = 0.0168.  

 
4 
who received ascorbic acid of 1.5 g/kg. Of the 24 patients in the study, only 4 recorded minor 
adverse events including headache, dizziness and diarrhea.30 
2.2. 
Ascorbate Preliminary Data 
2.2.1. Pre-clinical (in vitro).  
Figure 1 demonstrates that pharmacological ascorbate enhances sensitivity of NSCLC 
cell lines, H1299 and H292 to carboplatin. Cells were treated with ascorbate (0.5mM) 
and carboplatin (10µM) for one hour. Cell survival was determined by clonogenic 
cell survival assay. These results support the hypothesis that ascorbate enhances 
radiation induced cell killing of NSCLC cells. 
2.2.2. Pre-clinical (in vivo) 
To determine if treatment of established NSCLC tumors in a xenograft model with 
ascorbate would inhibit growth, H292 tumor cells (2 x 106) were delivered 
subcutaneously into the flank region of nude mice and allowed to grow until they 
reached 3 mm in greatest dimension (~ 10 days), at which time they were randomly 
assigned to a treatment group. This was defined as day 1 of the experiment. The 
animals were randomized to receive either: sham treatment (control), ascorbate (4 
g/kg) i.p. given to mice every day for two weeks, and ascorbate with radiation (12Gy 
in 2 fx) administered during the middle of ascorbate therapy in select mice. Data from 
Dr. Mark Levine’s laboratory have demonstrated that 4 g/kg i.p. ascorbate resulted in 
blood concentration from baseline of 40 µM to peaks of 40 mM while tumor 
extracellular fluid increased to peaks of 20 mM for up to 3 hours [personal 
communication].22 The primary outcomes of interest were tumor growth over time 
and the potential toxicity of combining carboplatin, radiation and pharmacological 
ascorbate. Tumor size (mm3) was periodically measured via calipers throughout the 
experiments, resulting in repeated measurements across time for each mouse. Linear 
mixed effects regression models were used to estimate and compare the group-
specific tumor growth curves. The observed tumor volumes for all mice are plotted 
over time in Figure 2. 
2.2.3. Clinical trial data: 
Combining carboplatin and paclitaxel with high dose ascorbate was studied in a phase 
I clinical trial in ovarian cancer 31. This combination was shown to significantly 
decrease the adverse effects from chemotherapy. The sample size was too small to 
show increased efficacy of this combination.  
2.3. 
Rationale 
Metastatic NSCLC is the most common stage of NSCLC with a poor overall survival. We 
propose to investigate an entirely new approach, using pharmacological ascorbate, combined 
with chemotherapy to treat NSCLC. Intravenous ascorbate (i.e., ascorbic acid, vitamin C), 
but not oral ascorbate, produces high plasma concentrations, which are in the range that can 
be cytotoxic to tumor cells. Though ascorbate has been utilized in cancer therapy, few studies 
have investigated intravenous delivery of ascorbate. Preliminary studies from our group have 
demonstrated that ascorbate induces cytotoxicity in NSCLC cells. Phase I clinical trial 
showed the combination of high dose ascorbate with carboplatin and paclitaxel in ovarian 
cancer improved the toxicity profile associated with this chemotherapy regimen. Proceeding 
to a phase II clinical trial to study efficacy of carboplatin and paclitaxel with high dose 
ascorbic acid as a first line treatment for stage IV NSCLC patients is a logical next step in 
evaluation. 

 
5 
3. SUBJECT SELECTION 
3.1. 
Eligibility Criteria  
3.1.1. Patients must have newly diagnosed histologically or cytologically confirmed 
NSCLC, staged IIIB or IV, for which they have not received first-line cytotoxic 
chemotherapy (first-line EGFR inhibitors or ALK inhibitors are allowed given 
disease progression).  
3.1.2. Patient with recurrent disease for whom palliative intent systemic therapy is indicated 
are also eligible regardless of stage of their disease. Patients who received prior neo-
adjuvant, adjuvant chemotherapy or chemo-radiation or radiation with curative intent 
for non-metastatic NSCLC must have experienced a treatment-free interval of at least 
6 months from signing the informed consent since the last chemotherapy or chemo-
radiation or radiation treatment/cycle. Patients developing recurrent disease while 
receiving consolidation immunotherapy after definitive chemo-radiation or surgery 
for whom palliative intent therapy is indicated will be eligible for the study as far as 
their last cycle of immunotherapy is 3 weeks from the day of consent (6 months’ 
time-line is not applicable to consolidation immunotherapy).     
3.1.3. Patients with CNS metastasis will be allowed on the study if the metastasis is treated, 
no clinical signs of metastasis progression following treatment, and the patient is off 
steroids for at least 3 days (only if steroids are prescribed specifically for brain 
metastasis).  
3.1.4. Age ≥ 18 years 
3.1.5. ECOG performance status 0-2 (see Appendix A). 
3.1.6. Screening labs should be within the following limits and obtained within 21 days of 
cycle 1, day 1: 
• 
Absolute neutrophil count (ANC) ≥ 1500 cells per mm3 
• 
Platelets ≥ 100,000 per mm3 
• 
Hemoglobin ≥ 8 g/dL 
• 
Creatinine ≤ 1.5 x the institutional upper limit of normal 
• 
Total bilirubin ≤ 1.5 x the institutional upper limit of normal 
• 
ALT ≤ 3 times the institutional upper limit of normal 
• 
AST ≤ 3 times the institutional upper limit of normal 
3.1.7. Tolerate a 15g ascorbate infusion (screening dose). 
3.1.8. Not pregnant. Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control or abstinence) prior to 
study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while receiving study drug, she should inform her 
treating physician immediately. Pregnancy tests will be obtained per physician 
discretion. 
3.1.9. Not breastfeeding. 
3.1.10. Ability to understand and willingness to sign a written informed consent document.  
3.2. 
Exclusion Criteria 
3.2.1. Known sensitizing EGFR mutations or ALK gene rearrangement  as these patients 
will benefit from targeted oral tyrosine kinase inhibitors as a first line treatment. If 
patient’s biopsy did not allow EGFR or ALK gene analysis (e.g., inconclusive, not 

 
6 
enough tissue, etc.), the patient is considered eligible for study. Enrollment on this 
clinical trial after progression on targeted therapy is allowed.  
3.2.2. Patient with strong PD-L1 expression (≥ 50% of tumor cells expressing PD-L1 or 
tumor proportion score (TPS) ≥ 50% ) will be excluded as they may derive more 
benefit from  from immunotherapy. Patient’s with unknown PD-L1 expression or 
when PD-L1 expression can’t be determine due to insufficient tumor sample or other 
reasons will be eligible for this study. At progression or due to intolerable toxicity on 
immunotherapy, these patients will then be eligible for the study. Receiving warfarin 
therapy and cannot tolerate drug substitution. 
3.2.3. Active hemoptysis within 1 week of screening (more than ½ teaspoon per day) 
3.2.4. Actively receiving insulin at time of ascorbate infusion (unless an exception is 
granted by the IND sponsor, medical monitor, and the PI). 
3.2.5. Leptomeningeal disease 
3.2.6. G6PD (glucose-6-phosphate dehydrogenase) deficiency 
3.2.7. Patients who are on the following drugs and cannot have a drug substitution: 
flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose 
ascorbic acid may affect urine acidification and, as a result, may affect clearance rates 
of these drugs. 
3.2.8. Patient with known active invasive malignancy other than NSCLC. .(Exceptions: 
non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder) 
3.2.9. Patients may not be receiving any other investigational agents with the intention to 
treat their cancer (imaging trials are acceptable). 
3.2.10. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.  
3.2.11. Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 
inducer, which results in lower serum levels of antiretroviral drugs.32  
3.3. 
Inclusion of Women and Minorities 
Female and male patients of all ethnic groups will be eligible for treatment on this protocol.  
4. REGISTRATION PROCEDURES 
Once informed consent is obtained: 
• 
Fax a copy of completed eligibility criteria to DSMC, labeled with subject ID and initials.  
• 
Enter subject into the OnCore database of the Holden Comprehensive Cancer Center 
• 
Scan the record of consent into the subject’s medical record. 
• 
Scan the G12 into the subject’s medical record. 
5. TREATMENT PLAN 
Protocol should not supersede standard of care procedures for patient safety.  
5.1. 
Post-consent Screening Procedures 
If subjects fail the G6PD or test doses of ascorbate, they are considered a screen failure. 
• 
G6PD test (off-site test, so draw immediately). If subject has a prior G6PD test, this can 
be used as G6PD levels do not fluctuate (i.e., there is no window for this test). 
• 
Ascorbate initiation (one test dose of ascorbate): Can be given any time through the day 

 
7 
prior to chemotherapy with one 15-g infusion. Failure of the 15g test dose is defined as 
any toxicity ≥ CTCAE grade 3 (except transient increase in blood pressure) or a 
significant medical event (in the opinion of the principal investigators). 
5.2. 
Concomitant Ascorbate (High-dose Ascorbic Acid) Infusions with Carboplatin and 
Paclitaxel 
5.2.1. Participant dose. After completing a 15g test dose for screening, subjects will 
receive 75g / infusion for therapy. Dose modifications are not made for weight or 
body surface area. 
5.2.2. Administration. Based on subject tolerance; infusion rate should not exceed 500 
mL/hour without consulting with physician. Recommended infusions times are 
provided (Table 1) but may be adjusted for subject comfort. Changes in infusion rates 
should be recorded. 
5.2.3. Schedule. Schedule two times weekly, must be on separate calendar days.  
5.2.4. Cycle. Concomitant with carboplatin and paclitaxel, 21 day cycle. 
5.2.5. Duration. Subjects will continue with therapy for 4 chemotherapy cycles or until one 
of the criterion for removal are met (Section 5.7).  Patients with complete response, 
partial response or stable disease will continue for two more cycles of 
paclitaxel/carboplatin, ascorbate and another CT will be done to assess response after 
4 cycles. After 4 cycles study therapy will be complete and maintenance therapy will 
be allowed in accordance with standard care.  
5.2.6. Dose modifications. Provided in Section 8  
5.3. 
Chemotherapy (paclitaxel / carboplatin regimen) 
The carboplatin / paclitaxel regimen is administered following standard practice adopted at 
UIHC, based on the chemotherapy doses established by CALGB 9633. 
5.3.1. Initiation. Within 21 days of signing the consent form. If a subject has a delay of 
therapy, the subject may be re-screened/re-consented for participation.  
5.3.2. Body weight: C1D1 weight will be used for chemotherapy calculations unless there 
is a change of >10% from C1D1 weight 
5.3.3. Body height: C1D1 height will be usedfor chemotherapy calculations.   
5.3.4. PACLITAXEL Premedications. UIHC standard of care premedication procedures 
should be followed for chemotherapy administration. Thirty minutes before 
administering paclitaxel: 
• 
dexamethasone 20 mg intravenously (IV) 
Table 1. Recommended Infusion Times for Pharmacological Ascorbate † 
Ascorbate dose  
(500 mg / mL) 
Total volume* 
Osmolarity 
(mOsm/L)§ 
Infusion Time 
 
15g (30 mL) 
 
250 mL 
 
681 
 
30 minutes 
 
75g (150 mL) 
 
1000 mL 
 
851.7 
 
120 minutes 
† Provided by Drug Information Center at the University of Iowa, July 2011 
*  Sterile water for injection only. Do not use D5W 
§  Theoretical calculations provided by Drug Information Center; targeted osmolarity range is 500 – 900 mOsm/L 

 
8 
• 
diphenhydramine, 25-50 mg orally 
• 
famotidine, 20 mg orally 
• 
antiemetic  
5.3.5. PACLITAXEL dose. 200 mg/m2 (sections 5.3.2, 5.3.3) over 3 hours continuous 
infusion. Paclitaxel must be administered prior to carboplatin. 
5.3.6. CARBOPLATIN dose. AUC = 6 using the Cockcroft-Gault formula. Administered 
6 mg/mL x min over 1 to 2 hours (sections 5.3.2, 5.3.3). 
• 
Creatinine adjustment. If creatinine is <1 mg/dl, then the creatinine used for 
carboplatin dose calculation will be adjusted to 1 mg/dl.  
• 
BMI adjustment. For patients with high BMI, the maximum allowed calculated 
creatinine clearance will be males at 125 ml/min and females at 125 ml/min. 
5.3.7. Administration. Paclitaxel must be infused prior to carboplatin. Infuse per standard 
UIHC practices. 
5.3.8. Schedule. Once every 21 days. May be adjusted ± 7 calendar days to allow for 
scheduling. 
5.3.9. Cycle. A total of 4 cycles of paclitaxel/carboplatin will be administered for the 
purposes of this study. 
5.3.10. Antiemetics. Use Zofran (ondansetron) with caution as this medication may interact 
with high-dose ascorbic acid, resulting in sub-efficacious levels of Zofran. 
5.3.11. Dose modifications. Provided in Section 8. 
5.4. 
General Concomitant Medication and Supportive Care Guidelines 
5.4.1. Prophylactic antibiotics for neutropenia: To be considered by the treating 
physician for neutropenia. Ciprofloxacin 500 orally, twice daily, is encouraged if 
ANC < 500/mm3  
5.4.2. Imaging Contrast (CT). Imaging contrast for CT should not be administered on the 
same day with ascorbate infusion. If administered within the same day, monitor liver 
function tests and contact the medical monitor for the IND. 
5.4.3. Imaging Contrast (MRI). Use of imaging contrast for MRI is permitted on the same 
day as ascorbate infusion. 
5.4.4. CYP450 3A4 interactions. Review drugs for the potential for interactions. Medically 
monitor subjects receiving a potentially interactive drug.  
5.4.5. Warfarin (coumadin). Warfarin has a theorized interaction with high-dose ascorbate 
and must not be prescribed. Subjects requiring warfarin (coumadin) therapy should be 
removed from trial. 
5.4.6. Hyperuricemia (gout). Initial dose of colchicine should be 0.6 mg with a subsequent 
dose of 0.3 mg an hour later if the first dose is well-tolerated. Liver function tests 
(AST / ALT) should be monitored. 
5.4.7. Hypertension. Subjects should have blood pressure monitored at the start of each 
cycle. For subjects with documented hypertension, treating physicians should 
consider subsequent monitoring. Hypertensive medication should be initiated or 
increased for optimal blood pressure control according to standard public health 
guidelines.  

 
9 
5.4.8. Fluid intake. Subjects will be encouraged to maintain adequate hydration to decrease 
the risk of nephrolithiasis. Those unable to maintain oral hydration should be 
considered for supplemental IV hydration per institutional care guidelines.  
5.4.9. G-CSF products. The use of G-CSF products is allowed on the study per the treating 
physician’s discretion. 
5.4.10. Palliative Radiotherapy: Palliative radiotherapy, unless required due to progressive 
disease, is permitted during the study. Area receiving palliative radiation should be 
different than target lesion/s to utilized for RECIST response assessment. Patient will 
not receive concurrent protocol specified therapy until completion of radiation. Study 
therapy may resume (chemotherapy and ascorbate infusions) as per study protocol 
after 72 hours of completing radiation therapy or when acute toxicities related to 
radiation resolve to CTCAE grade 2 or less. Therapy is not delayed for hair loss 
and/or decreased lymphocyte count.  
5.5. 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for 4 
cycles or until criteria for removal is met (Section 5.7). If there are delays due to adverse 
events, continuation of the protocol and continued treatment will be determined by the 
treating medical oncologist and IND sponsor. 
5.6. 
Duration of Follow Up 
5.6.1. Early termination. Subjects who withdraw or were removed from study prior to 
completing all 4 cycles of therapy will be followed a minimum of 21 days from the 
final ascorbate infusion (Section 5.8.1). Further follow-up is per investigator 
discretion. 
5.6.2. Completed therapy. Subjects who complete all four cycles of therapy will be 
followed passively for 2 years from the end of study-directed therapy. Follow-up 
assessments are listed in Section 6.5. Post study therapy follow-up appointment will 
be 28 d (± 1 calendar week) after the last infusion of study drug. Further follow-up 
will be per standard of care and subjects will be followed passively for events 
(progression of disease or death). . 
5.7. 
Criteria for Removal from Treatment 
5.7.1. Progressive disease (as defined by RECIST 1.133) 
5.7.2. Extraordinary medical circumstances. If at any time the constraints of this protocol 
are detrimental to the patient’s health, the patient will be removed from protocol 
therapy. In this event, the reasons for withdrawal will be documented. 
5.7.3. Patient’s refusal to continue treatment. In this event, the reasons for withdrawal will 
be documented. 
5.8. 
End of Study Visit (early termination) 
If a subject is removed from study, or elects to withdraw, an End-of-Study (EOS) visit should 
be scheduled within 7 calendar days of the decision. End-of-Study does not apply to subjects 
who complete all 4 cycles of chemotherapy. 
5.8.1. Minimum follow-up. Every effort will be made to follow patients off study for 
toxicity for 28 days (±7 calendar days to accommodate scheduling) after removing 
the subject from study. If the subject is removed due to toxicity, follow-up should 
continue until ascorbate-associated adverse events are resolved. 

 
10 
 
 

 
11 
5.8.2. Labs. CBC w/diff and a comprehensive metabolic panel should be ordered when the 
subject is removed from study (within 7 calendar days). If labs were ordered 
clinically within window, these can be used at the discretion of the medical monitor, 
sponsor, and investigator. 
5.9. 
Additional Therapy 
Subjects who have left study, or who have completed the chemotherapy treatment, may 
continue standard therapies or other clinical trials at the discretion of their treating medical 
and radiation oncologists. This treatment is beyond the scope of the protocol, as these 
patients have completed participation in the protocol. 
6. ASSESSMENTS 
After initial disease progression, subjects will receive salvage care as prescribed by their oncology 
team. Follow-up will be maintained through chart review and/or visits with clinical personnel. 
Subjects should have life-long follow-up for this study. 
6.1. 
Pre-treatment Assessments (baselines) 
Baseline assessments should be performed within 21 days of the start of therapy; they may be 
completed C1D1 pre-therapy. 
6.1.1. Fatigue 
6.1.2. Neuropathy 
6.1.3. Infection 
6.1.4. Nausea 
6.1.5. Vomiting 
6.1.6. Pain (headache) 
6.1.7. Comprehensive metabolic panel (screening or cycle 1 d 1) 
6.1.8. Complete blood count with differential (screening or cycle 1 d 1) 
6.1.9. Uric acid (baseline only) 
6.1.10. Ascorbate levels (draw this prior to the 15g test dose). Draw in a 4mL green-top Na 
Heparin tube. 
6.1.11. Finger-stick glucose. The finger-stick glucose should be done at the same time as the 
ascorbate level blood draw. This is research only and should not be entered into the 
medical record, only recorded in the study chart.  
6.1.12. Blood sample for ROS testing (draw prior to the 15g test dose). Draw 5-6 cc in a 
pink-top tube and put on ice for transport. 
6.1.13. Iron panel (Iron, transferrin, TIBC, and % saturation) 
6.1.14. Ferritin  
6.2. 
Assessments During Chemotherapy  
Assessments will be done once at the start of each chemotherapeutic cycle. No further 
assessments are required during the treatment cycle.  
6.2.1. Fatigue 
6.2.2. Neuropathy 
6.2.3. Infection 
6.2.4. Nausea 
6.2.5. Vomiting 

 
12 
6.2.6. Pain (headache) 
6.2.7. Comprehensive metabolic panel (screening may be used for cycle 1 d 1 per physician 
discretion) (may be done up to 1 week before cycle day 1) 
6.2.8. Complete blood count with differential (screening may be used for cycle 1 d 1 per 
physician discretion) (may be done up to 1 week before cycle day 1) 
On cycle day 1 (D1): 
6.2.9. Ascorbate levels – prior to infusion. Draw in a 4mL green-top Na Heparin tube. 
6.2.10. Blood sample for ROS testing – prior to infusion. Draw in a 5-6 cc pink top (EDTA) 
tube and put on ice for transport. 
6.2.11. Ascorbate levels – end of ascorbate infusion. Draw in a 4mL green-top Na Heparin 
tube. 
6.2.12. Finger-stick glucose using research glucometer. Test prior to ascorbate infusion and 
at the end of infusion (i.e., at the same time as the blood draws for ascorbate levels). 
This is research only and should not be entered into the medical record, only recorded 
in the study chart. The finger-stick glucose should be done at the same time as the 
post-infusion ascorbate level blood draw. The research glucometer will give an 
elevated reading that does not represent blood glucose, but blood ascorbate 
(serum/plasma glucose via pathology tests remains unaffected) (Ma and Drisko, 
2013). Subjects should be informed fingerstick glucose is inappropriate for them and 
that healthcare providers will need to check blood glucose through a blood draw. 
On cycle day 2 (D2): 
6.2.13. Blood sample for ROS testing – pre-infusion. Draw in a 5-6 cc pink top (EDTA) tube 
and put on ice for transport. 
6.2.14. Cycles 1 and 3 only. Order an iron panel (Iron, transferrin, TIBC, and % saturation) 
and ferritin. Results should be entered into the medical record. 
6.3. 
Assessments During Ascorbic Acid Infusions 
Blood pressure should be done, at minimum, pre- and post-infusion for each infusion. If the 
infusion runs for longer than 1 hour, blood pressure assessment should be done in the interm 
as clinically indicated. 
Pre-infusion is defined as any time during the same calendar day prior to infusion. 
Post infusion is ≤ 15 minutes from end of infusion. 
6.4. 
Radiologic Assessments (CT imaging) 
CT imaging of the chest/abdomen/pelvis should be obtained for the following time-points 
and should be consistent with standard-of-care imaging done at the UIHC. CT imaging with 
contrast cannot be performed on the same day as an ascorbate infusion. 
6.4.1. Baseline (≤ 30d of cycle 1, day 1) 
6.4.2. End of cycle 2 (± 7 days of cycle 2, day 21) 
6.4.3. End of cycle 4 (± 7 days of cycle 4, day 21)  
6.5. 
Follow-up Assessments 
The following assessments should be done at follow-up visits after completion of protocol-
directed therapy. The Post-study therapy follow up is 28 days after the last ascorbate infusion 
(± 1 calendar week to coincide with other clinical appointments). 

 
13 
6.5.1. (Post study therapy follow-up ) Blood sample for ROS testing. Draw 5-6 cc in a pink-
top tube and put on ice for transport [this sample should be drawn regardless of 
additional therapy; can be drawn subsequent cycles D1 if within window]. 
6.5.2. (Post study therapy follow-up) CBC w/differential 
6.5.3. (Post study therapy follow-up) Comprehensive metabolic panel.  
6.5.4. If labs were ordered for another clinic visit, and within window, these can be used at 
the discretion of the medical monitor, sponsor, and investigator. 
6.5.5. Further follow up is per standard of care. This follow up will be performed by review of 
the medical record, contact with care providers, and/or telephone contact as needed every 
3-4 months for 2 years. Lab information, including CBC w/differential and plasma 
chemistries, ordered for standard of care or other reasons may be pulled from 
subsequent follow-up visits or physician’s visits, for the purposes of monitoring 
treatment effects and adverse events long-term. 
6.5.6. Medical record information will be reviewed for the purposes of monitoring treatment 
effects and adverse events long-term. 
6.5.7. Follow up CT scans as clinically indicated for standard of care  
6.6. 
End of Study Assessments 
The following assessments should be performed when a criteria for removal is met (Section 
5.7). An End-of-Study (EOS) visit should be scheduled within 7 calendar days of the 
decision. An existing clinical visit may be used for the EOS visit. 
6.6.1. Minimum follow-up. Every effort will be made to follow patients off study for 
toxicity for 21 days after removing the subject from study. If the subject does not 
return to clinic, phone call contact is acceptable. If phone call contact cannot be 
made, and the subject does not return a phone call, documentation should be made of 
at least 3 attempts. 
6.6.2. Adverse event follow-up. The participant will be followed clinically or the local 
provider contacted (as appropriate) until all ascorbate-associated adverse events have 
resolved/stable. 
6.6.3. Labs. CBC w/diff and a comprehensive metabolic panel should be ordered when the 
subject is removed from study (+ 7 calendar days). If labs were ordered clinically 
within window, these can be used at the discretion of the medical monitor, sponsor, 
and investigator. 
7. DRUG THERAPY 
7.1. 
Carboplatin. Please refer to the FDA approved package insert for additional information. 
7.1.1. Availability. Commercially available for multiple strengths as a generic drug.  
7.1.2. Compatibility. Compatible with D5W (dextrose 5%) and NS (Normal saline – 
sodium chloride 0.9%).  
7.1.3. Storage and stability. Unopened vials of carboplatin aqueous solution for injection 
are stable to the date indicated on the package when stored at 25°C (77°F); excursions 
permitted from 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. 
Protect from light. Carboplatin aqueous solution multidose vials maintain microbial, 
chemical, and physical stability for up to 14 days at 25°C following multiple needle 
entries. Parenteral drug products should be inspected visually for particulate matter 

 
14 
and discoloration prior to administration. Solutions for infusion should be discarded 8 
hours after preparation. 
7.1.4. Black box warning. Bone marrow suppression with carboplatin is dose-related and 
may be severe, resulting in infection and/or bleeding. Anemia may be cumulative and 
may require transfusion support. Vomiting is another frequent drug-related side 
effect. Anaphylactic-like reactions to carboplatin have been reported and may occur 
within minutes of carboplatin administration 
7.1.5. Toxicities. The most common adverse reactions include alopecia, hypocalcemia, 
hypokalemia, hypomagnesia, hyponatremia, abdominal pain, diarrhea, nausea, 
vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, elevated alkaline 
phosphatase, elevated AST/SGOT, abnormal blood urea, elevated serum creatinine, 
and pain. Serious adverse events include myelosuppression, hypersensitivity reaction 
(~ 2%), and unexplained visual loss/visual disturbance.  
7.2. 
Paclitaxel. Please refer to the FDA approved package insert for additional information. 
7.2.1. Availability. Commercially available for multiple strengths as a generic drug.  
7.2.2. Compatibility. Compatible with D5W (dextrose 5%) and NS (Normal saline – 
sodium chloride 0.9%).  
7.2.3. Storage and stability. Unopened vials of paclitaxel for injection are stable until the 
date indicated on the package when stored between 20°–25°C (68°–77°F), in the 
original package. Neither freezing nor refrigeration adversely affects the stability of 
the product. Upon refrigeration, components in the vial may precipitate, but will 
redissolve upon reaching room temperature with little or no agitation. There is no 
impact on product quality under these circumstances. If the solution remains cloudy 
or if an insoluble precipitate is noted, the vial should be discarded. Solutions for 
infusion prepared as recommended are stable at ambient temperature (approximately 
25°C) and lighting conditions for up to 27 hours. Store the vials in original cartons 
between 20°–25°C (68°–77°F). Retain in the original package to protect from light. 
7.2.4. Black box warning. Paclitaxel should be administered under the supervision of a 
physician experienced in the use of cancer chemotherapeutic agents. Appropriate 
management of complications is possible only when adequate diagnostic and 
treatment facilities are readily available. Anaphylaxis and severe hypersensitivity 
reactions characterized by dyspnea and hypotension requiring treatment, angioedema, 
and generalized urticaria have occurred in 2 to 4% of patients receiving Paclitaxel in 
clinical trials. Fatal reactions have occurred in patients despite premedication. All 
patients should be pretreated with corticosteroids, diphenhydramine, and H2 
antagonists. Patients who experience severe hypersensitivity reactions to Paclitaxel 
should not be rechallenged with the drug. Paclitaxel therapy should not be given to 
patients with solid tumors who have baseline neutrophil counts of less than 1500 
cells/mm3 and should not be given to patients with AIDS-related Kaposi’s sarcoma if 
the baseline neutrophil count is less than 1000 cells/mm3. In order to monitor the 
occurrence of bone marrow suppression, primarily neutropenia, which may be severe 
and result in infection, it is recommended that frequent peripheral blood cell counts 
be performed on all patients receiving Paclitaxel. 
7.2.5. Toxicities. The most common adverse reactions (≥10%) flushing, abnormal ECG, 
edema, hypotension, alopecia, rash, nausea, vomiting, diarrhea, mucositis, stomatitis, 
abdominal pain, neutropenia, leukopenia, anemia, thrombocytopenia, elevated 

 
15 
alkaline phosphatase, elevated AST, injection site reaction, peripheral neuropathy, 
arthralgia/myalgia, weakness, increased creatinine, infection. Serious adverse events 
include hypersensitivity reaction.  
7.3. 
Ascorbic Acid Injection, USP; Ascorbate; NDC 67457-118-50 
7.3.1. Availability. IND 105715 utilizes two available drug product from McGuff 
Pharmaceuticals, Inc. and Bioniche Pharma USA LLC. McGuff Pharmaceuticals, Inc. 
is the preferred supplier. 
7.3.2. Ascor L-500 (ascorbic acid injection, USP) (McGuff Pharmaceuticals, INC) is 
available under IND authorization only (IND 105715) for trials contracted to McGuff 
from the sponsor. Drug is available in sterile 50 mL vials containing 25 g of ascorbic 
acid (500 mg/mL) 
7.3.3. Ascorbic Acid Injection, USP (Bioniche Pharma USA LLC) is a commercially 
available injection available in sterile single-use 50 mL vials containing 25 g of 
ascorbic acid (500 mg/mL). 
7.3.4. Compatibility. Ascorbate is considered a CYP4503A4 inducer.32 Therefore close 
monitoring of subjects who may be concomitantly receiving CYP3A4 substrates with 
narrow therapeutic indexes for toxicities is required. A table of CYP3A4 substrates, 
inhibitors, and inducers is provided in the Appendix. Ascorbate may decrease 
plasma/blood concentrations of substrates (Appendix B, tables 1, 2, and 3). 
Ascorbate may increase CYP3A4 induction (Appendix B, Table 4). CT imaging 
contrast should not be given on the same day as an ascorbate infusion. 
7.3.5. Storage and Stability. Unopened vials of Ascorbic Acid for Injection USP are stable 
until the expiration date indicated on the package when stored between 2° – 8°C 
(36°–46°F). Protect from light and store in the carton until time of use. 
7.3.6. Toxicities. Diarrhea, nausea and/or vomiting, kidney stones, dry mouth/thirst, 
headache, abdominal pain, fatigue, facial flushing, sweating, weakness, injection site 
irritation, and faint/dizzy (after rapid infusion) have been reported in the literature. 
When administered on the same day as CT imaging contrast, liver function tests may 
be elevated. Recommendation is to not schedule CT imaging with contrast on the 
same day as an ascorbate infusion. 
8. DOSE MODIFICATIONS AND DELAYS 
8.1. 
Hypersensitivity reactions—Paclitaxel 
8.1.1. Non-Life threatening. Stop paclitaxel infusion and consider / per physician discretion 
• 
Methylprednisone sodium succ 125 mg intravenously 
• 
Benadryl 25-50 mg IV 
• 
Famotidine 20 mg IV 
Twenty minutes after resolution of the reaction symptoms, resume paclitaxel infusion 
at a slower rate per the chemotherapy suite protocol at UIHC. If the subject reacts 
again to paclitaxel in the same day, then remove from the study 
8.1.2. Life threatening reaction. Stop paclitaxel and proceed with anaphylaxis 
management as indicated – treatment suggestions per below:  
• 
Keep infusion-related anaphylaxis kit available. Call physician immediately for 
severe reactions. 
• 
EPINEPHrine 0.3 mg, intramuscular, once as needed.  

 
16 
• 
Methylprednisolone sodium succ 125 mg, intravenous, once as needed. 
• 
Benadryl 50 mg, intravenous, once as needed. 
• 
BLS/ACLS intervention as needed.  
Subject will be removed from the study. Reaction must be filed as a life-threatening 
adverse event (expected). 
8.2. 
Hematologic toxicities—paclitaxel and carboplatin 
8.2.1. Febrile neutropenia. Febrile neutropenia is defined as temp of 38.2 C (100.8F) and 
ANC < 500. In addition to management of febrile neutropenia per standard of care 
that includes antibiotics and infectious work up as needed, the interventions below 
will be conducted for subsequent treatment cycles without reverting to the previous 
chemotherapy dose 
Neutropenic Fever 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
G-CSF 
None 
6 
200 
None 
1st episode 
6 
200 
Yes 
2nd episode 
5 
160 
Yes 
3rd episode 
4 
130 
Yes 
8.2.2. Neutropenia and thrombocytopenia (on the date of chemotherapy: management 
and chemotherapy dose adjustment). Carboplatin and paclitaxel will be dose reduced 
per the guidelines below. Once the dose has been reduced, this will apply to the 
subsequent cycles. 
ANC 
Platelets 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
≥ 1,500 
and 
100,000 
6 
200 
1,000 – 1,499 
or 
75,000 – 99,999 
4 
140 
< 1,000 
or 
< 75,000 
Delay* 
Delay* 
< 500§ 
 
 
Delay* 
Delay* 
* Check CBC w/diff weekly and resume treatment when ANC ≥1,000 and platelets ≥ 
75,000. The treatment can be delayed for a maximum of 3 weeks. 
§ consider prophylactic ciprofloxacin 500 mg orally twice daily as long as ANC is <500 
8.3. 
Non-Hematologic Toxicity—paclitaxel and carboplatin 
8.3.1. Gastrointestinal. Nausea and vomiting treatment per the treating physician’s 
discretion. Use Zofran (ondansetron) with caution as this medication may be less 
efficacious with high-dose ascorbic acid. 
8.3.2. Neurotoxicity. Chemotherapy dose modification as shown below 
Neurotoxicity 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
Grade 1 
6 
200 
Grade 2 
5 
175 
Grade 3 
Delay* 
Delay* 
* evaluate weekly and resume chemotherapy when neurotoxicity < grade 3. The treatment 
can be delayed for a maximum of 3 weeks. 
8.3.3. Fatigue. This can be a side effect from chemotherapy. Consider treating with 
dexamethasone 4 mg orally twice daily for 3 days following the day of chemotherapy. 
Otherwise, chemotherapy dose adjustment as shown in the table below. Once 
chemotherapy reduced, there will be no dose re-escalation in the subsequent cycles. 

 
17 
Fatigue 
Carboplatin (AUC) 
Paclitaxel (mg/m2) 
Grade 1 
6 
200 
Grade 2 
5 
175 
Grade 3 
Delay* 
Delay* 
* evaluate weekly and resume chemotherapy when fatigue < grade 3. The treatment can 
be delayed for a maximum of 3 weeks. 
 
8.3.4. Hepatotoxicity. Adjust paclitaxel as shown below. No dose adjustment needed for 
carboplatin. Rule out other causes for hepatotoxicity.  
AST or ALT 
Bilirubin mg/dl 
Paclitaxel (mg/m2) 
<2.5 x ULN 
and 
<1.5 
200 
2.5 - 5.0 x ULN 
and 
<1.5 
100 
>5.0 x ULN 
or 
>1.5 
Delay* 
* evaluate weekly and resume chemotherapy when AST and ALT are both at < 5.0xULN 
and bilirubin is < 1.5 mg/dL. Treatment can be delayed for a maximum of 3 weeks. 
8.3.5. High body mass index (carboplatin). This will only affect the dose of carboplatin, 
not paclitaxel. The maximum allowed calculated creatinine clearance will be 125 
mL/min (males) and 125 mL/min (females). 
8.4. 
Ascorbate 
8.4.1. Dose modifications. There are no dose adjustments for toxicities.  
8.4.2. Dose delays. Doses may be delayed by up to three weeks with treating physician and 
PI approval. Reason for treatment delay should be noted in the study chart. Missed 
doses should not be made up. 
8.4.3. Test/retest. If an unexpected adverse event is observed, the treating physicians may 
withhold ascorbic acid for up to 1 calendar weeks to determine if the effect 
diminishes or resolves entirely. Considering the nature and severity of the event, if 
reasonable ascorbic acid should then be continued to determine if the event again 
presents. This will function as a test for causality.  
9. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
This study will also be monitored by internal oversight specialists at the University of Iowa. The 
Data and Safety Monitoring Plan of the Holden Comprehensive Cancer Center provides standard 
operating procedures to monitor all clinical cancer trials at the UIHC. All investigator-initiated trials 
are automatically monitored by the Data and Safety Monitoring Committee (DSMC). A detailed data 
and safety monitoring plan for this study is provided (Appendix). This study has been assigned as a 
risk level 4 as a physician sponsored IND phase study.  
9.1. 
Determination of Reporting Requirements 
An adverse event (AE) is defined in the CTEP, NCI Guidelines [2005] as “any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probably or definite).” 

 
18 
9.1.1. Adverse event recording. The clinical research team is responsible for identifying, 
collecting, and recording clinical data, including adverse events, through 21 days after 
the last dose of study drug (ascorbate).  
 
 

 
19 
9.1.2. Adverse event grading. Adverse events will be graded according to NCI’s Common 
Toxicity Criteria (CTCAE v4). Grading may be done by any licensed medical 
personnel (e.g., research nurse, treating physician, etc.) with final determination made 
by the principal investigator. 
9.1.3. Adverse event attribution. Initial attribution of ascorbate to a grade 3 or greater 
event may be assigned by any licensed medical personnel (e.g., research nurse, 
treating physician, etc.). The principal investigator will make the final determination 
regarding the attribution of the study drug to the adverse event and also decide course 
of action for the study participant. CTCAE grade 2 and lesser events do not require 
attribution unless the event is unexpected (i.e., not related to chemotherapy, tumor, or 
previously diagnosed underlying condition). 
9.2. 
Routine Adverse Event Reporting Requirements 
Adverse events attributed to the study drug will be reported to the Data Safety Monitoring 
Committee (DSMC) via the Clinical Research Safety Officer (CRSO) following established 
standard operating procedure of the DSMC.  
9.3. 
Expedited Adverse Event Reporting 
Investigators MUST immediately report to the DSMC any serious adverse events (SAE), 
whether or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64). Reporting requirements are in Table 2. 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
 
 

 
20 
 
Table 2:  CTEP/NCI’s Recommended  Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention 
(Phase 1 and Early Phase 2 Studies)1 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported within the timeframes detailed in 
the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour  
5 Calendar Days 
Not resulting in Hospitalization ≥ 24 hrs 
Not required 
NOTE:  Adverse events that are not deemed serious are reported through routine adverse event requirements. 
Expedited AE reporting timelines are defined as: 
- 
“24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, followed by a 
complete expedited report within 5 calendar days of the initial 24-hour report. 
- 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the 
AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
Effective Date:  May 5, 2011 
10. CORRELATIVE/SPECIAL STUDIES 
10.1. Parameters of Oxidative Stress.  
Research blood for ROS testing will be obtained at each cycle: 
• 
Cycle day 1, prior to ascorbate infusion 
• 
Cycle day 2, prior to infusion 
In addition, the last ROS blood sample will be obtained at the first follow-up visit (protocol 
section 6.5 Follow-up Assessments) prior to any therapy that would be administered that day. 
ROS research samples are 5-6 mL in an EDTA tube (pink top) and placed immediately on 
ice. The basic science RA must be contacted immediately after the blood draw is obtained. 
Samples should be spun to yield plasma using standard procedures as soon as possible. 
Plasma should then be transferred to a cryovial and frozen immediately at -80°C. It is 
imperative that plasma is not thawed until analysis in the Eicosanoid Core Laboratory as F2-
IsoPs can be generated in plasma ex vivo, even at temperatures of -20°C. A minimum of 1 
mL plasma is required for analysis. This research analysis will not be added to the subject’s 
medical record.  
 
 

 
21 
10.2. Patient Reported Outcomes (optional) 
Previous studies demonstrated the potential for increase in toxicities when multiple anti-
cancer agents were combined to treat patients with non-small cell lung cancer. The FACT 
questionnaires (the FACT-Lung (FACT-L) and FACT-Taxane (FACT-Tax)) will be used in 
this study to capture the subject’s assessment of their overall quality of life (QOL), disease 
symptoms and treatment related side effects. Both of these instruments have been rigorously 
validated.34,35 
Results of FACT-L will be reported as: 
• 
Trial Outcome Index-Lung (TOI-L): Sum of FACT-L subscales (PWB + FWB + LCS) 
• 
Total FACT-L: Sum of all FACT-L subscales (PWB + SWB + EWB + FWB + LCS) 
• 
LCS subscale  
Where the higher score indicates a better quality of life. 
Results of FACT-Tax will be reported as: 
• 
Taxane subscale  
• 
Neurotoxicity Subscale  
Where a higher the score indicates higher treatment related toxicities. 
10.2.1. Questionnaires administration timings 
FACT-L and FACT-Tax questionnaire are administered:   
• 
Baseline (before receiving any trial therapy; can be on C1D1) 
• 
Day 1 of each subsequent cycle of chemotherapy (i.e., C2, C3, C4) 
• 
On the day of last ascorbate infusion (approximately 12th week of the trial)  
10.2.2. Analysis 
The objective of the PRO assessment in this study is to describe changes in subject 
reported QOL, lung cancer symptoms, and treatment related-toxicities by using 
FACT-L/Taxane questionnaires. Changes in LCS, FACT-L, TOI-L, Taxane and 
Neurotoxicity subscale scores will be calculated from baseline to week 12 and 
summarized with means.  Additionally, proportions of patients experiencing clinically 
meaningful changes will be calculated.  Clinically meaningful changes in each of the 
subscale of these questionnaires, TOI-L, and Total FACT-L have been pre-defined 
and validated in the previous studies and are defined in the table below. 
Established threshold values corroborating with clinically meaningful change for each 
subscale or indices of the FACT- L & FACT-Tax instrument:  
Instrument 
Scale/Subscale 
Clinically meaningful 
change (points) 
Reference 
FACT-L 
LCS 
Total FACT-L 
TOI-L 
3 
9 
6 
Cella et al 200236 
FACT-Taxane 
Taxane-Subscale 
Neurotoxicity Subscale 
3 
3 
Cella et al 200334 
 

 
22 
Based on the differences in subscale scores over time, study subjects will be 
categorized to have improved, remained stable or worsened in terms of their quality 
of life and have either developed significant or no-significant treatment related 
neurotoxicity.   
• 
Improved health-related QOL: if the magnitude of increase in LCS, TOI-L and 
FACT-L score from baseline to week 12 is equal or greater than the established 
threshold for these scales/subscale. 
• 
Worsened health-related QOL: if the magnitude of decrease in his or her LCS, 
TOI-L and FACT-L score from baseline to week 12 is equal or greater than the 
established threshold.  
• 
Stable health-related QOL: if the change does not fall into any of the above 
category.  
• 
Significant paclitaxel related neurotoxicity: if the magnitude of increase in the 
taxane and/or neurotoxicity subscale score from baseline to week 12 is equal or 
greater than established threshold.  
• 
Non- significant paclitaxel-related neurotoxicity: if the magnitude of increase 
in the taxane and neurotoxicity score from baseline to week 12 is less than 
previously established threshold for these scales.  
Mean changes and category-specific proportions will both be reported along with 
95% confidence intervals, and compared descriptively to previously published 
studies.37,38 
 
 

 
23 
11. STUDY CALENDAR 
 
screena 
therapy 
end of studyb 
F/Uc 
Historyd & physicald 
X 
d1 
X 
X 
Vitals (BP, temp, HR)e 
X 
e 
X 
 
Weight, BSAf 
 
f 
X 
 
G6PDa 
X 
 
 
 
Uric Acid 
 
baseline 
 
 
Iron panel, ferritin 
 
s 
 
 
Pregnancy testa 
X 
 
 
 
Ascorbate 15g test dose 
X 
 
 
 
HRQOL (optional) 
 
X r 
 
 
Comprehensive metabolic panel g 
X a 
d1g 
X 
Xc 
CBC w/diff 
X a 
d1 
X 
Xc 
Ascorbate infusion h,e 
 
X h,e 
 
 
Blood for ascorbate levels i 
X 
X i 
X 
 
Blood for ROS k 
X 
X k 
X 
X 
Adverse events m 
X m 
X 
X 
X 
CT, chest/abdomen/pelvis n 
X 
Xn 
 
 
Brain MRI o 
 
X o 
X o 
X o 
PET or bone scan o 
 
X o 
X o 
X o 
Survival p 
 
 
 
X p 
a 
study day 1 is  cycle 1, day 1. Screening labs and history/physical must be obtained ≤ 21d from d1. G6PD may be 
obtained at any time prior to test dose as the value does not fluctuate. Pregnancy test at physician discretion. 
b 
off-study evaluation (if subject is removed from study or withdraws), ± 7 calendar days from removal. Follow at least 
monthly until resolution of all ascorbate-associated adverse events or a new baseline is established. There should be a 
follow-up visit 28d (± 7d) after the last ascorbate infusion (preferably in person, phone call is acceptable); Section 5.8 
c 
Follow-up is 28d (±1 calendar week) after the last ascorbate infusion; further follow-up is passive through chart 
review. Obtain lab & research assessments at 28d follow-up only. See 5.6.2. 
d 
history is only taken at the screening and/or baseline visit; screening physical should be done within 21d of C1D1 and 
then on D1 of each cycle (physical can be up to/including –1 week) 
e 
blood pressure should be obtained before and after (≤ 15 min EOI) ascorbate infusion 
f 
chemotherapy calculations using actual body weight, see section 5.3.3 and 5.3.4 
g 
comprehensive metabolic panel: albumin, total bilirubin, calcium, CO2, creatinine, glucose, alkaline phosphatase, 
potassium, total protein, sodium, ALT, AST, BUN, chloride; labs for D1 of chemo can be up to/including –1 week. 
h 
twice weekly through 4 cycles of paclitaxel/carboplatin. See sections 6.2, 6.3, and 6.4 for assessments  
i 
Draw blood specimens ~4cc green top tube pre- and post- infusion drawn once per cycle.  
At the same time, use a finger-stick glucometer (study provided) to obtain ascorbate levels.  
Do not chart in medical record; store only in research record. 
k 
Draw 1 EDTA pink-top tube (5-6 mL) D1 pre-infusion and D2 pre-infusion. Also draw 1 sample at FU#1 prior to any 
subsequent therapy.. 
m baseline constitutional assessment should be done at screening and/or  prior to infusion on cycle 1, day 1. 
n 
baseline obtained ≤ 30d from d1; obtain after cycle 2 and after cycle 4  (approximately 21 – 28 days after d1) 
DO NOT schedule on days with ascorbate infusions. Ascorbate and CT contrast are contraindicated. 
o 
at the discretion of the treating physician 
p 
through passive chart review 
r 
baseline (before therapy D1), then D1 of each subsequent cycle, then prior to last ascorbate infusion. 
s 
draw at baseline and only on day 2 of cycles 1 and 3 

 
24 
12. MEASUREMENT OF EFECT 
12.1. Tumor Response (Primary End-Point) 
Tumor response will be defined using the RECIST 1.1 guidelines.33 
12.2. Progression Free Survival 
Time from start of therapy (day 1, cycle 1) to documented disease progression. Progression 
will be defined using the RECIST 1.1 guidelines.33  
12.3. Overall Survival 
Time from start of therapy (day 1, cycle 1) to death.  
12.4. Toxicity 
Categorize and quantify adverse events from start of therapy (day 1, cycle 1) to end of cycle 4.  
13. STATISTICAL CONSIDERATIONS 
13.1. Endpoints 
• 
Tumor response 
• 
Time to progression 
• 
Progression free survival (PFS) 
• 
Overall survival (OS) 
13.2. Analysis Plan 
The primary objective of this trial is to evaluate initial tumor response. A response rate above 
40% is considered clinically important, whereas a rate below 20% is considered 
uninteresting. In statistical terms, we are testing the null hypothesis H0: π < 0.20 versus the 
alternative H1: π > 0.40, where π is the probability of response. Sample size requirements for 
the trial are based on an optimal Simon two-stage design. Seventeen (17) patients will be 
enrolled in the first stage, and the study terminated if 3 or fewer respond. Otherwise, an 
additional 20 patients will be enrolled in the second stage. If 11 or more of the 37 total 
patients respond, the treatment will be deemed worthy of further study. The proposed design 
has an average sample size of 26.0 and a probability of early termination equal to 0.55. 
Furthermore, the design will ensure a 0.90 probability of correctly identifying an effective 
treatment. Conversely, if the treatment is not effective, there is a 0.10 probability of 
incorrectly concluding that it is. For the secondary objectives, time to progression, 
progression-free survival, and overall survival will be estimated with the methods of Kaplan-
Meier. Estimated survival probabilities will be plotted and medians reported, along with 95% 
confidence intervals. 
13.3. Accrual Strategy 
The Holden Comprehensive Cancer Center consults approximately 300 new lung cancer 
patients per year. Of these, approximately 60% are staged IIIB or greater. This results in 
approximately 160 potential participants with an expected accrual rate of 12% and 
enrollment rate of 10%. This results in an estimated enrollment of 16 subjects per year, 
closing the trial to accrual in approximately 2 ½ years. 
13.4. Study Duration 
The study is expected to close to accrual in 2.5 years with primary objective being completed 
by year 3. With a median survival of 9 months, the study’s duration to complete the 
secondary objectives should be 4 years. 

 
25 
14. REFERENCES 
1. 
Parkin DM, Bray F, Ferlay J, and Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 
2005;55(2):74-108. 
2. 
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71-96. 
3. 
Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors 
in resected stage I lung cancer. J Thorac Cardiovasc Surg. 1995;109(1):120-129. 
4. 
Martini N, Burt ME, Bains MS, McCormack PM, Rusch VW, and Ginsberg RJ. Survival after 
resection of stage II non-small cell lung cancer. Ann Thorac Surg. 1992;54(3):460-465; 
discussion 466. 
5. 
Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 
1997;111(6):1710-1717. 
6. 
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for 
advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98. 
7. 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-
small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550. 
8. 
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med. 2009;361(10):947-957. 
9. 
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-
cell lung cancer. N Engl J Med. 2010;363(18):1693-1703. 
10. 
McCormick W. Cancer: the preconditioning factor in pathogenesis. Arch Pediat. 1954;71:313-
322. 
11. 
McCormick W. Cancer: a collagen disease, secondary to a nutritional deficiency? . Arch Pediat. 
1959;76:166-171. 
12. 
Cameron E, Rotman, D. Ascorbic acid, cell proliferation, and cancer. Lancet. 1972;299:542. 
13. 
Cameron E, Pauling, L. Ascorbic acid and the glycosaminoglycans. An orthomolecular approach 
to cancer and other diseases. Oncology. 1973;27:181-192. 
14. 
Cameron E, Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: 
Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 
1976;73:3685-3689. 
15. 
Cameron E, Campbell, A. The orthomolecular treatment of cancer. II Clinical trial of high-does 
ascorbic acid supplements in advanced human cancer. Chem Biol Interact. 1974; 9:285-315. 
16. 
Cameron E, Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: 
reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci 
USA 1978;75:4538-4542. 
17. 
Cameron E, Campbell, A:. Innovation vs. quality control: an ‘unpublishable’ clinical trial of 
supplemental ascorbate in incurable cancer Med Hypotheses. 1991;36:185-189. 
18. 
Campbell A, Jack, T, Cameron, E. Reticulum cell sarcoma: two complete ‘spontaneous’ 
regressions, in response to high dose ascorbic acid therapy. A report on subsequent progress. 
Oncology. 1991;48:495-497. 
19. 
Murata A, Morishige, F, Yamaguchi, H. Prolongation of survival times of terminal cancer patient 
by administration of large doses of ascorbate. Int J. Vitam Nutr Res Suppl. 1982; 23:103-113. 
20. 
Creagan E, Moertel, CG, O’Fallon, JR, Schutt, AJ, O’Connell, MJ, Rubin, J, Frytak, S. Failure of 
high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer: A 
controlled trial. N Engl J Med. 1979;301:687-690. 
21. 
Moertel C, Flemin, TR, Creagan, ET, Rubin, J, O’Connell, MJ, Ames, MM: . High-dose vitamin 
C versus placebo in the treatment of patients with advanced cancer who have had no prior 
chemotherapy. A randomized double-blind comparison. N Engl J Med 1985;312:137-141. 
22. 
Levine M, Conry-Cantilena, C, Wang, Y, Welch, RW, Washko, PW, Dhariwal, KR, Park, JB, 
Lazarev, A, Graumlich, JF, King, J, Cantilena, LR. . Vitamin C Pharmacokinetics in healthy 
volunteers: Evidence for a recommended dietary allowance. Proc Natl Acad Sci USA. 
1996;93:3704-3709. 
23. 
Padayatty SJ, Levine, M. Reevaluation of vitamin C in cancer treatment: emerging evidence, 

 
26 
open minds and serendipity. J. Amer. Coll. Nutr. 2000;19:423-425. 
24. 
Graumlich J, Ludden, TM, Conry-Cantilena, C, Cantilena, Jr LR, Wang, Y, Levine, M. 
Phamacokinetic model fo ascorbic acid in healthy male volunteers during depletion and 
repletion. Pharm Res 1997;14:1133-1139. 
25. 
Riordan N, Riordan, HD, Meng, X, Li, Y, Jackson, JA. Intravenous ascorbate as a tumor 
cytotoxic chemotherapeutic agent. Med Hypotheses. 1995; 44:207-213. 
26. 
Chen Q, Espey, MG, Krishna, MC, Mitchel,l JB, Corpe, CP, Buettner, GR, Shacter, E, Levine, 
M. . Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-
drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA. 2005;102:13604-13609. 
27. 
Chen Q, Espey, MG, Sun, AY, Lee, JH, Krishna, MC, Shacter, E, Choyke, PL, Pooput, C, Kirk, 
KL, Buettner, GR, Levin, M. Ascorbic acid in pharmacologic concentrations: a pro-drug for 
selective delivery of ascorbate radical and hydrogen peroxide to extracellular fluid in vivo Proc 
Natl Acad Sci USA. 2007;104:8749-8754. 
28. 
Padayatty S, Sun, H, Wang, Y, Riordan, HD, Hewitt, SM, Katz, A, Wesley, RA, Levine, M. . 
Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 
2004;140:533-537. 
29. 
Chen Q, Sun, AY, Espey, MG, Levine, M. Ascorbic acid as a pro-oxidant therapeutic agent in 
cancer. Free Radical Biology and Medicine. 2007;43:S52. 
30. 
Hoffer LJ, Levine M, Assouline S, 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. 2008;19(11):1969-1974. 
31. 
Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, and Chen Q. High-dose parenteral 
ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. 
Sci Transl Med. 2014;6(222):222ra218. 
32. 
van Heeswijk RP, Cooper CL, Foster BC, et al. Effect of high-dose vitamin C on hepatic 
cytochrome P450 3A4 activity. Pharmacotherapy. 2005;25(12):1725-1728. 
33. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
34. 
Cella D, Peterman A, Hudgens S, Webster K, and Socinski MA. Measuring the side effects of 
taxane therapy in oncology: the functional assesment of cancer therapy-taxane (FACT-taxane). 
Cancer. 2003;98(4):822-831. 
35. 
Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, and Bonomi P. Reliability and validity 
of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. 
Lung Cancer. 1995;12(3):199-220. 
36. 
Cella D, Eton DT, Fairclough DL, et al. What is a clinically meaningful change on the 
Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern 
Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol. 2002;55(3):285-295. 
37. 
Kelly K, Crowley J, Bunn PA, Jr., et al. Randomized phase III trial of paclitaxel plus carboplatin 
versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung 
cancer: a Southwest Oncology Group trial. J Clin Oncol. 2001;19(13):3210-3218. 
38. 
Hirsh V, Okamoto I, Hon JK, et al. Patient-reported neuropathy and taxane-associated symptoms 
in a phase 3 trial of nab-paclitaxel plus carboplatin versus solvent-based paclitaxel plus 
carboplatin for advanced non-small-cell lung cancer. J Thorac Oncol. 2014;9(1):83-90. 
 

 
27 
PROTOCOL 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. 
 
 
 
 

 
28 
PROTOCOL APPENDIX B: CYP3A4 INTERACTION TABLE 
 
CYP3A4 INTERACTION TABLE  
(Ascorbate may decrease the plasma/blood concentrations of substrates) 
Drugs with strikeout text are antiretroviral drugs that are not allowed for use on this study. 
* 3A4 substrate & inhibitor; # 3A4 substrate & inducer 
abiraterone 
acetaminophen 
ado-trastuzumab  
alfentanil 
alfuzosin 
aliskiren 
alitretinoin 
almotriptan 
alprazolam 
ambrisentan 
amiodarone* 
amitriptyline 
amlodipine 
amprenavir 
apixaban 
aprepitant* 
aripiprazole 
armodafinil# 
artemether 
asenapine 
astemizole 
atazanavir* 
atorvastatin 
avanafil 
axitinib 
beclomethasone 
bedaquiline 
benzphetamine 
bexarotene  
bisoprolol 
boceprevir 
bortezomib 
bosentan# 
bosutinib 
brentuximab 
bromazepam 
bromocriptine 
budesonide 
buprenorphine 
buspirone 
busulfan 
cabazitaxel 
cabozantinib 
caffeine 
canagliflozin 
carbamazepine# 
cevimeline 
chlordiazepoxide 
chloroquine 
chlorpheniramine 
ciclesonide  
cilostazol 
cinacalcet 
cisapride  
citalopram 
clarithromycin* 
clindamycin 
clobazam 
clomipramine 
clonazepam 
clopidogrel 
clorazepate 
clozapine 
cobicistat* 
cocaine 
codeine 
colchicine 
conivaptan* 
crizotinib 
cyclobenzaprine 
cyclophosphamide 
cyclosporine* 
dantrolene 
dapsone 
darifenacin 
darunavir 
dasatinib 
delavirdine* 
desogestrel  
dantrolene 
dexamethasone# 
dexlansoprazole 
dextromethorphan 
diazepam 
diclofenac 
dienogest 
dihydroergotamine 
diltiazem* 
disopyramide 
docetaxel 
dofetilide 
dolasetron 
domperidone 
donepezil 
doxorubicin 
dronedarone 
droperidol 
dutasteride 
efavirenz*# 
eletriptan 
elvitegravir 
enzalutamide 
eplerenone 
ergoloids 
ergonovine 
ergotamine 
erlotinib 
erythromycin* 
escitalopram 
esomeprazole 
estazolam 
estradiol 
estradiol valerate 
estrogens 
eszopiclone 
ethinyl estradiol 
ethosuximide 
etonogestrel 
etoposide 
etravirine 
everolimus 
exemestane 
felbamate 
felodipine 

 
29 
CYP3A4 INTERACTION TABLE  
(Ascorbate may decrease the plasma/blood concentrations of substrates) 
Drugs with strikeout text are antiretroviral drugs that are not allowed for use on this study. 
* 3A4 substrate & inhibitor; # 3A4 substrate & inducer 
fentanyl 
fesoterodine 
fexofenadine 
finasteride 
fingolimod 
flunisolide 
flurazepam 
flutamide 
fluticasone 
fosamprenavir* 
fosaprepitant 
fulvestrant 
galantamine 
gefitinib 
granisetron 
guanfacine 
haloperidol* 
hydrocodone 
hydrocortisone 
ifosfamide 
iloperidone 
imatinib* 
imipramine 
indacaterol 
indinavir* 
irinotecan 
isosorbide dinitrate 
isosorbide 
mononitrate 
isradipine 
itraconazole* 
ivacaftor 
ixabepilone 
ketamine 
ketoconazole* 
lansoprazole  
lapatinib 
lercanidipine 
letrozole 
levonorgestrel 
lidocaine* 
linagliptin 
lomitapide 
loperamide  
lopinavir 
loratadine 
losartan 
lovastatin 
lumefantrine 
lurasidone 
maraviroc 
marijuana 
medroxyprogesterone 
mefloquine 
meloxicam 
mestranol 
methadone 
methylergonovine 
methylprednisolone 
miconazole* 
midazolam 
mifepristone 
mirabegron 
mirtazapine 
modafinil 
mometasone 
montelukast 
nateglinide 
nefazodone* 
nelfinavir* 
nevirapine# 
nicardipine* 
nifedipine 
nilotinib 
nimodipine 
nisoldipine 
nitrendipine 
norethindrone 
norgestrel 
nortriptyline 
omeprazole 
ondansetron 
ospemifene 
oxybutynin 
oxycodone 
paclitaxel 
paliperidone 
palonosetron 
pantoprazole 
paricalcitol 
paroxetine 
pazopanib 
perampanel 
perphenazine 
pimozide 
pioglitazone 
pomalidomide 
ponatinib 
prasugrel 
prednisolone 
prednisone  
primaquine 
progesterone/ 
progestins 
propafenone 
propranolol 
quazepam 
quetiapine 
quinidine*  
quinine 
rabeprazole 
ramelteon 
ranolazine 
regorafenib 
repaglinide 
rifabutin# 
rilpivirine 
risperidone 
ritonavir* 
rivaroxaban 
roflumilast 
romidepsin 
ruxolitinib 
salmeterol 
saquinavir* 
saxagliptin 

 
30 
CYP3A4 INTERACTION TABLE  
(Ascorbate may decrease the plasma/blood concentrations of substrates) 
Drugs with strikeout text are antiretroviral drugs that are not allowed for use on this study. 
* 3A4 substrate & inhibitor; # 3A4 substrate & inducer 
selegiline 
sertraline 
sibutramine 
sildenafil 
silodosin 
simvastatin 
sirolimus 
sitagliptin 
solifenacin 
sorafenib 
sufentanil 
sunitinib 
tacrolimus 
tadalafil 
tamoxifen 
tamsulosin 
telaprevir 
telithromycin* 
temsirolimus 
teniposide 
terfenadine 
testosterone  
tetracycline* 
theophylline 
tiagabine 
ticagrelor 
ticlopidine 
tinidazole 
tipranavir 
tofacitinib 
tolterodine 
tolvaptan 
topotecan 
toremifene 
tramadol 
trazodone 
triazolam 
trimethoprim 
trimetrexate 
trimipramine 
ulipristal 
vandetanib 
vardenafil 
vemurafenib  
venlafaxine 
verapamil* 
vilazodone 
vinblastine 
vincristine 
vinorelbine 
vismodegib 
voriconazole 
warfarin 
zaleplon 
zileuton 
ziprasidone 
zolpidem 
zonisamide 
zopiclone 
 
 
 
References:  
1. Lexi-comp On-line. Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. (accessed 1/16/15) 
2. Pharmacist’s Letter/Prescriber’s Letter. Cytochrome P450 Drug Interactions. October 2013. 
3. P450 Drug Interaction Table. Indiana University Department of Medicine Division of Clinical Pharmacology.  
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
4. Hansten and Horn’s Drug Interactions Analysis and Management. Facts and Comparisons. 2014 
 
 
 
UIHC Drug Information Center: 1/15 
 
 
 
 
 

 
31 
PROTOCOL APPENDIX C: DATA AND SAFETY MONITORING PLAN 
In accordance with the NIH policy on procedures for data and safety monitoring of clinical trials, the 
Holden Comprehensive Cancer Center (HCCC) has developed systems to ensure the safety of 
participants, the validity and integrity of research data, and compliance with the approved protocol. 
HCCC Principal Investigators are required to include a general description of a data and safety 
monitoring plan as part of each new interventional research protocol, which they develop and submit 
for review. 
All investigator-initiated protocols will contain an appropriately detailed Data and Safety Monitoring 
Plan (DSMP) that will be reviewed and approved by the DSMC or Committee Chair. The DSMC 
dictates what constitutes a satisfactory plan for each study. All interventional clinical trials require 
monitoring for data veracity and safety, including physiologic, toxicity- and dose-finding studies 
(phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The 
method and degree of monitoring needed is related to the degree of risk and should also be 
commensurate with size and complexity of the trial. The Clinical Research Safety Officer (CRSO) of 
the DSMC will be the primary interface with the study’s PI and research team to collect and 
assemble all required materials for review by the Committee. 
Risk Level 
This protocol has been assessed by the Data and Safety Monitoring Committee (DSMC) of the 
HCCC and by the sponsor-investigator as a Risk Level 4. Specifically, a risk-level 4 clinical trial is 
one that has: 
– A risk of death (i.e., 100-day treatment-related mortality) of >5%, or, 
– A risk of a Grade 4 SAE (serious adverse event > 15%, or, 
– An investigator-sponsored investigational new drug (IND), or, 
– Gene therapy, gene manipulation, or viral vector systems, or, 
– High-risk clinical procedures performed solely for research purposes, or 
– A new chemical or drug for which there is limited or no available safety data in humans 
Required DSMP elements 
The Principal Investigator for institutional studies at the HCCC must include a trial-specific DSMP 
with each new protocol. The key items the plan must address are 
– A subject eligibility check-list (inclusion / exclusion criteria) 
– A list of expected toxicities 
– Stopping rules for suspension of accrual secondary to adverse events and safety parameters 
– PI’s estimate of the study’s risk level 
The Principal Investigator is to ensure that all required data for monitoring is provided to the DSMC by way of 
the CRSO and the HCCC Protocol Manager. 
 
 

 
32 
Eligibility Checklist 
Subject ID: ____________________________________________ 
Date: ___________________ 
Inclusion criteria. All responses must be marked YES or NA for patient to be eligible 
1. Histologically or cytologically confirmed NSCLC 
Yes No 
2. Cancer staged IIIB, IV, or recurrent (3.1.2) 
Yes No 
3. If CNS metastasis, metastasis is treated,  
Yes No 
no clinical signs of progression following treatment, and patient off steroids ≥ 3d 
(steroids must be prescribed specifically for brain metastasis) 
4. Tested G6PD status ≥ LLN 
Yes No 
5. Aged ≥ 18 years 
Yes No 
6. ECOG performance status of 0, 1, or 2 [KPS > 50] 
Yes No 
7. Screening labs within 21 days prior to cycle 1 day 1 
Yes No 
a. ANC ≥ 1500 cells/mm3 
Yes No 
b. Platelets ≥ 100,000/mm3 
Yes No 
c. Hemoglobin ≥ 8 g/dL 
Yes No 
d. CRT ≤ 1.5 x ULN  
Yes No 
 
e. TBIL ≤ 1.5 x ULN 
Yes No 
f. ALT ≤ 3 times the UIHC upper limit of normal 
Yes No 
g. AST ≤ 3 times the UIHC upper limit of normal 
Yes No 
8. Not pregnant 
Yes No NA 
If N/A, state reason:_____________________________________________________________ 
9. Agrees to adequate contraception during trial: 
Yes No NA 
If N/A, state reason:_____________________________________________________________ 
10. Tolerate one test dose (15g) of ascorbate  
Yes No 
11. Ability to understand & willingness to sign a consent document 
Yes No 
 
 
 
Signature: _____________________________________________ 
Date: ___________________ 
Amendment 7 release  (07 November 2018) 
 
 
 

 
33 
Eligibility Checklist 
Subject ID: ____________________________________________ 
Date: ___________________ 
Exclusion Criteria. All responses must be marked NO or NA for patient to be eligible 
1. Known sensitizing EGFR mutations or ALK gene rearrangement  
Yes No N/A 
unless progression after targeted therapy. (If patient’s biopsy  
did not allow EGFR or ALK gene analysis (e.g., inconclusive, not enough tissue, etc.),  
the patient is considered eligible for study.) 
2. PD-L1 expression of 50% or more on tumor cells (if available) 
Yes No N/A 
3. Receiving warfarin therapy and cannot tolerate drug substitution 
Yes No 
4. Known hemoptysis (more than ½ teaspoon per day) ≤ 1 week screen 
Yes No 
5. Actively receiving insulin 
Yes No 
or 
Exception is granted by IND sponsor, medical monitor, and PI. 
Yes 
6. Leptomeningeal disease 
Yes No 
7. Receiving the following drugs and cannot be substituted 
a. Flecainide 
Yes No 
b. Methadone  
Yes No 
c. Amphetamines  
Yes No 
d. Quinidine  
Yes No 
e. Chlorpropamide  
Yes No 
8. Known active invasive malignancy  
Yes No 
9. Other investigational agents with intent to treat  
Yes No 
10. Uncontrolled intercurrent illness including, but not limited to:  
Yes No 
a. Ongoing or active infection 
b. Symptomatic congestive heart failure 
c. Unstable angina pectoris 
d. Cardiac arrhythmia 
e. Psychiatric illness / social situations that would limit compliance 
f. Other condition that would limit compliance with study requirements 
11. Lactating woman 
Yes No 
12. Known HIV-positive status 
Yes No 
 
 
Signature: _____________________________________________ 
Date: ___________________ 
Amendment 7 release  (07 November 2018) 

 
34 
Expected toxicities 
In addition to the standard toxicities of chemotherapeutic treatment for non-small cell lung cancer, 
the following anticipated risks are identified in the IRB application due to this clinical trial: 
Serious: 
– 
diarrhea (<10%)  
– 
nausea, vomiting (<5%)  
– 
precipitation of cystine, oxalate, or urate crystals resulting in kidney damage or failure (<1%)  
Mild: 
– 
dry mouth / thirst (this happens in about 45% of those receiving high-dose ascorbate)  
– 
headache (<5%)  
– 
abdominal pain (<5%)  
– 
fatigue (<5%)  
– 
facial flushing (<5%)  
– 
sweating (<5%)  
– 
weakness (<5%)  
– 
injection site irritation (< 2%)  
– 
faintness or dizziness with rapid infusion (<5%)  
– 
ascorbate may leak outside vein (<2%)  
– 
risk of gout, gout-like symptoms, or exacerbation of existing gout (<2%) 
Radiation sensitization: 
In case radiation is needed in the for the lung cancer patients, it is anticipated that ascorbate will act 
as a radiation sensitizer. This could result in:  
– 
radiation side effects being observed sooner than expected  
– 
radiation side effects being more severe than anticipated  
Radiation will not be used concurrently with ascorbate in this trial.  
Imaging contrast: 
A sharp increase in a subject's liver function tests have been observed when the subject received CT 
imaging contrast on the same day as an ascorbate infusion. Kansas (Dr. Jeanne Drisko) noted similar 
observations. Therefore, ascorbate and CT imaging contrast (oral or IV) will not be administered on 
the same day. 
Stopping Rules 
As a phase II study, stopping rules do not apply. If a subject dies during active study treatment: 
– Trial will be placed on accrual hold until case review 
– The death will be reviewed by the principal investigator, IND medical monitor, and IND sponsor 
(and, as applicable, treating physician) 
– Adverse events, including deaths on study, will be reviewed at IND investigators’ meeting. 
 
 

 
35 
DSMC Monitoring and Compliance 
The University of Iowa’s Holden Comprehensive Cancer Center is an NCI-accredited cancer center 
meeting comprehensive requirements. All investigator-initiated protocols will be managed and 
monitored by its data and safety monitoring committee (DSMC). The templated DSMP has been 
filed with the National Cancer Institute; some minor adjustments to accommodate individual trial 
requirements are allowed with DSMC approval.  
Required elements 
Protocol. All investigator-initiated clinical trials must list the protocol number, title, and principal 
investigator. Additionally, sub-investigators, co-investigators, biostatisticians, and consultants must 
also be listed. The protocol must contain subject selection criteria (inclusion / exclusion), stopping 
rules (for both individual subject and the study), anticipated risks, and expected toxicities. 
Plan. All DSMPs must include an annual reporting requirement to the DSMC, subject registration in 
the clinical trials management system (OnCore), a plan for documenting adverse events, and a plan 
to document protocol deviations. The DSMP must be approved by the DSMC prior to IRB approval. 
The IRB will then review and approve the DSMP as filed. 
Risk level 
As a study conducted under an investigator-sponsored IND, this study has been assigned a risk level 
4 as per the NCI filed DSMP and requires the strictest level of monitoring.  
Individual trial plan 
Study Safety Review 
An independent study monitor and/or the DSMC Chair (or designee), will review study data (and 
communicate with the PI at least biannually.  A copy of this communication will be forwarded to the 
DSMC Chairs. Study data will be made available through OnCore. 
For this clinical trial, the DSMC chair has appointed an independent physician as acting Chair, as the 
DSMC chair also serves as medical monitor for the investigator-sponsored IND (105715, Cullen). 
The acting chair is a board-certified radiation oncologist, who also serves on the University of 
Iowa’s Biomedical IRB and is active in PRIM&R, the national IRB society.  
Reporting Requirements 
• 
A scanned copy of the completed eligibility checklist, with screening information and physician 
signature, will be attached in OnCore for ongoing review by DSMC staff.  
• 
Serious adverse events will be entered directly into an OnCore SAE report by the research team.  
OnCore will send an automatic notification to the Acting Chair and staff for review.  
Monitoring Requirements 
The DSMC utilizes a risk-based monitoring approach.  Monitoring may be done more frequently 
depending on the protocol, risks to subjects, reported serious/adverse events, patient population and 
accrual rate.  The trial's research records will be monitored at minimum twice per year with a 
minimum of 25% of subjects monitored for the entire study participation (from enrollment to 
completion of study intervention). 
 
 

 
36 
Monitoring will involve the following: 
• 
review eligibility of patients accrued to the study, 
• 
check for the presence of a signed informed consent, 
• 
determine compliance with protocol’s study plan, 
• 
determine if SAEs are being appropriately reported to internal and external regulatory agencies,  
• 
compare accuracy of data in the research record with the primary source documents, 
• 
review investigational drug processing and documentation, 
• 
assess cumulative AE/SAE reports for trends and compare to study stopping rules. 
Routine Adverse Event Reporting 
For non-serious Adverse Events, documentation must begin from the first day of study treatment and 
typically continue through the 30 day follow-up period after treatment is discontinued. 
Collected information should be recorded in OnCore for that subject. Event term and grade are 
according to NCI’s Common Toxicity Criteria (CTCAE v4), and onset and resolved dates (if 
applicable). For serious adverse events or events ≥ grade 3, the relationship to the study drug must 
be included. Documentation should occur in real time. For the purposes of documenting in OnCore, 
the principal investigator has final responsibility for determining the attribution of the event as it is 
related to the study drug.  
Serious Adverse Event Reporting 
For any experience or condition meeting the definition of a serious adverse event (SAE; 
21CFR312.32), from the first day of study treatment and typically continue through the 30 day 
follow-up period after treatment is discontinued.  
Investigators must report to the DSMC any SAE, regardless of attribution to study drug. SAEs must 
be reported via an OnCore SAE Report within 1 business day of learning of the event.  
An adverse event is considered serious if it results in ANY of the following outcomes:   
• 
Death 
• 
A life-threatening adverse event  
• 
An adverse event that results in inpatient hospitalization OR prolongation of existing 
hospitalization for ≥ 24 hours  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. (21 CFR 312.32; ICH E2A and ICH E6). 
 
 

 
37 
Data Monitoring and Management  
All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) 
resources are required to register subjects in OnCore. Subject registration includes the following: 
–  Consent date and the IRB approved consent used  
–  Date of eligibility and eligibility status (eligible, not eligible) 
–  On study date and subject’s disease site (and histology if applicable) 
–  On treatment date (if applicable)  
Subject Data 
In addition to the subject registration and status entered in OnCore, research staff also enter the 
subject study data into OnCore electronic case report forms (eCRFs) for HCCC investigator initiated 
studies. eCRFs are approved by the PI and statistician prior to study activation to ensure the most 
effective data acquisition. All information on eCRFs will be traceable to the source documents 
which are maintained in the subject’s file or in the electronic health record (EPIC). eCRF data are 
expected to be entered into OnCore within 30 calendar days after a subject’s study visit.  
Forms Monitoring 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all mandatory 
fields are entered completely, accurately, and within time requirements. The assigned DSMC 
monitor manages the logistics associated with the data monitoring review. Once the clinical trial is 
identified for monitoring, the monitor arranges for a selection of cases to review from among the 
subjects registered in OnCore.  As part of the forms monitoring process, the assigned monitor will 
issue queries within the eCRF to resolve missing, incomplete and/or incorrect information. A 
member of the research team is expected to respond to monitoring queries within 14 business days.  
This process can often identify a misunderstanding or deficiency in protocol requirements early in 
the study and can improve data quality.  
Final Reports 
A summary of each subject’s data record is continually available to the PI, research staff, and DSMC 
from OnCore’s Biostat Console. The availability of this information is a valuable tool for the 
preparation of final reports and manuscripts as well as ongoing deficiency reports. 
 
 

 
38 
IND 105715 (J. Cullen, sponsor) Monitoring and Compliance Plan 
As an independent research trial under an investigator-sponsored IND, the sponsor has approved the 
following individualized monitoring plan to fulfill the requirements set forth in 21 CFR§312.50 and 
§312.56 in addition to ICH E6 and the FDA Bioresearch Monitoring Program’s Compliance 
Program Guidance Manual CPGM 7348.811.  
The following plan was developed after reviewing the FDA’s Oversight of Clinical Investigations — 
A Risk-Based Approach to Monitoring (August 2013), the NIH guidance OD-00-038 Further 
Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials, the NCI’s Conducting 
Clinical Trials: Essential Elements, and the International Conference on Harmonisation E6: 
Guideline for Good Clinical Practice, which has been listed by the FDA in the Federal Register as 
an accredited guidance document. 
Per the FDA (August, 2013) sponsors are encouraged to “…tailor monitoring plans to the needs of 
the trial.” The FDA also places greater emphasis on centralized monitoring than the ICH E6 
document, citing that centralized monitoring as described by the FDA (August 2013) was not yet 
feasible when the E6 document was completed. 
Centralized Monitoring (CM) 
For the purposes of this study, centralized monitoring refers to timely and accurate data entry into a 
spreadsheet for review by the principal investigator, sponsor, and/or designee. Remote monitoring 
enables data to be evaluated for quality, safety, and an interim analysis in real-time. Data to be 
entered are those identified as critical by the principal investigator and sponsor. Critical data can be 
monitored remotely through centralized monitoring (FDA, 2013, page 11). 
CM — critical data 
– Eligibility criteria (lab values, performance status, date of G6PD result, date of 15g test dose) 
– Baseline constitutional assessments performed and graded (Y/N) 
– Labs at day 1 of each cycle ordered and reviewed (Y/N) 
– Constitutional assessments performed and graded at start of each cycle (Y/N) 
– Subject temperature at pre-infusion, hourly during, and post-infusion 
– List of adverse events, with CTCAE grading, collected from infusion to +21 days post-infusion 
with codified attribution as appropriate 
CM — frequency of entry and review 
Centralized data will be entered within 2 weeks of the ascorbate infusion. Data will be reviewed no 
less than quarterly by the PI, sponsor, or designee. Email or written documentation of review will be 
sent to the sponsor or the sponsor’s designee. Alternatively, review can be performed or confirmed 
at sponsor-directed IND meetings.  
On-Site Monitoring (On-Site) 
Additional monitoring may be ordered by the principal investigator or sponsor. The principal 
investigator may select the monitor for the study but final approval must be obtained from the 
sponsor prior to any monitoring activities.  
 
 

 
39 
On-Site— critical data 
At minimum, the outside monitor will review the protocol against the provided monitoring sheet. 
Additional data to be reviewed may be added at the request of the sponsor, the sponsor’s designee, 
the principal investigator, or the principal investigator’s designee. 
On-Site — frequency of review 
Frequency of review (in addition to the monitoring provided by the HCCC monitoring plan) will be 
determined by quality audits performed by the sponsor or sponsor’s designee. 
On-Site — reports 
Monitoring reports will comply with ICH E6 and the FDA’s Oversight of Clinical Investigations — 
A Risk-Based Approach to Monitoring (August 2013). Finalized reports will be submitted to the 
sponsor, the principal investigator, the principal investigator’s designee, and the sponsor’s designee 
within 30 calendar days of the on-site monitoring visit. A copy of the final report, and any corrective 
action plans, will be submitted to the institutional review board. 
Auditing 
The purpose of a sponsor's audit, which is independent of and 
separate from routine monitoring or quality control functions, 
should be to evaluate trial conduct and compliance with the 
protocol, SOPs, GCP, and the applicable regulatory requirements.  
 
To preserve the independence and value of the audit function, the 
regulatory authority(ies) should not routinely request the audit 
reports. Regulatory authority(ies) may seek access to an audit 
report on a case by case basis when evidence of serious GCP non-
compliance exists, or in the course of legal proceedings.  
 
~ International Conference on Harmonisation, E6 
 
The sponsor intends to comply with auditing procedures to evaluate conduct and compliance with 
protocol, SOPs, GCP, and the DSMP filed with this protocol. Audit findings will be disseminated and 
discussed at quality meetings by the sponsor. 
 
 

 
40 
PROTOCOL APPENDIX D: RECOMMENDED MONITORING WORKSHEETS 
Consent 
Subject ID: ______________________________________________________________________________  
Date of consent: _________________________________________________________________________  
Version signed ICF (mm/dd/yy): _____________________________________________________________  
Valid ICF date (mm/dd/yy): ___________________________________________ [from HawkIRB application] 
Valid ICF [Y/N]:___________________________________________________________________________  
Eligibility 
1. Histologically/cytologically diagnosed NSCLC: _______________________________________________  
2. Staged IIIB, IV, or recurrent: _____________________________________________________________  
3. At least 18 years: ______________________________________________________________________  
4. ECOG 0, 1, or 2: _______________________________________________________________________  
5. G6PD deficiency [N]: ___________________________________________________________________  
6. Hemoglobin ≥ 8g/dL (21d ≤ C1D1) ________________________________________________________  
7. ANC ≥ 1500 / microL (21d ≤ C1D1) ________________________________________________________  
8. Platelets at least 100k / microL (21d ≤ C1D1) ________________________________________________  
9. Creatinine ≤ 1.5 x ULN  (21d ≤ C1D1): ______________________________________________________  
10. T. Bili ≤ 1.5 x ULN  (21d ≤ C1D1): __________________________________________________________  
11. ALT ≤ 3x ULN (21d ≤ C1D1): _____________________________________________________________  
12. AST ≤ 3x ULN (21d ≤ C1D1): _____________________________________________________________  
13. Negative serum pregnancy test WCOBP: ___________________________________________________  
14. Actively receiving warfarin [N]: ___________________________________________________________  
15. Actively receiving insulin [N]: ____________________________________________________________  
16. Known EGFR or ALK gene abnormality unless treatment progression [N]: _________________________  
17. Known hemoptysis [N]: _________________________________________________________________  
18. Receiving brain radiation therapy [N]: _____________________________________________________  
19. On flecainide, methadone, amphetamines, quinidine, or chlorpropamide [N]: _____________________  

 
41 
20. Known active invasive malignancy other than NSCLC  [N]: _____________________________________  
(exceptions:  non-melanoma skin cancers or carcinoma in situ of the cervix or bladder) 
21. Other investigational agents with an intent to treat [N]: _______________________________________  
22. Concurrent illnesses clause [N]: __________________________________________________________  
23. Known HIV positive status [N]: ___________________________________________________________  
Eligibility confirmed [Y/N/NA]: ______________________________________________________________  
Subject ID & initials: ______________________________________________________________________  
 
 

 
42 
Baseline Assessments 
These assessments should be done within 21d of C1D1. Assessments may be completed C1D1 
before therapy. 
Mark the below Y/N  
Con meds reviewed 
 
 
Temperature 
 
Blood pressure 
 
 
Heart rate 
 
Weight 
 
 
 
 
Mark the below Y/N. To mark yes, each symptom should be have a grade 
Fatigue 
 
 
Neuropathy 
 
Infection 
 
 
Nausea 
 
Vomiting 
 
 
Pain (headache) 
 
Mark the below Y/N. Labs can be screening ( if ≤ 21 days of C1D1) or drawn on C1D1 
CBC w/diff 
 
 
Creatinine 
 
Potassium 
 
 
T. Bilirubin 
 
BUN 
 
 
AST 
 
ALT 
 
 
Alk Phos 
 
Albumin 
 
 
Glucose 
 
Calcium 
 
 
Sodium 
 
Chloride 
 
 
CO2 
 
Uric Acid 
 
 
 
 
 
 
 

 
43 
Cycle 1 
Labs. Drawn up to 1 week prior. Mark the below Y/N  
CBC w/diff 
 
 
Creatinine 
 
Potassium 
 
 
T. Bilirubin 
 
BUN 
 
 
AST 
 
ALT 
 
 
Alk Phos 
 
Albumin 
 
 
Glucose 
 
Calcium 
 
 
Sodium 
 
Chloride 
 
 
CO2 
 
Constitutional. Mark the below Y/N. To mark yes for symptoms they must have a grade 
Fatigue 
 
 
Neuropathy 
 
Infection 
 
 
Nausea 
 
Vomiting 
 
 
Pain (headache) 
 
History / Physical  
 
 
Other 
 
 
 
 
 
 
Infusion assessments. Mark the below Y/N/NA. Assessments should be done pre- and post-
infusion. Hourly only as clinically indicated. (protocol section 6.3) 
 
Cycle Infusion Number 
1 
2 
3 
4 
5 
6 
Pre-infusion 
 
 
 
 
 
 
Post-infusion (≤15 min EOI)  
 
 
 
 
 
Paclitaxel. Complete as prompted. Actual height and weight from day of infusion should be used 
per protocol. Dosing is 200 mg/m2 (5.3.3.) 
Date, day 1 
 
 
Actual height 
 
Dose infused 
 
 
Actual weight 
 
Dose modified [Y/N] 
 
 
Actuals used [Y/N] 
 
Carboplatin. Complete as prompted. (5.3.3.) 
Date, day 1 
 
 
After paclitaxel? 
 
Dose modified [Y/N] 
 
 
 
 
 
 

 
44 
Cycle 2 
Labs. Drawn up to 1 week prior to D1. Mark the below Y/N  
CBC w/diff 
 
 
Creatinine 
 
Potassium 
 
 
T. Bilirubin 
 
BUN 
 
 
AST 
 
ALT 
 
 
Alk Phos 
 
Albumin 
 
 
Glucose 
 
Calcium 
 
 
Sodium 
 
Chloride 
 
 
CO2 
 
Constitutional. Mark the below Y/N. To mark yes for symptoms they must have a grade 
Fatigue 
 
 
Neuropathy 
 
Infection 
 
 
Nausea 
 
Vomiting 
 
 
Pain (headache) 
 
History / Physical  
 
 
Other 
 
 
 
 
 
 
Infusion assessments. Mark the below Y/N/NA. Assessments should be done pre- and post-
infusion. Hourly only as clinically indicated. (protocol section 6.3) 
 
Cycle Infusion Number 
1 
2 
3 
4 
5 
6 
Pre-infusion 
 
 
 
 
 
 
Post-infusion (≤15 min EOI)  
 
 
 
 
 
Paclitaxel. Complete as prompted.. Dosing is 200 mg/m2 (5.3.3.) 
Date, day 1 
 
 
 
 
Dose infused 
 
 
 
 
Dose modified [Y/N] 
 
 
Actuals used [Y/N] 
 
Carboplatin. Complete as prompted. (5.3.3.) 
Date, day 1 
 
 
After paclitaxel? 
 
Dose modified [Y/N] 
 
 
 
 
 
MRI / CT ordered post cycle 2 [date]: _________________________________________________________  
 

 
45 
Cycle 3 
Labs. Drawn up to 1 week prior. Mark the below Y/N  
CBC w/diff 
 
 
Creatinine 
 
Potassium 
 
 
T. Bilirubin 
 
BUN 
 
 
AST 
 
ALT 
 
 
Alk Phos 
 
Albumin 
 
 
Glucose 
 
Calcium 
 
 
Sodium 
 
Chloride 
 
 
CO2 
 
Constitutional. Mark the below Y/N. To mark yes for symptoms they must have a grade 
Fatigue 
 
 
Neuropathy 
 
Infection 
 
 
Nausea 
 
Vomiting 
 
 
Pain (headache) 
 
History / Physical  
 
 
Other 
 
 
 
 
 
 
Infusion assessments. Mark the below Y/N/NA. Assessments should be done pre- and post-
infusion. Hourly only as clinically indicated. (protocol section 6.3) 
 
Cycle Infusion Number 
1 
2 
3 
4 
5 
6 
Pre-infusion 
 
 
 
 
 
 
Post-infusion (≤15 min EOI)  
 
 
 
 
 
Paclitaxel. Complete as prompted.. Dosing is 200 mg/m2 (5.3.3.) 
Date, day 1 
 
 
 
 
Dose infused 
 
 
 
 
Dose modified [Y/N] 
 
 
Actuals used [Y/N] 
 
Carboplatin. Complete as prompted. (5.3.3.) 
Date, day 1 
 
 
After paclitaxel? 
 
Dose modified [Y/N] 
 
 
 
 
 
 

 
46 
Cycle 4 
Labs. Drawn up to 1 week prior. Mark the below Y/N  
CBC w/diff 
 
 
Creatinine 
 
Potassium 
 
 
T. Bilirubin 
 
BUN 
 
 
AST 
 
ALT 
 
 
Alk Phos 
 
Albumin 
 
 
Glucose 
 
Calcium 
 
 
Sodium 
 
Chloride 
 
 
CO2 
 
Constitutional. Mark the below Y/N. To mark yes for symptoms they must have a grade 
Fatigue 
 
 
Neuropathy 
 
Infection 
 
 
Nausea 
 
Vomiting 
 
 
Pain (headache) 
 
History / Physical 
 
 
Other 
 
 
 
 
 
 
Infusion assessments. Mark the below Y/N/NA. Assessments should be done pre- and post-
infusion. Hourly only as clinically indicated. (protocol section 6.3) 
 
Cycle Infusion Number 
1 
2 
3 
4 
5 
6 
Pre-infusion 
 
 
 
 
 
 
Post-infusion (≤15 min EOI)  
 
 
 
 
 
Paclitaxel. Complete as prompted. Dosing is 200 mg/m2 (5.3.3.) 
Date, day 1 
 
 
 
 
Dose infused 
 
 
 
 
Dose modified [Y/N] 
 
 
Actuals used [Y/N] 
 
Carboplatin. Complete as prompted. (5.3.3.) 
Date, day 1 
 
 
After paclitaxel? 
 
Dose modified [Y/N] 
 
 
 
 
 
MRI / CT ordered post cycle 4 [date]: _________________________________________________________  
 
 
 

 
47 
Regulatory Review 
Adverse Events. Obtain a copy of the adverse event log. Determine if adverse events are recorded 
and reported per protocol: 
Reporting 
Table 2:  CTEP/NCI’s Recommended  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention (Phase 1 and Early Phase 2 Studies)1 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported within the timeframes 
detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour  
5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Adverse events that are not deemed serious are reported through routine adverse event requirements. 
Expedited AE reporting timelines are defined as: 
- 
“24-Hour; 5 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, followed 
by a complete expedited report within 5 calendar days of the initial 24-hour report. 
- 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
Effective Date:  May 5, 2011 
 
Deviations. Obtain a copy of the deviation log. Determine if deviations are recorded and if they are 
reported to the UIOWA IRB per policy: 
Immediate deviation reporting: 
(1) subject safety (reportable AE per HSO definitions),  
(2) a change to the ICF, or  
(3) a risk to be communicated to other enrolled subjects 
For all other deviations (which would be considered procedural deviations), the IRB requests that 
they be collected on an excel spreadsheet and then submit them at the time of a continuing review.