Conditions: Prostate Cancer Castration-resistant Prostate Cancer
Keywords: olaparib ascorbic acid PARP PARP-inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is a study to evaluate the safety and clinical activity of the combination of olaparib and high-dose IV ascorbate, as second or later line of therapy, in castration resistant prostate cancer patients with no known DNA repair gene mutations (DDRm). In brief, the primary endpoint is PSA50 response , defined by a 50% reduction in PSA from baseline . The secondary endpoints are assessing the PSA doubling time, radiographic and PSA PFS, safety and tolerability as defined by the incidence of grade 3 to 5 toxicities, and measuring overall survival.

Detailed description:

Arms:
arm 1: Olaparib will be administered at 300 mg by mouth, twice daily; ascorbate will be administered at 1 g/kg IV twice weekly at least 24 hours apart, until objective disease progression or unacceptable toxicities or patient withdrawal for other reasons.

Interventions: intervention 1: Olaparib intervention 2: Vitamin C
Intervention descriptions: intervention 1: Olaparib 300mg by mouth twice daily intervention 2: Ascorbic acid 1g/kg administered intravenously twice weekly

Protocol document:
Prot_SAP_000.pdf: 
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Phase II Study of PARP Inhibitor Olaparib and IV Ascorbate in 
Metastatic Castration Resistant Prostate Cancer 
 
NCT#: NCT05501548 
IND#: 158163 
Johns Hopkins Protocol ID: J21127 
AstraZeneca Protocol Number: ESR 19-20448 
Lead Site and Sponsor: Johns Hopkins University 
Principal Investigator/Protocol Chair: 
Channing Paller, MD 
Johns Hopkins University School of Medicine 
Sidney Kimmel Comprehensive Cancer Center at 
Johns Hopkins 
201 N. Broadway, Viragh 9125, Box 7 
Baltimore, MD 21287 
Phone: (410) 955-8239 (Office) or (202) 660-
6322 (Clinic) 
Fax: (410) 367-2668 
cpaller1@jhmi.edu 
 
Coordinating Center: 
Johns Hopkins University School of Medicine 
Sidney Kimmel Comprehensive Cancer Center  
201 N. Broadway, Viragh Floor 9 
Baltimore, MD 21287 
hcao7@jhmi.edu 
kdaughe5@jhmi.edu  
 
Participating Sites:  
Thomas Jefferson University 
Site PI: Nathan R. Handley, MD 
Thomas Jefferson University 
925 Chestnut St. Suite 320A 
Philadelphia, PA 19107 
Office: 215-955-8874 
Fax: 215-503-7662 
Email: Nathan.Handley@jefferson.edu 
 
Statistician: 
Marianna Zahurak, MS 
Phone: (410) 955-4219 
zahurma@jhmi.edu  
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Version 2.0 Protocol Date:  12/06/2023
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information contained 
herein will not be disclosed to others without written authorization from the lead site/sponsor, 
except to the extent necessary to initiate the study or conduct study-related activities. 


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INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
Title: Phase II Study of PARP Inhibitor Olaparib and IV Ascorbate in Metastatic Castration 
Resistant Prostate Cancer 
 
 
 
 
 
Principal Investigator Signature:  
_______________________________________________________ 
Principal Investigator Print:  
_______________________________________________________ 
Date:   
 
 
 
______________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
SCHEMA 
 
Total Number of Patients: 15 
 
 
 
 
 
 
 
 
Olaparib 300 mg po BID 
+ 
IV Ascorbic Acid (1 g/kg, 2x per week)  
Visits and 
labs q 4 
weeks 
Bone and 
CT scans at 
baseline, 
and q 12 
weeks 
 
 
Olaparib is taken 300 mg BID orally 
Ascorbate is given 1 g/kg, 2 times per week intravenously (first three doses [over 1.5 
weeks]: titrate 0.25 g/kg, 0.5 g/kg, and 0.75 g/kg. Starting with cycle 1 week 2, the dose of 
Ascorbate will be 1 g/kg as long as this dose is tolerated) 


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TABLE OF CONTENTS 
1.0 
SCHEMA ......................................................................................................................... 4 
2.0 
OBJECTIVES .................................................................................................................. 9 
2.1 
Primary Objective .................................................................................................................... 9 
2.2 
Secondary Objectives.............................................................................................................. 9 
2.3  
Exploratory Objectives .......................................................................................................... 9 
3.0 
STUDY DESIGN ............................................................................................................. 9 
4.0 
BACKGROUND ........................................................................................................... 10 
4.1 
Disease Background ............................................................................................................. 10 
4.2  
Treatment Background ...................................................................................................... 10 
4.2.1 Description and mechanism of action of Olaparib ................................................................... 10 
4.2.2 Description and mechanism of action of Ascorbic Acid ........................................................ 11 
4.2.3 Preclinical studies of Olaparib............................................................................................................. 12 
4.2.4 Preclinical studies of Ascorbic acid .................................................................................................. 12 
4.2.5 Preclinical evidence to support combination Olaparib and Ascorbate ........................ 13 
4.2.6 Clinical Efficacy and Safety of Olaparib .......................................................................................... 15 
4.2.7 Clinical Efficacy and Safety of IV Ascorbic Acid ......................................................................... 16 
4.2.8 Clinical efficacy and safety of combination Olaparib and IV Ascorbate ....................... 17 
4.3 
Rationale for combination Olaparib and Ascorbic Acid ........................................ 17 
5.0 
PATIENT SELECTION .............................................................................................. 18 
5.1 
Inclusion Criteria .................................................................................................................. 18 
5.2 
Exclusion Criteria .................................................................................................................. 19 
5.3 
Inclusion of Minorities and Women and Children ................................................... 21 
6.0 
REGISTRATION ......................................................................................................... 21 
6.1 
General Guidelines ............................................................................................................... 21 
6.2 
Registration Process ............................................................................................................ 22 
7.0 
TREATMENT/INTERVENTION PLAN .................................................................. 22 
7.1  
Study Calendar ....................................................................................................................... 22 
7.2 
Screening/Pretreatment Assessment (up to Day -28) ........................................... 26 
7.3 
Treatment/Intervention Period ..................................................................................... 26 
7.3.1 Clinical, Laboratory, and Radiographic Assessments............................................................. 27 
7.3.2 Safety Assessments.................................................................................................................................... 28 
7.4 
Duration of Therapy and Criteria for Removal from Study ................................. 28 
7.4.1 Disease Progression .................................................................................................................................. 29 
7.4.2 EOT Visit .......................................................................................................................................................... 29 
7.5 
Duration of Follow Up ......................................................................................................... 30 
7.5.1  Long Term Follow-Up ............................................................................................................................. 30 
7.6 
Agent Administration .......................................................................................................... 30 
7.6.1 Olaparib Administration ......................................................................................................................... 31 
7.6.2 Ascorbic Acid Administration .............................................................................................................. 31 
7.7 
Concomitant, Supportive, and Restricted Medication and Supportive Care 
Guidelines .............................................................................................................................................. 31 
7.8  
Contraception ......................................................................................................................... 34 
7.9 
Expected Adverse Events ................................................................................................... 34 


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7.9.1 Ascorbic Acid................................................................................................................................................. 34 
7.9.2 Olaparib............................................................................................................................................................ 35 
7.10 Overdose ................................................................................................................................... 35 
8.0 DOSING DELAYS/MODIFICATIONS .......................................................................... 36 
8.1 
Dosing Delays.......................................................................................................................... 36 
8.2 
Dose Modifications ............................................................................................................... 37 
8.2.1 Ascorbic Acid Dose Modification ....................................................................................................... 37 
8.2.2 Olaparib Dose Modifications ................................................................................................................ 37 
9.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS............................ 43 
9.1 
Definitions................................................................................................................................ 43 
9.1.1 Adverse Event (AE) ................................................................................................................................... 43 
9.1.2 Serious Adverse Event (SAE) ............................................................................................................... 43 
9.1.3 Olaparib adverse events of special interest ................................................................................. 45 
9.1.4 Progression of malignancy .................................................................................................................... 45 
9.1.5 Significant disability.................................................................................................................................. 45 
9.1.6 Pregnancy ....................................................................................................................................................... 45 
9.1.7 Medical Significance .................................................................................................................................. 46 
9.1.8 Deaths ............................................................................................................................................................... 46 
9.2 
Expectedness .......................................................................................................................... 47 
9.2.1 Expected Adverse Events ....................................................................................................................... 47 
9.2.2 Unexpected Adverse Events ................................................................................................................. 47 
9.3 
Recording and Grading ....................................................................................................... 47 
9.3.1 Recording ........................................................................................................................................................ 47 
9.3.2 Grading Severity .......................................................................................................................................... 48 
9.3.3 Attributing Causality................................................................................................................................. 48 
9.4 
Handling of Expedited Safety Reports .......................................................................... 49 
9.5 
Reporting Adverse Events ................................................................................................. 49 
9.5.1 Reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) ......................... 49 
9.5.2 Follow-up of Adverse Events and Serious Adverse Events................................................. 51 
9.5.3 Reconciliation of SAEs ............................................................................................................................. 52 
9.5.4 Institutional Review Board (IRB) ...................................................................................................... 52 
10.0 PHARMACEUTICAL INFORMATION ...................................................................... 52 
10.1 Ascorbic Acid........................................................................................................................... 52 
10.1.1 Agent Accountability .............................................................................................................................. 52 
10.1.2 Mode of Action........................................................................................................................................... 52 
10.1.3 Description .................................................................................................................................................. 52 
10.1.4 Preparation ................................................................................................................................................. 53 
10.1.5 Storage ........................................................................................................................................................... 53 
10.1.6 Stability.......................................................................................................................................................... 53 
10.1.7 Route of Administration ...................................................................................................................... 53 
10.1.8 Patient Care Implications .................................................................................................................... 53 
10.1.9 Returns and Reconciliation ................................................................................................................ 54 
10.2  Olaparib .................................................................................................................................... 54 
10.2.1 Agent Accountability .............................................................................................................................. 54 
10.2.2 Mode of Action........................................................................................................................................... 54 
10.2.3 Description .................................................................................................................................................. 54 
10.2.4 Preparation ................................................................................................................................................. 55 


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10.2.5 Storage ........................................................................................................................................................... 55 
10.2.6 Route of Administration ...................................................................................................................... 55 
10.2.7 Patient Care Implications .................................................................................................................... 55 
10.2.8 Returns and Reconciliation ................................................................................................................ 55 
11.0 CORRELATIVE/SPECIAL STUDIES ....................................................................... 55 
11.1 Tumor Tissue Studies .......................................................................................................... 56 
11.2 Peripheral Blood Studies ................................................................................................... 56 
11.2.1 Circulating tumor DNA (ctDNA) ...................................................................................................... 56 
11.2.2 γH2AX foci in CTCs and/or FFPE biopsy tissues .................................................................... 57 
11.3 Urine Studies ........................................................................................................................... 57 
11.3.1 8-oxo-2’-deoxyguanosine .................................................................................................................... 57 
11.3.2 F2-Isoprostanes ........................................................................................................................................ 57 
11.4 Genomic Analysis .................................................................................................................. 58 
12.0 DATA REPORTING/REGULATORY REQUIREMENTS ..................................... 58 
12.1 Data Management ................................................................................................................. 58 
12.2 Safety Meetings ...................................................................................................................... 59 
12.3 Monitoring ............................................................................................................................... 59 
12.4 Populations of Interest ....................................................................................................... 60 
12.5 Study Documentation .......................................................................................................... 60 
12.5.1 Informed Consent and Authorization for use and Disclosure of Protected Health 
Information ................................................................................................................................................................ 60 
12.5.2 Investigator Study Files........................................................................................................................ 60 
12.5.3 Case Report Forms and Source Documentation ..................................................................... 61 
12.5.4 Retention of Study Documents......................................................................................................... 61 
12.5.5 Data Confidentiality and Subject Anonymity ........................................................................... 61 
13.0 STATISTICAL CONSIDERATIONS ........................................................................... 62 
13.1 Study Design ............................................................................................................................ 62 
13.2 Primary Endpoint Definition ............................................................................................ 63 
13.3 Secondary Endpoint Definitions ..................................................................................... 63 
13.4 Correlative Endpoint Definitions .................................................................................... 63 
13.5 Sample Size/Accrual Rate .................................................................................................. 63 
13.6 Futility and Safety Monitoring Plan ............................................................................... 64 
13.7 Analysis of Primary Endpoint .......................................................................................... 64 
13.8 Analysis of Secondary Endpoints .................................................................................... 65 
13.9 Exploratory/Correlative Analysis .................................................................................. 66 
REFERENCES ......................................................................................................................... 67 
APPENDIX A: Performance Status Criteria .................................................................. 73 
APPENDIX B: Serious Adverse Event Reporting Form ............................................. 74 
APPENDIX C: Contraception ............................................................................................. 76 
APPENDIX D: Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law .................................................... 77 
APPENDIX E: Modified Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 Criteria for Evaluating Response in Solid Tumors ............................................. 81 


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APPENDIX F: Adverse Event of Special Interest Reporting Form ......................... 84 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
To estimate the proportion of patients with metastatic castration resistant prostate cancer 
(mCRPC) having a 50% reduction in PSA from baseline (PSA50 response). 
  
2.2 
Secondary Objectives 
1) To evaluate the safety and tolerability of olaparib in combination with IV ascorbic 
acid in patients with mCRPC. 
 
2) To estimate the median time to PSA doubling from baseline of patients with mCRPC 
receiving olaparib in combination with IV ascorbic acid. 
3) To estimate the median radiographic progression free survival (rPFS) of patients 
with mCRPC receiving olaparib in combination with IV ascorbic acid. 
4) To estimate the median PSA progression free survival (PSA PFS) of patients with 
mCRPC receiving olaparib in combination with IV ascorbic acid. 
5) To assess overall survival (OS) in patients with castration resistant prostate cancer. 
 
2.3  
Exploratory Objectives 
Examine correlates that may be predictive of PSA50 response and rPFS. 
1) To quantify ctDNA and perform mutational analysis in the peripheral blood and 
compare it to any baseline germline or somatic mutations (document prestudy on case 
report form). 
2) To quantify circulating tumor cells (CTCs) in the peripheral blood at baseline, 4 weeks, 
12 weeks, and upon progression and assess γH2AX foci in CTCs. 
3) Optional γH2AX foci FFPE biopsy tissues. 
4) To measure F2-isoprostanes in the urine as a pharmacodynamic measure of oxidant 
injury at baseline, 4 weeks, 12 weeks, and upon progression. 
5) To measure 8-oxo-2’-deoxyguanosine as a measure of oxidative stress in the urine at 
baseline, 4 weeks, 12 weeks, and upon progression. 
3.0 
STUDY DESIGN 
This is a multi-center phase II study to evaluate the safety and clinical activity of the 
combination of olaparib and high-dose IV ascorbate, as second or later line of therapy, in 
castration resistant prostate cancer patients with no known DNA repair gene mutations 
(DDRm). In brief, the primary endpoint is PSA50 response, defined by a 50% reduction in 
PSA from baseline. The secondary endpoints are assessing the PSA doubling time, 
radiographic and PSA PFS, safety and tolerability as defined by the incidence of grade 3 to 5 
toxicities, and measuring overall survival. For complete endpoint definitions, see Sections 
13.2-13.4. The total accrual for this clinical trial will be 12 men with castration resistant 
prostate cancer (n=12). 
 


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Olaparib will be administered at 300 mg PO BID; ascorbate will be administered at 1 g/kg IV 
twice weekly at least 24 hours apart until objective disease progression or unacceptable 
toxicities or patient withdrawal for other reasons. 
 
The study will consist of a screening period (within 28 days of the first dose), treatment 
period, and follow-up period. Dose reductions are allowed per Section 8.2. Enrollment will 
continue until 15 subjects (allows for 3 drop outs) have received at least one dose of study 
treatment.  
4.0 
BACKGROUND 
4.1 
Disease Background 
Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading 
cause of cancer death in men. Radical prostatectomy and radiation therapy are the 
established definitive treatments for clinically localized PC; yet, 50,000 men each year 
progress with a biochemical relapse while others develop metastatic disease resulting in 
over 30,000 deaths annually. While chemical castration is temporarily effective in many 
patients, most men eventually progress to castrate-resistant prostate cancer (CRPC) and are 
then treated with docetaxel-based chemotherapy. 
 
Figure 1: Clinical states of prostate cancer1 
 
4.2  
Treatment Background 
4.2.1 Description and mechanism of action of Olaparib 
PARP functions in the DNA repair pathway, specifically by serving in base excision 
repair of DNA single strand breaks.  Inhibition of PARP results in inability for cells to 
repair single strand breaks.  Cells normally would employ the error-free 
homologous recombination pathway to repair such defects.  However, in tumors 
that harbor defects in these DNA repair genes (such as BRCA1/2), the strand breaks 
lead to chromosomal instability and eventually cell death.2  Olaparib functions in 
cells to inhibit various isoforms of PARP. 
 
Investigators should be familiar with the current olaparib (AZD2281) Investigator 
Brochure (IB). 
 


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Olaparib (AZD2281, KU-0059436) is a potent polyadenosine 5’diphosphoribose 
[poly (ADP ribose)] polymerization (PARP) inhibitor (PARP-1, -2 and -3) that is 
being developed as an oral therapy, both as a monotherapy (including maintenance) 
and for combination with chemotherapy and other anti-cancer agents. Olaparib 
[Lynparza] was approved by the FDA for treatment of men with prostate cancer 
who have deleterious or suspected deleterious germline or somatic homologous 
recombination repair gene-mutated metastatic castration resistant prostate cancer 
who have progressed on Abiraterone or Enzalutamide.  
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA 
repair mechanisms.  PARP enzymes are essential for repairing DNA single strand 
breaks (SSBs).  Inhibiting PARPs leads to the persistence of SSBs, which are then 
converted to the more serious DNA double strand breaks (DSBs) during the process 
of DNA replication.  During the process of cell division, DSBs can be efficiently 
repaired in normal cells by homologous recombination repair (HR).  Tumors with 
HR deficiencies (HRD), such as ovarian cancers in patients with BRCA1/2 mutations, 
cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates.  In such tumor types, Olaparib may offer a potentially efficacious and 
less toxic cancer treatment compared with currently available chemotherapy 
regimens.  
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, 
both in tumor models3,4 and in the clinic.5 The mechanism of action for olaparib 
results from the trapping of inactive PARP onto the single-strand breaks preventing 
their repair.6,7 Persistence of SSBs during DNA replication results in their conversion 
into the more serious DSBs that would normally be repaired by HR repair. Olaparib 
has been shown to inhibit selected tumor cell lines in vitro and in xenograft and 
primary explant models as well as in genetic BRCA knock-out models, either as 
stand-alone treatment or in combination with established chemotherapies.  
4.2.2 Description and mechanism of action of Ascorbic Acid 
The mechanism of action of ascorbic acid-mediated tumor suppression appears to 
depend on hydrogen peroxide production in extracellular fluid; hydrogen peroxide 
induces necrosis in tumor cells but not in normal cells.8 Ascorbic acid treatment 
inhibits prostate cancer cell growth through three mechanisms: (1) ascorbic acid 
induces H2O2-dependent cytotoxicity in prostate cancer cells, (2) ascorbic acid 
treatment decreased ATP levels in prostate cancer cells, and (3) ascorbic acid 
treatment induced autophagy in prostate cancer cells.9 Ascorbic acid treatment also 
suppresses metastases in hormone-refractory prostate cancer.10 Cytotoxicity of 
ascorbic acid requires mM concentrations.11 The dose response curve for ascorbic 
acid on DU-15 and PC-3 prostate cancer cells, shown below (Source: Levine, NCI 
Developmental Therapeutics Program NSC 33832), demonstrate that ascorbic acid 
was more effective for DU 145, with nearly complete kill at 10 mM and produced no 
growth for PC3.  


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Figure 2: Dose response curve for ascorbic acid in DU-15 and PC-3 prostate cancer 
cells (Source: Levine, NCI Developmental Therapeutics Program NSC 33832) 
Bioavailability of ascorbic acid is tightly controlled in response to oral 
administration and reaches only 100 μM with consumption of five servings of fruits 
and vegetables, which contain approximately 250 mg of ascorbic acid. Oral 
supplementation even at many grams does not increase plasma concentration 
beyond 250 μM. IV administration bypasses the tight controls found with oral 
administration, and produces pharmacological ascorbic acid concentrations of 25-
30 mM.12 Pharmacological ascorbic acid concentrations of 10mM can be maintained 
for approximately 4 hours with infusion rates of 0.5 – 1.0 g/kg per minute.13,8 
4.2.3 Preclinical studies of Olaparib 
The pre-clinical experience is fully described in the current version of the olaparib 
Investigator’s Brochure (IB). 
 
Olaparib has demonstrated in vitro and in vivo efficacy in preclinical studies in 
certain prostate cancer cell lines. The study of Brenner et. al. tested VCaP cells in 
vitro and as xenografts and demonstrated efficacy of olaparib monotherapy 
compared to controls.14 Efficacy in 22Rv1 cell line xenografts was similarly seen 
with olaparib in a separate study.15 These included PC3 cells14 and LNCaP cells.16 
 
4.2.4 Preclinical studies of Ascorbic acid  
Gulo-/- murine models are deficient in the enzyme responsible for in vivo ascorbic 
acid synthesis, mimicking human’s need for an exogenous source of ascorbic acid. In 
a hepatoma xenograft Gulo-/-  mouse model, ascorbic acid given orally did not inhibit 
tumor growth. However, parenteral ascorbic acid was successful in inhibiting tumor 


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growth in these mice.17 This preclinical evidence provides support for intravenous 
infusion of ascorbate.  
 
Linus Pauling first considered ascorbic acid as a treatment for cancer in the early 
1970s. However, this research stalled for several years after investigators at the 
Mayo Clinic found cancer treatment with oral ascorbate to be ineffective.18 Recent 
insight into the pharmacokinetic properties of ascorbate revealed that ascorbate 
must be administered intravenously in order to achieve plasma concentrations 
necessary to effectively kill cancer cells. With a renewed focus on intravenous 
dosing, ascorbate has proved to be lethal to and highly selective for a variety of 
cancer cell types.11 There are several mechanisms currently under investigation to 
explain how ascorbate exerts anti-cancer effect; however, a simplified model depicts 
ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate 
intracellularly and generate DNA damage.19 The complete pre-clinical experience is 
described in the current version of the Ascorbic Acid Investigator’s Brochure (IB). 
4.2.5 Preclinical evidence to support combination Olaparib and Ascorbate 
Combination IV ascorbate and PARP inhibitors shows synergy of antitumor activity 
in two CRPC xenograft models, C4-2 and 22Rv-1. These results are shown in figures 
2 and 3. 
 
Figure 3. Ascorbate enhances the killing of C4-2 and 22Rv1 cells by PARP 
inhibitors. A) C4-2 cells were seeded in IMEM and allowed to settle overnight. They 
were then treated with a range of doses for three different PARP inhibitors: olaparib 
(left), niraparib (middle), and talazoparib (right) either alone or in combination 
with a sub-lethal dose of ascorbate (1mM). B) 22Rv1 cells were seeded in DMEM 
and allowed to settle overnight. They were then treated with a range of doses for the 
same three PARP inhibitors either alone or with a sub-lethal dose of ascorbate 
(50μM).20 
 


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Figure 4. CompuSyn was used to generate a combination index. >1 denotes 
antagonism, =1 denotes an additive effect, <1 denotes synergism20 
 
An in vivo model (figure 4) demonstrated that the combination of olaparib and 
ascorbate significantly slowed tumor growth compared to vehicle controls and 
monotherapy (results shown in figure 5). 20 
 
Figure 5: In vivo model of C4-2 cells, transplanted into mice and exposed to 4g/kg 
ascorbate daily, 50 mg/kg olaparib daily, a combination of the two agents daily, or a 
control20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 6: In vivo efficacy was profound in a model using castrated mice to mimic the 
effect of hormone therapy. While there was some antitumor effect with the single 
agents, there was a significant delay in tumor doubling time when the agents were 
used in combination.20  
 
4.2.6 Clinical Efficacy and Safety of Olaparib 
Many trials have studied the clinical efficacy and safety of olaparib. The complete 
clinical experience with olaparib, including toxicology and safety pharmacology, is 
fully described in the current version of the olaparib Investigator’s Brochure.  
 
Small numbers of advanced prostate cancer patients were included in initial clinical 
studies of olaparib. In the initial phase I report on olaparib, 3 patients with prostate 
cancer were included.5 In a follow-up study of patients with germline BRCA 
mutations, 8 prostate cancer patients were included.21 
Recently, a larger cohort of prostate cancer patients treated with olaparib was 
published.22 Patients were treated with the FDA-approved dose of 400mg by mouth 
twice daily. In the trial, 50 patients were enrolled. Three patients discontinued 
olaparib due to adverse events. There were 30 adverse events of grade 3-4 level. 
Grade 3-4 events occurring in greater than 1 patient were anemia (20%), fatigue 
(12%), leukopenia (6%), neutropenia and thrombocytopenia (4%).  
Of the patients in the study, 16 were identified to have a mutation in DNA repair 
genes (BRCA1, BRCA2, ATM, FANCA, CHEK2, PALB2, HDAC2, RAD51, MLH3, ERCC3, 
MRE11, or NBN).22 Eleven of 49 evaluable patients experienced a greater than 50% 
decline in PSA (a PSA50 response). Six patients achieved a partial radiographic 
response by RECIST criteria. Every patient with a radiographic response also had a 
PSA50 response. Of these 11 responders in the study, 10 were among the patients 
with the mutations in the tested DNA repair genes. One responder was among the 
remaining 33 without an identified mutation.  
There are currently no studies published in hormone sensitive prostate cancer 
patients.  
Clinical Studies in All Diseases 
The largest pool of data for olaparib is drawn from a phase II trial of patients with 
germline deleterious BRCA 1 or 2 mutations.21 That study included 298 patients, 
including 193 with ovarian cancer and 62 with breast cancer. The analysis of the 
ovarian cancer cohort in this study led to the FDA-approved Olaparib. The overall 
tumor response rate by RECIST criteria was 26.2% across all tumor types. 
Specifically for the ovarian cancer cohort, the median response duration was 7.9 
months.  
 
 
 


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Adverse events were reported in the trial and are summarized in Table 1 below: 
Table 1. Events occurring in >15% (any grade) or >5% (grade 3-4) in the trial.21 
Adverse Event 
Any Grade Toxicity 
Grade 3-4 Toxicity 
Fatigue 
59.1% 
6.4 
Nausea 
59.1% 
0.3 
Vomiting 
37.2% 
2.3 
Anemia 
32.9% 
17.4 
Diarrhea 
27.2% 
1.3 
Abdominal Pain 
25.8% 
5.7 
Decreased Appetite 
20.8% 
0.3 
Dyspepsia 
17.4% 
0.0 
Headache 
16.1% 
0.3 
Dysgeusia 
15.8% 
0.0 
 
4.2.7 Clinical Efficacy and Safety of IV Ascorbic Acid 
Multiple phase I trials of IV ascorbic acid safety and phase I/II trials of IV ascorbic 
acid safety and efficacy in cancer patients have been published. In one trial ascorbic 
acid in elderly patients with advanced cancer who had failed all other therapies, 2 
patients had unexpectedly stable disease after 8 weeks of ascorbic acid treatment.13 
In a trial of patients with metastatic stage 4 pancreatic cancer who received primary 
therapy with ascorbic acid, gemcitabine, and erlotinib, 8 of 9 patients had tumor 
shrinkage after 8 weeks of therapy as measured by CT imaging.23 A phase I trial of 
patients with metastatic stage 4 pancreatic cancer who were treated with 
gemcitabine + IV ascorbic acid as primary therapy until tumor progression showed 
few toxicities associated with the treatment. The 9 patients had a tripling of disease 
free internal in comparison to literature controls, and doubling of survival 
compared to retrospective controls.24 In a dose escalation study, no toxicity was 
found at doses even above 1.5g/kg, the doses used in the other three trials.25 In 
addition, a phase I/II trial of high-dose, IV ascorbic acid reduced grade 1 and 2 
toxicities associated with carboplatin and paclitaxel treatment by more than 50% in 
women with ovarian cancer in a small, randomized clinical trial. Patients receiving 
IV ascorbic acid reported lower levels of low-grade gastrointestinal, hepatobiliary, 
dermatological, immune/infection, pulmonary and renal toxicities commonly 
associated with carboplatin and paclitaxel treatment.26 A trial enrolling women with 
breast cancer randomized to IV ascorbic acid or placebo, in the first year following 
surgery, showed significant reductions in nausea (p=0.022), loss of appetite 
(p=0.005), fatigue (p=0.023), dizziness (p=0.004) and hemorrhagic diathesis 
(p=0.032). Reduced toxicities were experienced by patients independent of whether 
they were being treated with chemotherapy.27 Similarly, a phase I/II study of 
arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of 
relapsed or refractory multiple myeloma with ascorbic acid IV on days 1, 4, 8, and 
11 demonstrated a response rate of 27% in a heavily pretreated population. 
Ascorbic acid demonstrates activity at twice a week dosing.28 Taken together, these 
data support the starting dose of 1g/kg of ascorbic acid in patients with CRPC and 
mCRPC. 
 


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Intravenous ascorbic acid is in wide use by practitioners of complementary and 
alternative medicine. Estimates are that in the US approximately 10,000 patients 
receive IV ascorbic acid each year at average doses of 0.5/kg, with average number 
of doses of twenty per patients. Using multiple tracking mechanisms, minimal 
adverse events were reported in properly screened patients.29 
4.2.8 Clinical efficacy and safety of combination Olaparib and IV Ascorbate 
This trial seeks to assess the combination of olaparib and IV ascorbic acid in men 
with castration resistant prostate cancer. There is no clinical data to support this 
combination at this time as these two agents have not been combined in the past to 
treat castration resistant prostate cancer. The CRPC patient population is in 
desperate need of new treatment options, and the in vitro and in vivo data suggest 
that the combination of olaparib and ascorbate may be effective. The proposed 
clinical trial aims to determine the safety, tolerability, and provide preliminary data 
on efficacy of combining olaparib with intravenous ascorbate for the treatment of 
advanced prostate cancer.  
 
A drug-drug interaction between ascorbic acid and olaparib is not anticipated based 
on drug metabolism and drug transporters. Olaparib metabolism is primarily 
mediated by CYP3A4/5. Clinical drug-drug interactions have been noted with strong 
or moderate CYP3A4 inhibitors or a moderate CYP3A4 inducer. Olaparib is a 
substrate for Pgp. Olaparib is an inhibitor of CYP3A4, UGT1A1, Pgp, OATP1B1, OCT1, 
OCT2, OAT3, MATE1, and MATE2K in vitro. Olaparib is an inducer of CYP1A2, 
CYP2B6 (potentially clinically relevant), CYP3A4, and P-gp. Ascorbic Acid is 
reversibly oxidized to dehydroascorbic acid (DHA) and metabolized to inactive 
compounds including ascorbic acid-2-sulfate and oxalic acid. No drug interactions 
have been noted via the CYP450 pathway.  Ascorbic acid is a substrate of two 
sodium-ascorbate co-transporters (SVCT; both members of the SLC23 family).30  
Oxalic acid is a substrate of OAT331 and inhibitor of  OATP1B132.  There is a potential 
for an interaction via the drug transporters at the oxalic acid level but would not be 
anticipated to be clinically relevant. Therefore, a formal pharmacokinetic 
assessment will not be conducted. 
  
4.3 
Rationale for combination Olaparib and Ascorbic Acid 
There is significant evidence supporting single agent tumor stability of olaparib in DNA 
repair mutant prostate cancer and of the effectiveness of ascorbate in reducing toxicities of 
chemotherapy. The ability to manipulate DNA damage repair has made PARPi an attractive 
option for combination with DNA damaging agents, such as ascorbate. We therefore 
hypothesize that ascorbate’s ability to generate damage-inducing ROS would benefit from 
the addition of a PARP inhibitor designed to impede a tumor cell’s ability to repair DNA 
damage. Historically, response to olaparib was 88% in HRD+ and 6% in HRD- mCRPC 
patients.22 Per the data described in Section 4.2, as well as data from Ma et al26, we 
hypothesize that the combination of olaparib and ascorbic acid will synergize and increase 
efficacy to be greater than 6% with acceptable toxicities. 
 


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5.0 
PATIENT SELECTION 
5.1 
Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
 
[1] Have metastatic castration-resistant prostate cancer (prostate cancer progressing by 
PSA  (rise by 25% on prior therapy) or imaging despite castrate levels of testosterone 
[<50 ng/dL] using standard measures of progression defined by Prostate Cancer 
Working Group33). 
 
[2] Have a minimum PSA of 1 ng/mL. 
 
[3] Have a pathological diagnosis of prostate carcinoma. 
 
[4] Have been receiving and will continue to receive continuous hormonal ablation with 
surgical or medical castration with baseline testosterone <50ng/dL. 
 
[5] May be receiving bone-targeted agents. 
 
[6] May have received multiple lines of therapy including radium 223, sipuleucel T, and up 
to 2 lines of chemotherapy (One of 2 lines may be for hormone sensitive metastatic 
prostate cancer or both can be for castration resistant). 
 
[7] Age > 18. 
 
[8] Have ECOG performance status 0-1 (Appendix A). 
 
[9] Be able to take oral medication and willing to consider a port for ease of administration 
of ascorbate. 
 
[10] Must have progressed on one systemic line of treatment (can include LHRH 
agonist/antagonist or orchiectomy and at least one additional line of therapy 
(abiraterone, enzalutamide, apalutamide, darolutamide, docetaxel, etc)). 
 
[11] Have normal organ and marrow function measured within 28 days prior to 
administration of study treatment as defined below: 
 
- Absolute neutrophil count  
>1.5 x 109/L 
 
-Platelets  
 
 
> 100,000/mm³ 
 
-Hemoglobin  
 
> 9g/dL with no blood transfusion in the  
past 28 days 
 
-Total bilirubin 
 
< 1.5 x ULN 
-AST (SGOT)/ALT(SGPT) 
< 2.5 x ULN (<5x ULN if with known liver             
metastases provided bilirubin is normal 
-Creatinine 
< 1.6 x ULN (for patients with >1.6 x ULN, calculated 
or measured creatinine clearance must be > 60 
mL/minute (Cockcroft-Gault). 
 


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[12] Men of reproductive potential and those who are surgically sterilized (i.e. post- 
vasectomy) must agree to practice effective barrier contraception that has an expected 
failure rate of <1% during and for 6 months after discontinuation of study treatment. 
Female partners should also use a highly effective form of contraception ([see 
Appendix C for acceptable methods]) if they are of childbearing potential. 
o If condoms are used as a barrier contraceptive, a spermicidal agent should be 
added to ensure that pregnancy does not occur. 
[13] Have the ability to understand and have given written informed consent before 
performance of any study-related procedures not part of normal medical care, with the 
understanding that consent may be withdrawn by the subject at any time without 
prejudice to future medical care.  
5.2 
Exclusion Criteria 
Patients are ineligible to be included in the study if they: 
[1] Have a known DNA repair mutation (minimum list of genes that must be mutation 
negative for inclusion: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, 
FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). In addition, patients who have 
not completed germline and somatic testing to rule out such a mutation are ineligible 
until they have completed testing. If tissue or liquid ctDNA sequencing was not 
previously done, testing using the Foundation One liquid biopsy test or an equivalent 
FDA-approved test is acceptable as standard of care. 
• 
DNA repair mutation variant of unknown significance (VUS) allowed. 
[2] Have had known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
[3] Have symptomatic uncontrolled brain metastases.  A scan to confirm the absence of 
brain metastases is not required. The patient can receive a stable dose of corticosteroids 
before and during the study as long as these were started at least 4 weeks prior to 
treatment.  Patients with spinal cord compression unless considered to have received 
definitive treatment for this and evidence of clinically stable disease for 28 days. 
[4] Have had prior olaparib, rucaparib, or other PARP inhibitor. 
[5] Have had major surgery within 2 weeks of dosing of investigational agent. 
[6] Have had palliative radiation or another biological cancer therapy within 3 weeks prior 
to the first dose of study drug (2 week wash out required). 
[7] Are receiving any systemic chemotherapy or radiotherapy within 3 weeks prior to study 
treatment. 
[8] Have received other investigational drugs within 14 days prior to enrollment. 
[9] Is expected to require chemotherapy or radiation for pain palliation in the next 12 
weeks. 


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[10] Have used or plan concomitant use of the following medications in the past 6 months 
prior to enrollment: 5-alpha reductase inhibitors unless subject has been taking stable 
dose of medication for prior 6 months. 
[11] Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting study treatment is 2 weeks. See the following link for a complete 
list of known CYP3A inhibitors: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
[12] Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or 
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout 
period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital 
and 3 weeks for other agents. See the following link for a complete list of known CYP3A 
inhibitors: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
[13] Have moderate or severe cardiovascular disease: 
• 
Has the presence of cardiac disease, including a myocardial infarction within six 
months prior to study entry, unstable angina pectoris, New York Heart Association 
Class III/IV congestive heart failure, or uncontrolled hypertension. 
• 
Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as 
judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic 
arrhythmia, congestive heart failure, QTc prolongation >500 ms, electrolyte 
disturbances, etc.), or patients with congenital long QT syndrome. 
[14] Have uncontrolled intercurrent illness, including but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
[15] Have other malignancy unless curatively treated with no evidence of disease for >5 
years except adequately treated non-melanoma skin cancer. 
[16] Have persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE 
v5.0) grade 2) caused by previous cancer therapy, excluding alopecia. 
[17] Patients with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
[18] Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples 


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include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 
months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal 
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung 
disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric 
disorder that prohibits obtaining informed consent. 
[19] Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
[20] Immunocompromised patients, e.g., patients who are known to be serologically 
positive for human immunodeficiency virus (HIV). 
[21] Patients with known active hepatitis (i.e. Hepatitis B or C). 
[22] Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
[23] Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product.  
 
5.3 
Inclusion of Minorities and Women and Children 
Since prostate cancer is only a disease of men, only male patients will be enrolled. Men from 
all ethnic groups are eligible for this trial. The Sidney Kimmel Comprehensive Cancer Center 
at Johns Hopkins serves a prostate cancer population in which approximately 25% of these 
patients are African Americans. We anticipate that enrollment in this study will be reflective 
of our usual patient population. Minority patients who meet the eligibility requirements will 
be actively recruited to participate in the study. This study was designed to encourage 
minority accrual but was not designed to measure differences in racial or ethnic 
populations.  
6.0 
REGISTRATION 
6.1 
General Guidelines 
Potential study subjects will be identified and screened by the study team. Eligible patients 
will be consented prior to treatment initiation. Eligible, consented patients will be entered 
on study centrally at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins by 
the Lead Study Coordinator. Patient names and identifying information will only be linked 
in the CRMS (Clinical Research Management System) database, which is accessible through 
a password-protected encrypted university server. All sites should email Harry Cao  
hcao7@jhmi.edu to verify slot availabilities.  
 
Issues that would cause treatment delays should be discussed with Dr. Paller. If a patient 
does not receive protocol therapy within 7 days following registration, the patient’s 
registration on the study may be canceled. The Study Coordinator should be notified of 
cancellations as soon as possible.  


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6.2 
Registration Process 
Eligible patients will be entered on study centrally at the Sidney Kimmel Comprehensive 
Cancer Center at the Johns Hopkins University by the Lead Study Coordinator.  All sites 
should email Harry Cao at hcao7@jhmi.edu to verify drug availabilities.  The Registration 
Form, and Eligibility Worksheet will be supplied to each participating site.  
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Coordinating Center should be notified of 
cancellations as soon as possible.  
To register an eligible, consented patient, the following documents should be completed by 
the Research Nurse or Study Coordinator and emailed to the monitors Harry Cao at 
hcao7@jhmi.edu. 
• 
Signed patient consent form 
• 
Eligibility Screening Checklist 
• 
Copies of the prostate cancer pathology report 
• 
Copies of PSA and Testosterone results to determine eligibility 
• 
Copy of required screening labs and scans 
• 
Physician note that indicated prior therapies 
• 
Other materials may also be sent if considered pertinent for confirming patient 
eligibility 
The Research Nurse or Study Coordinator at the participating site will then email the 
monitors to verify eligibility. To complete the registration process, the monitors will: 
• 
Assign a patient study number 
• 
Register the patient on the study 
• 
Email the registration confirmation to the participating site 
7.0 
TREATMENT/INTERVENTION PLAN 
The following assessments and procedures will occur during the study. A schedule of 
assessments is provided in Section 7.1 
 
7.1  
Study Calendar 


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Required Studies
Pre-study 14
EOT14, 16
LONG TERM FU17
Screening
C1D114, 15
C1D8
C1D1514
C1D2214
CnDn20
Visit Windows (days)1
-28
+/-3
+/-3
+/- 3
+/- 3
+/- 3
-28
+/-28
TREATMENT
Olaparib
X
X
X
X
X
Ascorbic acid2,3
X
X
X
X
X
ELIGIBILITY
Inclusion/exclusion review
X
HRR status19
X
Informed consent 
X
ECG
X
PHYSICAL
Medical and Cancer History
X
Physical Exam, Weight and ECOG 4
X
X
X
X
X
X
X
X
Vital Signs5
X
X
X
X
X
X
X
X
AE/Toxicity Notation4
X
X
X
X
X
X
X
Concurrent meds4
X
X
X
X
X
X
X
X
LABORATORY
Chemistry6,7
X
X
X
X
X
X7
X
X
Hematology6,7
X
X
X7
X
X
Urinalysis
X
INR and PT/APTT18
X
Urine Creatinine8
X8
X8
X8
X8
Testosterone
X
PSA7
X
X
X7
X
X
G6PD9
X
CORRELATIVE 
Blood Samples10, 12
NA
X10
X10
X10
Urine Samples11, 12
NA
X11
X11
X11
Optional Biopsy (Encouraged)
X12
N/A
X12
DISEASE ASSESSMENT
Radiologic Evaluation/ RECIST 1.113  or PCWG2
X13
X13
X13
LONG TERM FOLLOW-UP17
X17
1 cycle = 28 days


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1 
Longer delays to be approved by the study sponsor. IRB approval is required for all eligibility waivers prior to enrollment. The window for the baseline 
Radiologic Evaluation/RECIST 1.1 is 6 weeks prior to C1D1.  
2 
Each treatment cycle is 4 weeks (28 days). Ascorbic Acid dosing must be 2 times per week except week 1 when Olaparib is giving alone. The first infusion 
must occur on day 1 of each cycle and the second infusion can occur any other day during the week as long as it is at least 24 hours from the prior 
infusion.  
3 
Ports are recommended but not mandatory due to the frequency of infusion.  
4 
After screening, physical exams may be limited as indicated by symptoms. ECOG – Eastern Cooperative Oncology Group performance status. Physical 
exam (including vital signs and weight), ECOG status, AE/Toxicity notation and concurrent medication review have a -3 day window of day 1 of the cycle.  
5 
Vital signs will be collected prior to infusion. Vital signs include temperature, blood pressure, respiration rate, and heart rate. Height is collected pre-
study only. There is a -3 day window of day 1 of each cycle that the vital signs can be collected within.  
6 
Clinical Hematology: CBC with differential ANC, ALC, AEC, and platelet count; Serum Chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, ALT, AST, alkaline phosphatase, total bilirubin, total protein, albumin, calcium.  
7 
Safety labs and PSA may be collected within a window of up to 3 days prior to scheduled visit/dosing. As of Cycle 2 and further cycles: at Day 1 visit, 
hematology and chemistry should be collected per hold parameters; at Days 8, 15, and 22 visits, only chemistry will be collected per hold parameters 
(hematology does not need to be drawn on Days 8, 15, and 22 unless clinically indicated). After C1D1, PSA is collected at CnD1 only (i.e., not weekly).  
8 
Urine creatinine will be collected at C1D1, C2D1 (4 weeks), C4D1 (12 weeks), and at EOT.  
9 
 G6PD testing: Red blood cell hemolysis may occur in people found to be deficient in the G6PD enzyme. 
10 
Up to 50mL of whole blood will be collected for ctDNA analysis at each time point. Blood samples should be drawn at screening (or pre-dose C1D1), 
C2D1 post infusion (4 weeks), C4D1 (12 weeks) post infusion, and at EOT. Bloods do not need to be collected at C1D1 if they were collected within 7 days 
prior to the visit.  γ H2AX will also be assessed at C1D1, C1D8, C2D1, C4D1 and progression. 
11 
Urine samples of up to 15mL will be collected to assess F2-isoprostanes and 8-oxo-2’-deoxyguanosine at screening (or pre-dose C1D1), C2D1 (4 weeks), 
C4D1 (12 weeks), and at EOT. Urine samples do not need to be collected at C1D1 if they were collected within 5 days prior. 
12 
Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff. An optional biopsy at baseline 
and at C4D1 (+/- 2 weeks) will be performed to look for γH2AX in tissue.  
13 
CT scan (chest/abdomen/pelvis or MRI if patient has contrast allergy) and bone scan to be assessed at baseline and every 12 weeks (+/- 1 week), and at 
EOT (if clinically indicated by PI/Sub-I). 
14 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person clinical trial visits or portions of 
clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to initiating 
telemedicine for study visits, the study team will explain to the participant what a telemedicine visit entails and confirm that the study participant is in 
agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of 
Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be 
conducted using HIPAA compliant methods approved by the Health System and within licensing restrictions. 
15 
There is a -7 day window to draw C1D1 labs. 
16 
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17 
Subjects who discontinued study treatment without documented disease progression should continue to be monitored for disease status by radiologic 
imaging.  Disease monitoring should continue to be assessed every two months (+/- 2 weeks) until: 1) start of a new antineoplastic therapy (information 
of the new cancer therapy will be collected), 2) disease progression, 3) death, 4) withdrawal of consent, or 5) study closure, whichever occurs first.  
Survival status and subsequent therapies will be collected during long term follow-up (LTFU) every 6 months (+/- 4 weeks) from the date of last 
treatment, by phone or chart review, for 3 years or until study closure. Gather date of death, date of radiographic and/or PSA progression, start and stop 
dates for subsequent therapies.  
18 
INR and PT/APTT will be performed at baseline and at subsequent timepoints if clinically indicated. 
19 
HRR status will be determined by evaluating patients for mutations in the genes ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, 
PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. DNA repair mutation variants of unknown significance will be allowed. Mutation status of these genes 
will be determined with standard of care tests, such as Invitae, Color, or Foundation One, using germline and somatic testing.  Tissue (prostatectomy or 
metastatic biopsy for somatic or germline testing), blood (somatic or germline) or saliva (germline) are all acceptable for standard of care testing prior 
to enrollment. Germline test results will be confirmed with somatic testing. If tissue is not available, confirmation testing using Foundation One liquid 
biopsy test or an equivalent FDA-approved test is acceptable. The type of test and results for each individual patient will be captured in the appropriate 
CRF in the database.  
20 
For all subsequent cycles, patients will repeat the four visits listed for Cycle 1 (CnD1, CnD8, CnD15, CnD22). 
 
 


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7.2 
Screening/Pretreatment Assessment (up to Day -28) 
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent to the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, patients should be asked to 
sign and date a Notice of Privacy Practice research authorization/HIPAA form and an IRB-
approved statement of informed consent that meets the requirements of the Code of 
Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50).  
The following assessments will be performed at the screening visit: 
• 
Obtain informed consent and research authorization. 
• 
Record demographics (including age) and medical history (including prior 
treatment for prostate carcinoma). 
• 
Conduct physical exam (including vital signs, height/weight). 
• 
Obtain history regarding prior treatment history for prostate cancer (including 
history of ADT, and history of radiation therapy or other local therapy). 
• 
Obtain histologic/radiographic confirmation of disease. If radiographic studies have 
not been performed within 6 weeks prior to Cycle 1 Day 1, they must be obtained as 
part of screening. 
• 
Perform laboratory tests: complete blood count w/diff, PSA, comprehensive 
metabolic panel, urinalysis, G6PD, testosterone. 
• 
Baseline ECG 
• 
Confirmation of 25% PSA rise on prior therapy. 
• 
Determine suitability for olaparib and ascorbate therapy. 
• 
Discuss concurrent medications. 
Relevant information should be documented for registration and monitoring purposes.  The 
institutional registration should be finalized, and appropriate documents faxed or emailed 
to the lead site/sponsor per Section 6.0.     
Information for patients who do not meet the eligibility criteria to participate in this study 
(i.e. screening failures) should be captured in consortium database at the pretreatment 
assessment. 
For any subject that has a DNA repair gene mutation identified during screening and is 
therefore not eligible for this trial will be referred to medical genetics for counseling and 
consideration of further targeted testing to determine if the identified mutation is present 
in the germline. 
7.3 
Treatment/Intervention Period  
Patients will be seen on D1 of each cycle of study therapy (consisting of 28 days +3 days). 
The following assessments will be performed at each visit: 
• 
Conduct physical exam (including vital signs, weight) 
• 
Obtain and medical history changes from prior assessment 
• 
Assess performance status (ECOG). (Appendix A) 
• 
Review concurrent medications  


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7.3.1 Clinical, Laboratory, and Radiographic Assessments 
Every week, patients will have a non-fasting blood drawn for the values listed 
below. Repeat labs are not needed on C1D1 as long as visit is within 7 days of 
screening visit blood draw. 
• 
CMP 
Note: Patients with creatinine clearance between 51-100 mL/min either at trial 
enrolment or during the course of the trial should be monitored every week for 
laboratory assessment and toxicity evaluation. 
On Day 1 of each cycle, patients will have a non-fasting blood drawn for the values 
listed below. Repeat labs are not needed on C1D1 as long as visit is within 7 days of 
screening visit blood draw. 
• 
CBC 
• 
PSA 
Every 3 cycles, patients will have radiographic studies: 
• 
CT chest, abdomen, and pelvis with contrast 
• 
NM bone scan 
Laboratory Safety Assessments 
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], 
platelets, mean cell volume [MCV], mean cell hemoglobin concentration [MCHC], 
mean cell hemoglobin [MCH], white blood cells [WBC], absolute differential white 
cell count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and 
absolute neutrophil count or segmented neutrophil count and Band forms should be 
performed at each Day 1 visit and when clinically indicated. If absolute differentials 
not available, please provide % differentials. Coagulation [activated partial 
thromboplastin time (APTT) and international normalized ratio (INR)] will be 
performed at baseline and if clinically indicated. Patients taking warfarin may not 
participate in this study. 
Biochemistry assessments for safety (sodium, potassium, calcium, glucose, 
creatinine, total bilirubin, gamma glutamyl transferase [GGT], alkaline phosphatase 
[ALP], aspartate transaminase [AST], alanine transaminase [ALT], urea or blood 
urea nitrogen [BUN], total protein, albumin) should be performed at each Day 1, Day 
8, Day 15, and Day 22 visit. 
Urinalysis by dipstick should be performed at baseline and at subsequent 
timepoints  only if clinically indicated. Microscopic analysis must be performed by 
the hospital’s local laboratory if required. 
Bone marrow or blood cytogenetic samples may be collected from patients with 
prolonged hematological toxicities as defined under Section 8.2.2.3 Dose 
Modifications for Toxicities. 
Additional analyses may be performed if clinically indicated. 


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Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. 
In case a subject shows an AST or ALT >3xULN or total bilirubin >2xULN please 
refer to Appendix D ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions.  
7.3.2 Safety Assessments 
Adverse events (AEs) will be monitored at each scheduled visit and throughout the 
study.  Toxicity will be assessed using the most recent National Cancer Institute 
(NCI) guidance: the most recent version of the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0.  
 
7.3.3 Study Treatment 
Treatment information is detailed in Agent Administration (Section 7.6). 
7.4 
Duration of Therapy and Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed apply. The reason for 
study removal and the date the patient was removed must be documented in the Case 
Report Form.  
 
In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
• 
Disease progression by RECIST criteria v1.1 (Appendix E) or bone progression per 
PCWG3 (see Section 7.4.1) 
• 
Disease progression by symptomatic assessment 
• 
PSA doubling from baseline value, confirmed by a second value at least 4 weeks 
apart, with a minimum time since initiation of therapy of 12 weeks (see Section 
7.4.1) 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s): toxicity (defined in Section 8.1) that has not 
recovered in 2 weeks or if the same toxicity recurs at the decreased dose (unless 
there is strong evidence of clinical benefit to justify continuation of dosing with 
study treatment, and the rationale must be discussed with the Principal Investigator 
before a decision is made) 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment 
• 
If, in the opinion of the Investigator, a change or temporal or permanent 
discontinuation of therapy would be in the best interest of the subject 
• 
Patient is noncompliant with respect to taking drugs, keeping appointments, or 
having tests required 
• 
for the evaluation of drug safety and efficacy Bone marrow findings consistent with 
myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) 
• 
Potential Hy’s Law cases (AST or ALT >3x ULN and TBL >2x ULN with no other 
reason) 
Because an excessive rate of withdrawals can render the study uninterpretable, 
unnecessary withdrawal of patients should be avoided. When a patient discontinues 


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treatment early, the investigator should make every effort to contact the patient and to 
perform a final evaluation. The reasons for withdrawal should be recorded. 
7.4.1 Disease Progression 
Progression will be evaluated on the basis of biochemical, radiographic, or 
symptomatic progression based on PCWG3 criteria, or by PSA doubling from 
baseline. Determinations of disease progression will be made by the investigator.  
 
Progression will be defined as follows: 
1. Radiographic progression defined by at least one of the following: 
• 
Soft tissue disease progression by modified RECIST criteria v.1.1 (See 
Appendix E) 
• 
Development of two or more new bone lesions not consistent with tumor 
flare per PCWG3. (If unclear, can repeat a bone scan in 6 weeks.) 
2. Symptomatic or clinical progression defined by one of the following: 
• 
Development of a skeletal related event (SRE) defined as pathologic fracture, 
spinal cord or nerve root compression, palliative radiation to bone, or 
surgery to bone 
• 
Worsening pain due to CRPC unable to be controlled by non-narcotic or 
narcotic medications 
• 
Sustained worsening of ECOG status resulting from CRPC (e.g., 2 to 3) 
• 
Treating physician decided to initiate new systemic anti-cancer therapy 
3. PSA doubling from baseline value, confirmed by a second value at least 4 weeks 
apart, with a minimum time since initiation of therapy of 12 weeks 
We will encourage investigators to continue study treatment until radiographically 
confirmed disease progression or PSA doubling from baseline requires initiation of 
new systemic antineoplastic therapy.  
7.4.2 EOT Visit 
Upon treatment discontinuation, patients will have an EOT Visit within 28 days of 
the last dose of ascorbic acid or olaparib, whichever is later. This visit will consist of 
the following: 
• 
Conduct physical exam (including vital signs, weight) 
• 
Perform laboratory tests: complete blood count w/diff, PSA, comprehensive 
metabolic panel 
• 
Assess performance status (ECOG) (Appendix A) 
• 
Review concurrent medications 
• 
Assess AEs 
• 
If patient is discontinuing participation in study, perform radiographic tests: 
CT C/A/P and NM bone scan (if these have not been performed in the prior 3 
months) 
• 
Blood and urine research samples 
 


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7.5 
Duration of Follow Up 
Subjects will be followed for adverse events for a minimum of 30 days after the last dose of 
study drug or death, whichever occurs first. Subjects removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event, 
initiation of new therapy for their cancer, or death, whichever occurs first. 
 
Subjects who discontinued study treatment without documented disease progression 
should continue to be monitored for disease status by radiologic imaging.  Disease 
monitoring should continue to be assessed every two months (+/- 2 weeks) until: 1) start of 
a new antineoplastic therapy (information of the new cancer therapy will be collected), 2) 
disease progression, 3) death, 4) withdrawal of consent, or 5) study closure, whichever 
occurs first. 
 
Details of first and subsequent therapies for cancer and/or details of surgery for the 
treatment of cancer, after discontinuation of treatment, may be collected. Reasons for 
starting subsequent anti-cancer therapies including access to other PARP inhibitors or 
investigational drugs will be collected and included in the exploratory assessments of 
survival.  
7.5.1  Long Term Follow-Up 
Survival status and subsequent therapies will be collected during long term follow-
up (LTFU) every 6 months (+/- 4 weeks), by phone or chart review, for 3 years or 
until study closure. Additionally, the following data will be collected: date of death, 
date of radiographic and/or PSA progression, start and stop dates for subsequent 
therapies. 
7.6 
Agent Administration 
Treatment will be administered on an outpatient basis. Expected adverse events and 
potential risks are described in Section 7.9. Appropriate delays and modifications are 
described in Section 8.1 and Section 8.2, respectively. Events that result in dose 
adjustments for each drug (i.e. increases, decreases, delaying, or omitting therapy) related 
to the AE after therapy has been initiated or AEs because of other therapies, such as surgery 
and radiation therapy, are considered treatment-limiting adverse events. Treatment-
limiting adverse events for ascorbic acid and olaparib are described in Section 8.1. No 
investigational or commercial agents or therapies older than those described below may be 
administered with the intent to treat the subject’s malignancy. The drug regimen for this 
trial is shown below in Table 2.  
Table 2: Regimen Description 
 
Regimen Description 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Olaparib1 
300 mg 
Oral 
Twice daily, 
days 1-28 
28 days (4 
weeks) 
Ascorbic Acid 
1 g/kg 2 
0.75-1 gram 
per minute IV3 
Twice weekly4 
First dose on 
day 1 of the 
cycle 


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1. Olaparib: two 150 mg tablets orally, with or without food, twice daily. The tablets are to be 
swallowed whole (do not chew, dissolve, or open the tablets). Administration should be in accordance 
with the package insert.34 
2.  For a subject weighing 75 kg, the goal dose is 75 grams (1 g/kg), and the titrated dose schedule is 
18.75 g, 37.5 g, and 56.25g for cycle 1 only. Rounding the calculated doses to 19 g, 38 g, and 56 g is 
acceptable. Subsequent doses would be 75 g. The maximum allowed dose for patients weighing over 
100 kg is 100 g.  
3.  Infusion time is approximate (± 15 minutes) and may need to be adjusted based on patient 
tolerability. Infusion time is estimated to be between 90-120 minutes. 
4.  The ideal schedule for ascorbic acid is 3-4 days apart for administration. However, ascorbic acid can 
be safely administered on consecutive days (at least 24 hours apart). The day that ascorbic acid can be 
administered can be shifted in the event of holidays, inclement weather, and other reasons for clinic 
closure to even three consecutive days. 
 
Subsequent ascorbic acid infusions may not be given less than 24 hours apart.  
 
Acute reactions will be managed using standard therapy for acute drug reactions as 
per institutional standard of care. 
 
7.6.1 Olaparib Administration 
 
Patients will be administered olaparib twice daily at 300mg continually. Two 150mg 
olaparib tablets should be taken twice daily at the same time each day, 
approximately 12 hours apart with one glass of water. The olaparib tablets should 
be swallowed whole and not chewed, crushed, dissolved, or divided. Olaparib 
tablets can be taken with or without food.  
7.6.2 Ascorbic Acid Administration 
 
For the first cycle, on cycle 1 day 8, collect blood for CTCs and then start Ascorbic 
Acid. The first three doses of ascorbic acid will be titrated as such: 0.25 g/kg, 0.5 
g/kg, 0.75 g/kg in 1000ml of sterile water (not to exceed 500 mL per hour). If 
tolerated, the subsequent doses will be 1 g/kg. Infusions will be twice a week, and 
should not be less than 24 hours apart. It is recommended that ascorbic acid be 
given through a port due to frequency of infusion, but a port is not required.  
 
7.7 
Concomitant, Supportive, and Restricted Medication and Supportive Care 
Guidelines 
The use of any natural/herbal products other than traditional remedies should be 
discouraged, but use of these products, as well as any medication or vaccine including over-
the-counter or prescription medicines, vitamins, and/or herbal supplements that the 
patient is receiving at the time of enrolment or receives during the study must be recorded 
in the case report form (CRF), along with reason for use, dates of administration including 
start and end dates, and dosage information including dose and frequency. Supportive care, 
including but not limited to anti-emetic medications, may be administered at the discretion 
of the Principal Investigator or Co-Investigators. Concurrent treatment with 
bisphosphonates is allowed. All concomitant treatments, including blood and blood 
products, must be reported on the case report form (CRF).  
 


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In order to better differentiate adverse events related to investigational study agents from 
those related to the COVID-19 vaccine, it is recommended where possible, that subjects not 
receive any dose of the COVID-19 vaccine within 3 days of study drug. If a live COVID-19 
vaccine becomes available to the public, an exemption specifically for live COVID-19 
vaccines will be discussed with the Protocol Manager.  
 
Restricted concomitant medications 
Medications prohibited 6 months prior to enrollment  
5-alpha reductase inhibitors are allowed if subject has been taking stable dose of 
medication for prior 6 months.  
Strong or moderate CYP3A inhibitors 
Known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should 
not be taken with olaparib. See this link for a complete list of known CYP3A inhibitors: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers. During the study, if co-
administration or a strong or moderate inhibitor is required because there is no suitable 
alternative medication, dose of olaparib should be reduced for the period of concomitant 
administration.  
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg twice daily for the 
duration of concomitant therapy with the strong inhibitor and for 5 half-lives 
afterwards. 
• 
Moderate CYP3A inhibitors - reduce the dose of olaparib to 150 mg twice daily for 
the duration of concomitant therapy with the moderate inhibitor and for 3 half-lives 
afterwards. 
• 
After the washout of the inhibitor is complete, the olaparib dose can be re-escalated.   
Strong or moderate CYP3A inducers 
Strong (e.g. phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St. John’s Wort) and moderate (e.g. bosentan, efavirenz, 
modafinil) CYP3A inducers should not be taken with olaparib. See this link for a complete 
list of known CYP3A inhibitors: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers. 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. 
Based on limited in vitro data, olaparib may reduce the exposure to substrates of 2B6 (and 
potentially substrates of CYP2C9, CYP2C19 and P-gp).  
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Appropriate clinical monitoring is recommended for patients receiving P-gp substrates or 
CYP3A substrates with a narrow therapeutic margin concomitantly with olaparib. 
Examples of substrates include: 
• 
CYP3A4 substrates with narrow therapeutic margin: e.g. cisapride, cyclosporine, 
ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and warfarin.  
• 
Sensitive CYP3A4 substrates: e.g. buspirone, felodipine, fluticasone, lovastatin, 
quetiapine, saquinavir, sildenafil and simvastatin.  
• 
CYP2B6 substrates: e.g. bupropion and efavirenz. 
• 
OATP1B1 substrates: e.g. bosentan, glibenclamide, repaglinide, statins and valsartan. 
• 
OCT1, MATE1 and MATE2K substrates: e.g.  metformin. 
• 
OCT2 substrates: e.g. cimetidine and metformin. 
• 
OAT3 substrates: e.g. furosemide and methotrexate. 
• 
BCRP substrates: e.g. methotrexate and rosuvastatin. 
• 
P-gp substrates: e.g. simvastatin, pravastatin, dabigatran, digoxin and colchicine. 
Anticoagulant Therapy 
Patients who are taking warfarin may not participate in this trial due to potential warfarin 
resistance due to its interaction with ascorbic acid.35,36 Non-vitamin K antagonist oral 
anticoagulants (NOACs), subcutaneous heparin and low molecular weight heparin may be 
given concomitantly with olaparib and INR monitoring is not required. If NOACs are used, it 
is preferable to avoid CYP3A substrates (e.g. apixaban and rivaroxaban) if possible. 
Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting, and/or diarrhea, then these symptoms should be 
reported as AEs (see Section 9.5) and appropriate treatment of the event given.  
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including 
investigational agents, while on study treatment. No other anti-cancer therapy 
(chemotherapy, immunotherapy, hormonal therapy (Hormone replacement therapy [HRT] 
is acceptable), radiotherapy, biological therapy or other novel agent) is to be permitted 
while the patient is receiving study medication. 
Vaccines 
Live virus and live bacterial vaccines should not be administered whilst the patient is 
receiving study medication and during the 30 day follow up period.  An increased risk of 
infection by the administration of live virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with olaparib are unknown.  
Other prohibited products 
It is prohibited to consume grapefruit juice while on olaparib therapy. Patients must not 
consume grapefruit or Seville oranges while on treatment with olaparib.  
See Table 3 for summary of Prohibited Medications. 


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Table 3: Prohibited medications 
Prohibited medication/class of drug: 
 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Hormonal therapy 
Radiotherapy (except palliative) 
Biological therapy 
Other novel agents 
Not permitted while the patient is receiving study 
medication 
Live virus vaccines 
Live bacterial vaccines 
Not permitted while the patient is receiving study 
medication and during the 30 day follow up period.  
An increased risk of infection by the administration 
of live virus and bacterial vaccines has been 
observed with conventional chemotherapy drugs 
and the effects with olaparib are unknown. 
 
7.8  
Contraception 
Male patients must use a condom during treatment and for 3 months after the last dose of 
olaparib when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male patients should also use a highly effective 
form of contraception (as described in Appendix C) if they are of childbearing potential.  
Male patients should not donate sperm throughout the period of taking olaparib and for 3 
months following the last dose of olaparib. 
For details of acceptable methods of contraception refer to Appendix C Acceptable Birth 
Control Methods. 
7.9 
Expected Adverse Events 
 
 
7.9.1 Ascorbic Acid 
Too rapid intravenous administration of the solution may cause temporary 
faintness or dizziness.  
 
The most common side effects of ascorbic acid include: pain and swelling at 
administration sites, nausea, vomiting, diarrhea, dry mouth, loss of appetite, muscle 
weakness, dizziness, headache, phlebitis, hypertension, fatigue, and leakage of 
protein.  
 
Less common side effects of ascorbic acid include: acute and chronic nephropathy, 
kidney stones, renal failure, hypernatremia, hypoalbuminemia, hyperglycemia, and 
hypokalemia. 


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Of note, it has been reported that patients with a history of glucose-6-phosphate 
dehydrogenase deficiency experienced hemolysis.  
 
7.9.2 Olaparib 
The most common side effects of olaparib include: nausea, fatigue (including 
asthenia), anemia, vomiting, diarrhea, decreased appetite, headache, neutropenia, 
dysgeusia, cough, dyspnea, dizziness, dyspepsia, leukopenia, thrombocytopenia, and 
upper abdominal pain.  
Less common side effects of olaparib include: constipation, lymphopenia, mean 
corpuscular volume [MCV] elevation, blood creatinine increased, hypersensitivity, 
dermatitis, stomatitis, MDS/AML, and rash. 
In a small number of patients, pneumonitis, and new primary malignancies have 
been reported, however totality of data from the whole development program does 
not support a conclusion that there is a causal relationship between olaparib and 
these events.  
7.10 
Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs (see Section 9.5.1). 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established. 
  
Olaparib must only be used in accordance with the dosing recommendations in this 
protocol. Any dose or frequency of dosing that exceeds the dosing regimen specified in this 
protocol should be reported as an overdose. The Maximum Tolerated Dose is 300 mg bid 
(tablet). 
 
Overdose with ascorbic acid may cause nausea, vomiting, diarrhea, facial flushing, rash, 
headache, fatigue or disturbed sleep. If overdose of ascorbic acid occurs, immediately 
discontinue administration, avoiding additional intake of ascorbic acid until symptoms are 
managed appropriately. 
 
Ascorbic acid must only be used in accordance with the dosing recommendations in this 
protocol. Any dose or frequency of dosing that exceeds the dosing regimen specified in this 
protocol should be reported as an overdose. The Maximum Tolerated Dose is 1 g/kg, with 
the maximum dose of 100 g for patients weighing over 100 kg. 
 
Adverse reactions associated with overdose should be treated symptomatically and should 
be managed appropriately. 
 
If an overdose on an AstraZeneca or McGuff study drug occurs in the course of the study, 
then investigators or other site personnel inform appropriate AstraZeneca or McGuff 


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representatives within one day i.e. immediately, but no later than the end of the next 
business day of when he or she becomes aware of it.  
 
The designated AstraZeneca or McGuff representative works with the investigator to ensure 
that all relevant information is provided to AstraZeneca or McGuff Patient Safety data entry 
site.  
8.0 DOSING DELAYS/MODIFICATIONS 
8.1 
Dosing Delays 
All scheduled cycles occur over a 28-day period. If necessary, treatment may be delayed for 
up to 4 weeks. If treatment is delayed more than two weeks, the Principal Investigator must 
be contacted for further instructions on continued treatment. Additional delays or 
modifications to the treatment schedule must be approved by the Protocol Chair. When the 
delay is due to toxicity, then the next cycle may begin with a dose reduction.  
 
Ascorbic acid will be withheld for the following drug-related toxicities: 
• 
Cr ≥ 1.6 x ULN (for patients with Cr >1.6 x ULN, calculated or measured creatinine 
clearance must be >50 mL/minute (Cockcroft-Gault)) 
• 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non-
hematologic toxicity excluding asymptomatic electrolyte aberrations 
• 
Any AE, laboratory abnormality, or intercurrent illness that, in the judgement of the 
investigator, warrants delaying the dose of study medication 
Olaparib will be withheld for the following drug-related toxicities: 
• 
Absolute neutrophil count  
≤ 750/ mm³, see Table 8 
• 
Platelets  
 
 
≤ 75,000/mm³, see Table 8 
• 
Hemoglobin 
 
 
≤ 8 hgb, If < 10, see Table 7 
• 
Total bilirubin  
 
≥ 1.5XULN 
• 
AST (SGOT)/ALT(SGPT) 
≥ 2.5 x ULN (<5x ULN if with known liver metastases    
                                                           provided bilirubin is normal) 
• 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non-
hematologic toxicity excluding asymptomatic electrolyte aberrations 
• 
Any AE, laboratory abnormality, or intercurrent illness that, in the judgement of the 
investigator, warrants delaying the dose of study medication 
If dosing parameters for Ascorbic Acid are not met, study participants may continue 
with olaparib therapy. If dosing parameters for olaparib or are not met, study 
participants may continue with Ascorbic Acid therapy. Dose interruptions are allowed 
as required, for a maximum of 4 weeks. Patients who require an interruption in olaparib 
or ascorbic acid for >4 weeks due to toxicity must permanently discontinue study drug 
unless an exemption is granted by the protocol chair (Refer to section 13.6 for stopping 
rule). Where toxicity reoccurs following re-challenge with study treatment, then the 
patient should be considered for dose reduction or must permanently discontinue study 
treatment per investigator judgement.  


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8.2 
Dose Modifications 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in 
Section 7.3.1. The NCI CTCAE v.5.0 will be used to grade adverse events.  
 
At each study visit for the duration of their participation in the study, patients will be 
evaluated for adverse events (all grades), serious adverse events (SAEs), and adverse events 
that require study drug interruption or discontinuation.  
 
Adverse events possibly related to either study drug must be resolved to grade 1 or baseline 
prior to resumption of dosing.  
 
Patients who experience grade 3 of 4 toxicities (individually defined in Section 8.1) that are 
eligible for retreatment will be dose reduced. After a two-week dose delay, if the grade 3 or 
4 toxicity resolves to grades 0-2 (grade 2 peripheral neuropathy must resolve to grade 1 if 
interfering with instrumental ADL), then the following dose reductions are to be applied. 
8.2.1 Ascorbic Acid Dose Modification 
One dose modification of ascorbic acid is allowed to 0.75 g/kg (if two dose 
reductions are required, the patient will go off protocol treatment).  
 
Ascorbic acid dose modifications for symptoms other than grade 3 or 4 toxicities 
should be discussed with and approved by the Protocol Chair.  
8.2.2 Olaparib Dose Modifications 
 
8.2.2.1 Dose Modifications for co-administration of strong or moderate CYP3A inhibitors 
or inducers, if co-administration becomes necessary during the study 
 
It is recommended that known strong CYP3A inhibitors (eg, itraconazole, 
telithromycin, clarithromycin, boosted protease inhibitors, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil) should not be taken with olaparib. 
If there is no suitable alternative concomitant medication, then the patient should 
discontinue protocol treatment. 
 
8.2.2.2 Olaparib Dose Modifications for concurrent Renal Impairment 
 
If subsequent to study entry and while still on study therapy, a patient’s estimated 
CrCl falls below the threshold for study inclusion (>51 mL/min), retesting should be 
performed promptly. 
 
For patients who develop moderate renal impairment (CrCl <50 mL/min), hold dose 
until recovery.  
 
Olaparib has not been studied in patients with severe renal impairment (creatinine 
clearance <30 mL/min) or end-stage renal disease; if patients develop severe 
impairment or end stage disease, it is recommended that olaparib be discontinued. 
 


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8.2.2.3 Olaparib Dose Modifications for Toxicities 
 
Any toxicity observed during the course of the study could be managed by 
interruption of the dose of study treatment or dose reductions.  
 
Patients who require an interruption in olaparib >4 weeks due to toxicity must 
discontinue all study therapy.  
 
Olaparib can be dose reduced to 250mg twice daily as a first step and to 200mg 
twice daily as a second step with the exception of cases of CTCAE v5.0 grade 3 or 4 
anemia when dose should be reduced to 200mg twice daily as first step. If the 
reduced dose of 200mg twice daily is not tolerable, no further dose reduction is 
allowed and all study treatment should be discontinued.  
Once dose is reduced, escalation is not permitted.  
For guidance on dose reductions for management of AEs (including renal 
impairment) refer to Table 4 and Table 5. 
In case a dose reduction is necessary, the Study treatment will be administered as 
follows:  
Table 4 
Dose reductions for study treatment to manage adverse events 
Initial Dose 
Following re-challenge post 
interruption: Dose 
reduction 1 
Dose reduction 2 
300 mg twice daily 
250 mg twice daily 
200 mg twice daily 
 
 
Table 5 
Dose reduction for study treatment if patient develops moderate 
renal impairment  
Initial Dose 
Moderate renal impairment (calculated creatinine 
clearance by Cockcroft -Gault equation or based on a 24 
hour urine test between 31 and 50 ml/min): Dose 
reduction  
 
300 mg twice daily 
200 mg twice daily 
 


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Table 6 
Dose reductions for study treatment if patient has to start taking a 
strong or moderate CYP3A inhibitor 
Initial Dose 
Moderate CYP3A inhibitor 
Strong CYP3A inhibitor 
300 mg twice daily 
150 mg twice daily 
100 mg twice daily 
 
For guidance on dose reductions when concomitant strong or moderate CYP3A 
inhibitors cannot be avoided refer to Table 6. 
When dose reduction is necessary patients will take one 150 mg tablet and one 100 mg tablet 
twice daily or two x 100 mg tablet twice daily or one 150 mg tablet twice daily or one 100 mg 
tablet twice daily. 
Management of hematological toxicity 
Management of anemia 
Table 7 
Management of anemia 
Hemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive 
treatment (eg transfusion) or interrupt dose for a maximum of 2 
weeks.  
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for max of 2 weeks) 
until Hb ≥ 10 g/dl and upon recovery dose reduction to 250 mg twice 
daily as a first step and to 200 mg twice daily as a second step may 
be considered. 
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and 
investigate causality.  
Interrupt olaparib for a maximum of 2 weeks until improved to Hb ≥ 
10 g/dl. 
Upon recovery dose reduce to dose should be reduced to 200 mg 
twice daily as first step. If the reduced dose of 200 mg twice daily 
is not tolerable, no further dose reduction is allowed and study 
treatment must be discontinued. 
 
Common treatable causes of anemia (e.g. iron, vitamin B12, or folate deficiencies 
and hypothyroidism) should be investigated and appropriately managed. In some 
cases management of anemia may require blood transfusions.  
Management of neutropenia, leukopenia and thrombocytopenia 


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Table 8 
Management of neutropenia, leukopenia and 
thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, 
this should be for a maximum of 2 weeks; appropriate supportive 
treatment and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE grade 1 or better for a 
maximum of 2 weeks. If repeat CTCAE grade 3-4 occurrence, dose 
reduce olaparib to 250 mg twice daily as a first step and 200 mg 
twice daily as a second step 
Discontinue therapy in cases of febrile neutropenia and 
thrombocytopenia associated with hemorrhage 
 
Adverse event of neutropenia and leukopenia should be managed as deemed 
appropriate by the investigator with close follow up and interruption of study drug 
if CTCAE grade 3 or worse neutropenia occurs.  
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment 
should be stopped and appropriate management including G-CSF should be given 
according to local hospital guidelines. Please note that G-CSF should not be used 
within at least 24 h (7 days for PEGylated G-CSF) of the last dose of study treatment 
unless absolutely necessary.  
Platelet transfusions, if indicated, should be done according to local hospital 
guidelines.  
Management of prolonged hematological toxicities while on study treatment 
Discontinue olaparib if a patient develops prolonged hematological toxicity such as: 
>2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
anemia and/or development of blood transfusion dependence 
>2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
neutropenia (ANC <1 x 109/L) 
>2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence 
(Platelets <50 x 109/L) 
Adverse events possibly must be resolved to grade 1 or baseline prior to resumption 
of dosing. Study treatment should be discontinued if blood counts do not recover to 
CTCAE grade 1 or better within 4 weeks of dose interruption. 
Check weekly differential blood counts including reticulocytes and peripheral blood 
smear. If any blood parameters remain clinically abnormal after 2 weeks of dose 


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interruption, the patient should be referred to hematologist for further 
investigations. Bone marrow analysis and/or blood cytogenetic analysis should be 
considered at this stage according to standard hematological practice. Development 
of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the investigator to 
AstraZeneca Patient Safety. Olaparib treatment should be discontinued if patient’s 
diagnosis of MDS and/or AML is confirmed.  
Bone marrow or blood cytogenetic analysis 
Bone marrow or blood cytogenetic analysis may be performed according to 
standard hematological practice for patients with prolonged hematological 
toxicities. Bone marrow analysis should include an aspirate for cellular morphology, 
cytogenetic analysis and flow cytometry, and a core biopsy for bone marrow 
cellularity. If it is not possible to conduct cytogenetic analysis or flow cytometry on 
the bone marrow aspirate, then attempts should be made to carry out the tests on a 
blood sample.  If findings are consistent with MDS/AML, study drug should be 
discontinued and a full description of findings should be submitted with an SAE 
report by the investigator to AstraZeneca Patient Safety for documentation on the 
Patient Safety database.    Presence or absence of blood cytogenetic abnormalities 
and flow cytometry will be documented on the clinical database. 
Management of non-hematological toxicity 
Dose interruptions are allowed as required, for a maximum of 4 weeks. Patients 
who require an interruption in study drug >4 weeks due to toxicity must 
discontinue study drug. Where toxicity reoccurs following re-challenge with study 
treatment, then the patient should be considered for dose reduction or must 
permanently discontinue study treatment.  
Olaparib can be dose reduced to 250mg bid as a first step and to 200mg bid as a 
second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse 
event occurs which the investigator considers to be related to administration of 
study treatment.  
Adverse events possibly related to study drug must be resolved to grade 1 or 
baseline prior to resumption of dosing. 
Note: In case a patient shows an AST or ALT ≥3 ULN or total bilirubin ≥2 ULN please 
refer to Appendix D ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions. Potential 
Hy’s Law cases (AST or ALT ≥3x ULN and TBL ≥2xULN with no other reason) must 
discontinue the study.   
Management of new or worsening pulmonary symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological 
abnormalities occur in the absence of a clear diagnosis, an interruption in study 
treatment dosing is recommended and further diagnostic workup (including a high 
resolution CT scan) should be performed to exclude pneumonitis. 


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Following investigation, if no evidence of abnormality is observed on CT imaging 
and symptoms resolve, then study treatment can be restarted, if deemed 
appropriate by the investigator. If significant pulmonary abnormalities are 
identified, these need to be discussed with the Principle Investigator. 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. 
In study D0810C00019 nausea was reported in 71% of the olaparib treated patients 
and 36% in the placebo treated patients and vomiting was reported in 34% of the 
olaparib treated patients and 14% in the placebo treated patients. These events are 
generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and 
manageable on continued treatment. The first onset generally occurs in the first 
month of treatment for nausea and within the first 6 months of treatment for 
vomiting. For nausea, the incidence generally plateaus at around 9 months, and for 
vomiting at around 6 to 7 months. 
No routine prophylactic anti-emetic treatment is required at the start of study 
treatment, however, patients should receive appropriate anti-emetic treatment at 
the first onset of nausea or vomiting and as required thereafter, in accordance with 
local treatment practice guidelines.  Alternatively, olaparib tablets can be taken with 
a light meal/snack (i.e. 2 pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), 
generally a single agent antiemetic should be considered e.g. dopamine receptor 
antagonist, antihistamines or dexamethasone. 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution 
should be kept as short as possible. If a patient cannot restart study treatment 
within 4 weeks for resolution of intercurrent conditions not related to disease 
progression or toxicity, the case should be discussed with Principle Investigator. 
All dose reductions and interruptions (including any missed doses), and the reasons 
for the reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped at least 3 days prior to a planned surgery. After 
surgery study treatment can be restarted when the wound has healed. No stoppage 
of study treatment is required for any needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient 
undergoes radiation treatment. Study treatment should be restarted within 4 weeks 
as long as any bone marrow toxicity has recovered. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery if these 
symptoms occur.  
 


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Renal Impairment 
If subsequent to study entry and while still on study therapy, a patient’s estimated 
CrCl falls below the threshold for study inclusion (≥51 ml/min), retesting should be 
performed promptly.  
A dose reduction is recommended for patients who develop moderate renal 
impairment (calculated creatinine clearance by Cockcroft-Gault equation or based 
on a 24 hour urine test of between 31 and 50 ml/min) for any reason during the 
course of the study: the dose of olaparib should be reduced to 200 mg twice daily. 
Because the CrCl determination is only an estimate of renal function, in instances 
where the CrCl falls to between 31 and 50 mL/min, the investigator should use his 
or her discretion in determining whether a dose change or discontinuation of 
therapy is warranted. 
Olaparib has not been studied in patients with severe renal impairment (creatinine 
clearance ≤ 30 ml/min) or end-stage renal disease; if patients develop severe 
impairment or end stage disease it is recommended that olaparib be discontinued. 
9.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
9.1 
Definitions 
9.1.1 Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). New medical conditions / diseases 
occurring before starting the study treatment but after signing the informed consent 
form will not be recorded as AEs. Additionally, expected progression of the disease 
being studied will not be recorded as an adverse event. In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
 
The term AE is used to include both serious and non-serious AEs. 
9.1.2 Serious Adverse Event (SAE)  
The investigator must assess each event to determine if it meets the criteria for 
classification as an SAE or serious adverse drug reaction. 
 
All SAEs (including death) occurring from the first dose study drug, throughout the 
study, and 30 days after the last dose of study drug or before initiation of a new 
antineoplastic treatment (whichever comes first) must be reported. All SAEs that 
the investigator considers related to the study drug occurring after the follow-up 
periods must be reported. 


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A serious adverse event is an AE occurring during any study phase (i.e., screening, 
run-in, treatment, wash-out, follow-up), at any dose of the study drugs that fulfills 
one or more of the following criteria: 
• 
Results in death 
• 
Is life threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly/birth defect (note: reports of congenital 
anomalies/birth defects must also be reported on the Pregnancy Form) 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention [e.g., medical, surgical] to prevent one of 
the other serious outcomes listed in the definition above.) Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization), potential drug induced liver injury, 
hemophagocytic lymphohistiocytosis 
• 
Suspected transmission of an infectious agent (e.g., pathogenic or 
nonpathogenic) via the study drug is an SAE. 
• 
Is a new cancer that is not a condition of the study (see clarification below) 
• 
Is associated with an overdose 
Events not considered to be SAEs are hospitalizations for:  
• 
Admissions as per protocol for a planned medical/surgical procedure or to 
facilitate a procedure 
• 
Routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health 
state and was planned prior to entry into the study. Appropriate 
documentation is required in these cases.  
• 
Admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, care-giver respite, family circumstances, 
administrative). 
• 
Admissions for monitoring of treatment-related infusion reactions that do 
not otherwise meet the criteria for a SAE. 
 
Hospitalization for chronic or long-term patients and inpatient admission also 
includes transfer within the hospital to an acute or intensive care inpatient unit. 
Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 


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Of note, Adverse Events (AEs) for malignant tumors reported during a study should 
generally be assessed as Serious AEs. 
The above instruction applies only when the malignant tumor event in question is a 
new malignant tumor (i.e., it is not the tumor for which entry into the study is a 
criterion and that is being treated by the IP under study and is not the development 
of new or progression of existing metastasis to the tumor under study). Malignant 
tumors that – as part of normal, if rare, progression – undergo transformation (e.g., 
Richter's transformation of B cell chronic lymphocytic leukemia into diffuse large B 
cell lymphoma) should not be considered a new malignant tumor. 
The causality of SAEs (their relationship to all study treatment/procedures) will be 
assessed by the investigator(s) and communicated to AstraZeneca and McGuff.  
9.1.3 Olaparib adverse events of special interest 
Adverse events of special interest (AESI) are events of scientific and medical interest 
specific to the further understanding of olaparib’s safety profile and require close 
monitoring and rapid communication by the investigators to AstraZeneca. Any AESI 
that occur should be reported using the form in Appendix F. An AESI may be 
serious or non-serious. Adverse Events of Special Interest for olaparib are the 
Important Potential Risks of MDS/AML, new primary malignancy (other than 
MDS/AML) and pneumonitis.  
 
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be 
reported to AstraZeneca Patient Safety whether it is considered a non-serious AE 
(e.g. non-melanoma skin cancer) or SAE, and regardless of investigator’s assessment 
of causality or knowledge of the treatment arm.  
 
A questionnaire will be sent to any investigator reporting an AESI, as an aid to 
provide further detailed information on the event. During the study there may be 
other events identified as AESIs that require the use of a questionnaire to help 
characterize the event and gain a better understanding regarding the relationship 
between the event and study treatment.  
 
9.1.4 Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation of the patient’s 
condition. If disease progression results in death or hospitalization while on study 
or within 30 days of the last dose of study drug, progressive disease will be 
considered an SAE. 
9.1.5 Significant disability 
Disability is a substantial disruption of the patient’s ability to conduct normal life 
functions.  
9.1.6 Pregnancy 
Male participants should refrain from fathering a child or donating sperm during the 
study and for 3 months following the last dose.  
 


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Pregnancy of the patient’s partners is not considered to be an adverse event. 
However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should if 
possible be followed up and documented.  
 
The outcome of any conception occurring from the date of the first dose until 3 
months after the last dose should be followed up and documented. 
 
All outcomes of pregnancy should be reported to AstraZeneca and McGuff. 
 
9.1.7 Medical Significance  
An event that is not fatal or life-threatening and that does not necessitate 
hospitalization may be considered serious if, in the opinion of the investigator, it 
jeopardizes the patient’s status and might lead to medical or surgical intervention to 
prevent any of the above outcomes. Such medically significant events could include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or abuse.  
9.1.8 Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-
study follow-up period after the administration of the last dose of study treatment, 
must be reported as follows: 
 
Death clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the eCRF but 
should not be reported as an SAE. 
 
When death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as an SAE 
within 24 hours (see Section 9.5.1 for further details). The report should contain a 
comment regarding the co-involvement of progression of disease, is appropriate, 
and should assign main and contributory causes of death. This information can be 
captured in the ‘death eCRF’.  
 
Deaths with an unknown cause should always be reported as an SAE. A postmortem 
may be helpful in the assessment of the cause of death, and if performed a copy of 
the postmortem results should be forwarded to AstraZeneca and McGuff within the 
usual timeframes.  
 
The NCI CTCAEv5.0 will be used for adverse event descriptions and grading.  
 
Follow-up of adverse events should continue until the event and any sequel resolve 
or stabilize at a level acceptable to the investigator and the medical monitor. 
 
Events that are not considered serious adverse events include: 


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• 
Routine treatment or monitoring of the studied indication, nor associated 
with any deterioration in condition, or for elective procedures 
• 
Elective or pre-planned treatment for a pre-existing condition that did not 
worsen emergency outpatient treatment for an event not fulfilling the 
serious criteria outlined above and not resulting in inpatient admission 
• 
Respite care 
9.2 
Expectedness 
 
Adverse events can be considered, “expected”, or “unexpected”. 
9.2.1 Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. An adverse event can be considered expected 
when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.  
9.2.2 Unexpected Adverse Events 
An adverse event can be considered unexpected when it varies in nature, intensity 
or frequency from the information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk. Contact the lead site, Principal 
Investigator or sponsor to confirm unexpected adverse events when necessary. 
9.3 
Recording and Grading 
9.3.1 Recording 
All adverse events, regardless of treatment group, severity, suspected causal 
relationship, expectedness, or seriousness will be documented. 
 
A clinically significant change in a physical examination finding or an abnormal test 
result (i.e. laboratory, x-ray, EKG) should be recorded as an AE if it: 
• 
Is associated with accompanying symptoms 
• 
Requires additional diagnostic testing or medical or surgical intervention 
• 
Leads to a change in study dosing or discontinuation from the study 
• 
Requires additional concomitant drug treatment or other therapy, or 
• 
Is considered clinically significant by the investigator or sponsor 
An abnormal test result that is subsequently determined to be in error does not 
require recording as an adverse event, even if it originally met one or more of the 
above criteria. 
The following factors should also be considered:  
• 
The temporal sequence from study drug administration – The event should 
occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event.  
• 
Underlying, concomitant, intercurrent diseases – Each report should be 
evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have.  


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• 
Concomitant medication – The other medications the subject is taking or the 
treatment the subject receives should be examined to determine whether 
any of them might be recognized to cause the event in question.  
• 
Known response pattern for this class of study drug – Clinical and/or 
preclinical data may indicate whether a particular response is likely to be a 
class effect.  
• 
Exposure to physical and/or mental stresses – The exposure to stress might 
induce adverse changes in the recipient and provide a logical and better 
explanation for the event.  
• 
The pharmacology and pharmacokinetics of the study drug – The known 
pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study drug should be considered.  
 
9.3.2 Grading Severity 
The investigator will make an assessment of grade for each AE and SAE reported 
during the study, which will be recorded in the eCRF. The assessment will be based 
on the National Cancer Institute’s CTCAE (Version 5.0):  
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the eCRF at the 
highest level experienced by the subject. For example, if a patient experiences a 
Grade 2 AE that worsens to Grade 3, Grade 3 would be recorded for the entire 
duration of the event in the eCRF. 
9.3.3 Attributing Causality  
The relationship of an AE to the administration of the study drug is to be assessed 
by the investigator according to the following definitions:  
• 
No (unrelated, not related, no relation):  The time course between the 
administration of study drug and the occurrence or worsening of the adverse 
event rules out a causal relationship and another cause (concomitant drugs, 
therapies, complications, etc.) is suspected.  
 
• 
Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, 
etc.) can be identified. 
 


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9.4 
Handling of Expedited Safety Reports 
In accordance with local regulations, the Protocol Chair or designee will notify investigators 
of all SAEs that are unexpected (i.e., not previously described in the IB), and related to 
olaparib and IV ascorbic acid. This notification will be in the form of an expedited safety 
report (ESR) that is to be faxed to the investigators and the study coordinators. Upon 
receiving such notices, the investigator must review and retain the notice with the IB and 
where required by local regulations, the investigator will submit the ESR to the appropriate 
IRB. The investigator and IRB will determine if the informed consent requires revision. The 
investigator should also comply with the IRB institutional guidelines for reporting any other 
safety information.  
 
9.5 
Reporting Adverse Events 
9.5.1 Reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) 
All AEs (both expected and unexpected) occurring from the first dose of study drug 
will be captured on the appropriate study-specific case report forms (CRFs).  
 
All AEs experienced by subjects will be collected and reported from the first dose of 
the investigational agent, throughout the study, and will be followed for 30 days after 
last dose of study drug unless related to the investigational agent. 
 
All SAEs (including death) occurring from the first dose study drug, throughout the 
study, and 30 days after the last dose of study drug or before initiation of a new 
antineoplastic treatment (whichever comes first) must be reported. All SAEs that 
the investigator considers related to the study drug occurring after the follow-up 
periods must be reported. 
In addition, all SAEs, regardless of causality to study drug and/or administration 
device, will be reported promptly to the IND sponsor (e-mail: hcao7@jhmi.edu, 
juram1@jhmi.edu ), and kdaughe5@jhmi.edu, within 24 hours of recognition of the 
event (Appendix B).  If this falls on a weekend or holiday, an email notification is 
acceptable but must be followed by an SAE reporting form on the next business day. 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance of 
documentation of adverse events and is responsible for submitting adverse event 
reports to the Protocol Chair promptly.  The Coordinating Center will maintain 
documentation of all adverse event reports for each participating site.  Adverse event 
reports submitted to the Coordinating Center must be signed and dated by the 
participating site’s Principal Investigator.  The Coordinating Center will provide 
appropriate forms to be used by all participating sites for reporting adverse events.  
Information to be provided must include: 
• 
Subject ID number, and initials 
• 
Date of the event 
• 
Description of the event 
• 
Description of site's response to the event 


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• 
Assessment of the subject's condition 
• 
Subject's status on the study (on study, off study, etc.) 
• 
Attribution of event to study drug 
 
Participating Sites 
Participating sites are responsible for reporting adverse events to their IRB 
according to its specific requirements and to the Coordinating Center as follows: 
Fatal Events whether anticipated or unanticipated, and whether or not related to 
the study must be reported to the Coordinating Center within 24 hours of the 
participating site Principal Investigator's learning of the event. 
Serious and Unanticipated Adverse Events as defined above must be reported to 
the Coordinating Center within 24 hours of the participating site Principal 
Investigator's learning of the event.  
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be reported 
within three (3) working days of the participating site Principal Investigator's 
learning of the event.  
Adverse Events which result in no change to protocol, informed consent, or risk to 
subjects must be reported to the Coordinating Center on a monthly basis.  
Adverse event reports are to be faxed to the Coordinating Center at SKCCC. Follow-
up reports are faxed, mailed, or sent electronically to the Coordinating Center as 
necessary. 
The investigator must also report follow-up information about SAEs within the 
same time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided within the same time frames described above. 
All SAEs must be collected whether or not they are considered causally related to 
the investigational product.  Investigators and other site personnel are responsible 
for reporting all casually related SAEs to their IRB and the Protocol Chair. 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report the pregnancy of a male patient’s female 
partner within 4 weeks days of completing the trial. All pregnancies of female 
partners of patients must be followed to the completion/termination of the 
pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and 
stillbirth must be reported as SAEs (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported to the IND 
sponsor, CRO, McGuff and AZ. 
 


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Report AEs to the Protocol Chair and CRO within 24 hours once identified as 
an unacceptable toxicity (defined in Section 8.1). 
 
Report Olaparib AESIs to Lead Study Coordinator, Protocol Chair, and 
AstraZeneca within 24 hours once identified (defined in Section 9.1.3) using 
the form found in Appendix F. 
 
Channing Paller (Protocol Chair):     cpaller1@jhmi.edu 
 
Harry Cao (Monitor): hcao7@jhmi.edu 
 
 
 
 
 
 
 
AstraZeneca:   
 
               TrialTCS@astrazeneca.com 
 
 
 
 
 
Fax: 302-886-4114 
 
 
All SAEs (including death) occurring from the first dose study drug, throughout the 
study, and 30 days after the last dose of study drug or before initiation of a new 
antineoplastic treatment (whichever comes first) must be reported. All SAEs that 
the investigator considers related to the study drug occurring after the follow-up 
periods must be reported. 
SAEs will be reported promptly to the Protocol Chair, AstraZeneca, and McGuff 
within 24 hours of recognition of the adverse event using the form found in 
Appendix B. If this falls on a weekend or holiday, an email notification is acceptable 
but must be followed by an SAE reporting form on the next business day. 
 
SAE reports and any other relevant safety information are to be sent to: 
Harry Cao (Monitor): hcao7@jhmi.edu 
 
 
Channing Paller (Protocol Chair):     cpaller1@jhmi.edu 
 
 
AstraZeneca:   
 
               TrialTCS@astrazeneca.com 
 
 
 
 
 
Fax: 302-886-4114 
 
 
 
McGuff: 
 
 
 
ooviedo@mcguff.com  
9.5.2 Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow 
each subject and provide further information to the safety department concerning 
the subject’s condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 


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• 
The subject is lost to follow-up 
• 
Death 
 
As soon as relevant information is available, a follow-up SAE report will be 
submitted to the Protocol Chair, Monitors, AstraZeneca, and McGuff. 
9.5.3 Reconciliation of SAEs 
The Principal Investigator will reconcile the clinical database SAE cases (case level 
only) transmitted to Monitors, AstraZeneca (TrialTCS@astrazeneca.com), and 
McGuff (ooviedo@mcguff.com). Frequency of reconciliation should be 
approximately every 3 months and prior to the database lock or final data summary. 
AstraZeneca and McGuff will email, upon request from the Principal Investigator, 
the reconciliation report. The data elements listed on the AstraZeneca reconciliation 
report will be used for case identification purposes. If the Principal Investigator 
determines a case was not transmitted to the Protocol Chair, Monitors , AstraZeneca, 
and McGuff, the case should be sent immediately to the Protocol Chair, Monitors, 
AstraZeneca, and McGuff. 
9.5.4 Institutional Review Board (IRB)  
Participating sites will be responsible for reporting to their IRB. Serious adverse 
events will be reported to the IRB per institutional standards. Upon receipt, follow-
up information will be given to the IRB (as soon as relevant information is available) 
per institutional standards. 
10.0 PHARMACEUTICAL INFORMATION 
10.1 
Ascorbic Acid 
10.1.1 Agent Accountability 
The sponsor/investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational products in accordance with the protocol 
and any applicable laws and regulations. 
 
10.1.2 Mode of Action 
Ascorbic Acid (vitamin C) is a water-soluble vitamin. In humans, an exogenous 
source of ascorbic acid is required for collagen formation and tissue repair. Ascorbic 
acid is reversibly oxidized to dehydroascorbic acid in the body. These two forms of 
the vitamin are believed to be important in oxidation-reduction reactions. The 
vitamin is involved in tyrosine metabolism, conversion of folic acid to folinic acid, 
carbohydrate metabolism, synthesis of lipids and proteins, iron metabolism, 
resistance to infections, and cellular respiration. 
10.1.3 Description 
Ascor L 500® (Ascorbic Acid Injection, USP) 500mg/mL, is available in a 50-mL 
sterile dispensing vial. Ascorbic Acid injection is a clear, colorless to slightly yellow 
sterile, solution of Ascorbic Acid in Water for injection. 


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10.1.4 Preparation 
When dispensing vials, use aseptic technique. Dispense entire contents in aliquots 
under a laminar flow hood without delay. Prepare stoppers with a suitable 
antiseptic technique. Do not use unless solution is clear and seal is intact. Parenteral 
drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever the solution and container permit. Ascorbic acid 
should be diluted in sterile water for injection (final volume of 1000ml). 
 
The ascorbic acid for infusions will be prepared by the pharmacy.  The calculated 
dose of ascorbic acid will be diluted in Sterile Water for injection USP.  
 
A study-specific worksheet will be completed when preparing ascorbic acid 
infusions. The worksheet will document the dose prepared and calculations for dose 
preparation. 
10.1.5 Storage 
Store between 2°- 8°C. Do not freeze. 
10.1.6 Stability 
The administration of ascorbic acid infusion must be completed within 72 hours of 
preparation. If not used immediately, the infusion solution must be refrigerated 
while also protected from light to keep the product stable. The maximum 72-hour 
period under refrigeration and protected light conditions includes the product 
administration period. 
10.1.7 Route of Administration 
Ascorbic acid should be administered by intravenous infusion. For intravenous 
injection, dilution into a large volume parenteral of water is recommended to 
minimize the adverse reactions associated with intravenous injection. Infusion will 
be administered at 0.75-1 gram per minute not to exceed 500 mL per hour. Ports are 
recommended but not mandatory due to frequency of infusion. 
 
10.1.8 Patient Care Implications 
Too rapid intravenous administration of the solution may cause temporary 
faintness or dizziness. Expected adverse events and potential risks are described in 
Section 7.9. Appropriate dose modifications are described in Section 8.2. No 
investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient’s malignancy.  
 
Diabetics, patients prone to recurrent renal calculi, those undergoing stool occult 
blood tests, and those on sodium-restricted diets or warfarin anticoagulant 
therapy35,36 should not take excessive doses of ascorbic acid over an extended 
period of time. Diabetics taking more than 500 mg of ascorbic acid daily may obtain 
false readings of their urinary glucose test. No exogenous ascorbic acid should be 
ingested for 48 to 72 hours before amine dependent stool occult blood tests are 
conducted because possible false-negative results may occur. Heparin, enoxaparin, 
aspirin, NSAIDS, or other anticoagulant therapies are allowed. 
 


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Ascorbic acid at pharmacologic doses can give false positive results for blood 
glucose with some commercial point of care glucometers (glucose meters), although 
this has not been seen with clinical chemistry laboratory autoanalyzers. 
Glucometers should not be used to measure blood glucose during and up to 10 
hours after intravenous ascorbate administration56,57. Patients should be counseled 
that correction of falsely high blood glucose levels with excess insulin may cause 
hypoglycemia and death, that some strips provide false readings while others, such 
as Bayer Contour are less likely to do so. They should also be counseled that if they 
do see high blood glucose readings following IV ascorbic acid, they should not 
increase their insulin unless the high glucose reading is confirmed at least 10 hours 
after IF AA administration. 
10.1.9 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies, 
the amount dispensed to and returned by the patients, and the amount remaining at 
the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational products will be destroyed at the site per institutional standards. 
10.2  
Olaparib 
10.2.1 Agent Accountability 
The sponsor/investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational products in accordance with the protocol 
and any applicable laws and regulations. 
10.2.2 Mode of Action 
The mechanism of action for olaparib activity as a single agent has been proposed to 
involve the trapping of inactivated PARP onto the single-strand breaks preventing 
their repair and generating a potential block for cellular DNA replication.6,7 An 
important consequence of this is that processing of trapped PARP-DNA complexes 
and/or the stalling of replication forks, or collapsing of replication forks, is 
predicted to lead to the generation of the more serious DNA DSBs.6,7  
 
10.2.3 Description 
Olaparib is available as 150 mg and 100 mg tablets.  
• 
150 mg tablets: green to green/grey, oval, bi-convex, film-coated tablet, with 
debossment ‘OP150’ on one side and plain on the reverse, are available in: 
o Bottles of 60 tablets (NDC 0310-0679-60) and  
o Bottles of 120 tablets (NDC 0310-0679-12).  
• 
100 mg tablets: yellow to dark yellow, oval, bi-convex, film-coated tablet, 
with debossment ‘OP100’on one side and plain on the reverse, are available 
in:  
o Bottles of 60 tablets (NDC 0310-0668-60) and  
o Bottles of 120 tablets (NDC 0310-0668-12) 
 


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10.2.4 Preparation 
Olaparib is presented for oral administration as a green, film-coated tablet 
containing 100 mg or 150 mg of drug substance. The 100 mg strength is also 
available as a yellow, film-coated tablet. Olaparib tablets are supplied in high-
density polyethylene (HDPE) bottles containing desiccant. Bottles are secured with 
a child-resistant closure; induction-sealed membranes provide tamper evidence. 
 
Dosing containers will be supplied to contain sufficient medication for at least 28 
days plus coverage, in form of four 32-count bottles for the standard dose, for 
example. Olaparib will be dispensed to patients on Day 1 and every 28 days 
thereafter until the patient completes the study, withdraws from the study, or 
closure of the study.  
10.2.5 Storage 
Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 
86°F). Store in original bottle to protect from moisture. 
 
10.2.6 Route of Administration 
Olaparib will be administered orally every 12 hours without regard to food at the 
dose specified. 100mg and 150mg tablets will be supplied.  
 
10.2.7 Patient Care Implications 
Expected adverse events and potential risks are described in Section 7.9. 
Appropriate dose modifications are described in Section 8.2. No investigational or 
commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy.  
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should 
only be replaced if all of the intact tablets can be seen and counted. Should any 
patient enrolled on the study miss a scheduled dose for whatever reason (e.g., as a 
result of forgetting to take the tablets or vomiting), the patient will be allowed to 
take the scheduled dose up to a maximum of 2 hours after the scheduled dose time. 
If greater than 2 hours after the scheduled dose time, the missed dose is not taken 
and the patient should take their allotted dose at the next scheduled time. 
10.2.8 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies, 
the amount dispensed to and returned by the patients, and the amount remaining at 
the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational products will be destroyed at the site per institutional standards. 
11.0 
CORRELATIVE/SPECIAL STUDIES 
Complete instructions for the collection, processing, and shipment of correlative samples 
will be provided in a separate laboratory manual. All specimens should be correctly labeled 
with patient initials, study-specific ID number, protocol number, and date of collection. 


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11.1 
Tumor Tissue Studies 
Tumor tissue samples will be submitted for whole exome sequencing to identify mutations 
(or liquid biopsy prior to study entry). Detailed instructions for tissue collection, processing 
and shipment are provided in the laboratory manual. FFPE block and 1 H&E side will be 
sent to Matt Schiewer lab for processing. Tumor tissue on slides are optimally 25mm2 in 
area and 4-5 microns thick. For optional on study biopsy see γH2AX discussion (Section 
11.2.2). 
11.2 
Peripheral Blood Studies 
Blood for measuring circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and 
γH2AX in CTCS at C1D1 (pre-infusion), C1D8 (pre-infusion), 4 weeks (C2D1) post infusion, 
12 weeks (C4D1) post infusion, and at EOT – see study calendar for details.  Baseline sample 
at screening should be collected before patient receives study drug. Complete instructions 
for the collection, processing, and shipment of samples will be provided in a separate lab 
manual. 
11.2.1 Circulating tumor DNA (ctDNA) 
Circulating tumor DNA (ctDNA) can be found in the blood of cancer patients37, 
including prostate cancer patients38, as part of “liquid biopsy” efforts. There is 
evidence that ctDNA has value in diagnosis and/or therapeutic applications39, 
including in guiding use of PARP inhibitors in prostate cancer.40 
 
Baseline, 4 week, 12 week, and progression plasma samples will be collected in 
order to evaluate the mutational patters as a function of therapeutic intervention, 
with the potential to identify new mutations after treatment. Plasma will be 
obtained by phlebotomy. Blood will be collected in tubes provided in kits supplied 
by Foundation Medicine. Tubes of 10ml of whole blood are optimally collected for 
this assay. Collected specimens can be stored at room temperature in the collection 
tubes and sent via overnight shipment to the processing laboratory.  
 
It was recently reported that a Phase II trial (NCT01485861)41 of mCRPC patients 
treated with abiraterone +/- ipatasertib demonstrated that “Baseline (BL) ctDNA 
positively correlated with radiological progression-free survival (fPDS; HR: 1.8 [95% CI 
1.3-2.6], p < 0.01); this association with rPFS was maintained in a multivariate cox 
model with >5 baseline clinical variables (HR: 1.6 [95% CI 1.1-2.4], p=0.011). Patients 
with a C3D1 reduction in ctDNA had superior rPFS compared to patients with a C3D1 
increase in ctDNA (HR: 2 [95% CI 1.3-3.2]; p < 0.01). The rate of ctDNA clearance at 
C3D1 was higher with Ipastasertib 400mg arm compared to placebo (56.3% versus 
24.4%, p < 0.1). We find that changes in ctDNA associated with best confirmed overall 
response (p=0.024); CR patients had greatest reduction in ctDNA (mean of -23.4%), 
followed by PR (-16.3%), then SD (-4.1%), and lastly PD patients (-1.3%). Changes in 
ctDNA levels correlated with SLD changes (rs = 0.289, p = 0.05) and also PSA changes 
(rs = 0.33, p < 0.01). Changes in ctDNA were associated with rPFS in a multivariate cox 
analysis that included PSA change (p < 0.01), as well as in a separate multivariate 
analysis that included SLD change (p < 0.01).”41 
 
We hypothesize that we will be able to retrospectively predict which patients will 
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assessment of treatment response, including correlation with rPFS, and will 
potentially identify mechanisms of resistance.  
 
11.2.2 γH2AX foci in CTCs and/or FFPE biopsy tissues 
Given that pharmacological ascorbate generates ROS which in turn elicits DNA 
double-strand breaks, and that PARP inhibition leads to diminished capacity to repair 
DNA damage, an exploratory endpoint to this study will be to evaluate DNA double-
strand breaks via immunostaining for γH2AX foci in CTCs and optional FFPE biopsy 
tissues. The extent of DNA damage as determined by γH2AX foci will be correlated 
with patient response.  
Additionally, given that olaparib targets PARP activity, the impact of the combination 
of pharmacological ascorbate and olaparib on PARP activity will be evaluated as an 
exploratory endpoint of this study via immunostaining for PAR (the enzymatic output 
of PARP activity) in CTCs and optional FFPE biopsy tissues. The extended PARP 
activity as determined by PAR staining will be correlated with patient response. 
https://www.embopress.org/doi/pdf/10.15252/emmm.201708816 
  
 
11.3 
Urine Studies 
Urine for measuring F2-Isoprostanes and 8-OHdG (markers of oxidative stress) will be 
collected at Screening, 4 weeks (C2D1), 12 weeks (C4D1), and at EOT - see study calendar 
for details. Baseline sample at screening should be collected before patient receives study 
drug. Complete instructions for the collection, processing, and shipment of samples will be 
provided in a separate lab manual. 
11.3.1 8-oxo-2’-deoxyguanosine 
8-hydrozy-2’deoxyguanosine is a form of damaged DNA caused by excess free 
radicals and is a marker of DNA oxidation which can be measured in the urine.44 At 
baseline, men with prostate cancer have an intermediate level of 8-OH-dG detected 
in urine, which has transiently increased after radiation therapy in a small study of 
seven men.45 Urinary levels were shown to be decreased in men who were treated 
in a trial of antioxidants with selenium-enriched yeast.46 Serum levels were shown 
in one study of 32 men with localized prostate cancer to be decreased following 
dietary intervention with lycopene.47 Prostatic tissue levels of 8-OHdG were not 
significantly decreased in a neo-adjuvant trial of 70 men randomized to 
pomegranate extract or placebo.48 In our population, we hypothesize 8-OHdG will be 
increased after being treated with the study intervention, and will correlate with 
response to treatment. 
11.3.2 F2-Isoprostanes 
F2-Isoprostanes are prostaglandin like compounds that are produced by the 
peroxidation of arachidonic acid, which is catalyzed by free radicals and is 
independent of cyclooxygenase.49 Urinary measurement gives an accurate measure 
of in vivo oxidative stress and is considered to be one of the most reliable 
biomarkers of oxidative stress.50 Within men with prostate cancer, there have been 


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cross-sectional associations with lower levels of 8-isoprostane with higher 
antioxidant intake.51 The data is mixed on association of isoprostanes and incident 
prostate cancer with some studies showing a positive association with F2-
isoprostane level and risk of incident prostate cancer52,53 and others showing no 
association with urinary F2-isoprostanes and incident prostate cancer.54,55 However, 
the literature suggests this is the most reliable biomarker50 and warrants further 
study in our prostate cancer patients. 
11.4 
Genomic Analysis 
Prior genomic sequencing will be collected to document any mutations that are germline or 
somatic. 
12.0 
DATA REPORTING/REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 9.0. 
12.1 
Data Management 
All information will be collected on study-specific case report forms (CRFs) in RedCap by 
study staff. These data will be reviewed for completeness and accuracy by the Principal 
Investigator.  
CRFs will be used to capture study results and data. The study coordinator or other 
authorized study personnel will transcribe data from source documents onto paper or 
eCRFs. Before or between visits, the Protocol Chair (or designee) may request copies of the 
CRFs for preliminary medical review. Once the CRFs are complete and source-verified, the 
investigator must sign and date all required pages, verifying the accuracy of all data 
contained within the CRF. 
Protocol Chair 
The Protocol Chair and/or designee is responsible for performing the following tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as 
well as its subsequent amendments. 
• 
Assuring that all participating institutions are using the correct version of the 
protocol. 
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
• 
Reviewing and ensuring reporting of SAE 
• 
Reviewing data from all sites. 
 
Coordinating Center (Johns Hopkins University) 
The Coordinating Center (or its representative) is responsible for performing the following 
tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first subject registration at that site, and maintaining copies of IRB approvals from 
each site. 
• 
Monitoring subject registration. 
• 
Collecting and compiling data from each site. 
• 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 


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• 
Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
• 
Submitting data to the Coordinating Center. 
• 
Consent subjects promptly and randomize eligible subjects in EDC. 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center. 
• 
Collecting and submitting data according to the schedule specified by the protocol. 
• 
Comply with auditing and monitoring requests 
 
12.2 
Safety Meetings 
Scheduled meetings will take place weekly, biweekly or monthly depending on patient 
enrollment, and will include the protocol principal investigator, study coordinator(s), data 
manager(s), sub-investigators (as appropriate), collaborators (as appropriate), and 
biostatisticians (as appropriate) involved with the conduct of the protocol. During these 
meetings matters related to the following will be discussed: safety of protocol participants, 
validity and integrity of the data, enrollment rate relative to expectation, characteristics of 
participants, retention of participants, adherence to protocol (potential or real protocol 
violations), data completeness, and progress of data for objectives. 
 
Monthly teleconferences will be scheduled to include the Coordinating Center and the 
clinical trial sites. During these meetings, the Coordinating Center and clinical trial sites 
shall discuss the following: study protocol updates, safety data, enrollment status, and 
progress of data for objectives. 
12.3 
Monitoring 
The SKCCC Compliance Monitoring Program will provide external monitoring in accordance 
with SKCCC DSMP (Version 6.0, 02/21/2019).  The SMC Subcommittee will determine the 
level of patient safety risk and level/frequency of monitoring. Data monitoring of this 
protocol will occur on a regular basis with the frequency dependent on the rate of subject 
accrual and the progress of the study. Eligibility for all sites will be monitored by the 
Protocol Chair or authorized representatives of the Coordinating Center. The protocol will 
be internally monitored by the Principal Investigator at each site. The PI shall internally 
monitor the progress of the trial, including review and confirmation of all safety/treatment-
related outcomes, response assessments, safety reports and/or any related source 
documentation. Protocol Chair is ultimately responsible for external monitoring of the trial. 
External monitoring will occur according to the following guidelines: 
 
 
Participating Site(s): The protocol will be monitored by authorized representatives of the 
Coordinating Center. 
 


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Authorized representatives of the Coordinating Center will conduct remote monitoring of 
satellite sites to perform audits or inspections, including source data verification. The 
purpose of these audits or inspections is to systematically and independently examine all 
trial-related activities and documents to determine whether these activities were conducted 
and data were recorded, analyzed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), and any applicable regulatory requirements. 
 
Additional data and safety monitoring oversight will also be performed by the SKCCC Safety 
Monitoring Committee (SMC - as defined in the DSMP). 
12.4 
Populations of Interest 
The safety population includes all subjects who received at least one dose of olaparib and IV 
ascorbic acid study treatment. The safety population will be conducted on the basis of the 
actual treatment received.  All safety outcomes will be assessed using the safety population 
for analysis. 
12.5 
Study Documentation 
12.5.1 Informed Consent and Authorization for use and Disclosure of Protected 
Health Information 
Written informed consent and authorization of use and disclosure of protected 
health information (PHI) must be obtained from each subject (or the subject’s 
legally authorized representative) before performing any study-specific 
screening/baseline period evaluations.  One copy of the signed informed consent 
form (ICF) and authorization for use and disclosure of the PHI form will be given to 
the subject and the investigator will retain the original.  The ICF and authorization 
for use and disclosure of PHI, which is prepared by the investigator or the site, must 
be reviewed and approved by the Protocol Chair, the study monitor (if applicable) 
and the site’s IRB before the initiation of the study. The ICF must contain the 20 
elements of informed consent described in ICH E6, Section 4.8. The authorization for 
use and disclosure of PHI must contain the elements required by Title 45 of the Code 
of Federal Regulations (CFR), Section 164.508(b), for valid authorizations. 
12.5.2 Investigator Study Files 
Documentation about the investigator and study staff, the IRB and the institution, is 
required before study site initiation. A list of required documents will be provided 
by the Protocol Chair or designee to each participating investigator. Copies of these 
documents as well as supplemental information, such as the investigator’s 
obligations, IB, clinical study protocol and amendments, safety information, 
investigational agent information, biological samples and laboratory procedures, 
SRM, study logs and Protocol Chair/investigator/study monitor correspondence will 
be kept on-site in study site-specific files. 
The Protocol Chair or designee will be responsible for maintaining original and 
backup of all CRF data. The investigator is responsible for maintaining backup of all 
electronic data systems used for primary documentation or source documentation. 
Backup of electronic data will be performed periodically as described in the site-
specific SOPs. Backup records must be stored at a secure location on site and backup 
and recovery logs must be maintained to facilitate data recovery. If an electronic 


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medical records system that is not supported by the Protocol Chair or designee (or 
is discontinued or decommissioned) is used, the investigator must maintain a 
system to retrieve these records or arrange for the transfer of these records to an 
alternate electronic format or to paper. 
Changes to any electronic records require an audit trail, in accordance with 21 CFR 
11.10(e), and should include who made the changes and when and why the changes 
were made. An audit trail is defined as a secure, computer-generated, time-stamped 
electronic record that will allow reconstruction of the course of events relating to 
the creation, modification and deletion of an electronic record. Audit trails must be 
created incrementally, in chronological order and in a manner that does not allow 
new audit trail information to overwrite existing data. Audit trails should be in a 
readable format and readily available at the study site and any other location where 
electronic study records are maintained. 
Audit trails are generated automatically for eCRFs. The investigator is responsible 
for maintaining audit trails of all electronic data systems used for primary 
documentation or source documentation. 
12.5.3 Case Report Forms and Source Documentation 
The investigator must make study data accessible to the site monitor, to other 
authorized representatives of the Protocol Chair (or designee) and to the 
appropriate regulatory authority inspectors. The original CRF for each subject will 
be checked against source documents at the study site by the site monitor. 
12.5.4 Retention of Study Documents 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic 
documentation and administrative records, must be retained for at least 2 years 
after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of an individual product. Longer 
retention periods may apply. The Protocol Chair will notify investigators as to when 
documents no longer need to be retained. No study documents will be destroyed or 
moved to a new location without prior written approval from the Protocol Chair. If 
the investigator relocates, retires or withdraws from the clinical study for any 
reason, all records required to be maintained for the study should be transferred to 
an agreed-upon designee, such as another investigator at the institution where the 
study was conducted. 
Audit trails for electronic documents must be retained for a period at least as long as 
that required for the subject electronic records to which they pertain. The 
investigator must retain either the original or a certified copy of audit trails. 
12.5.5 Data Confidentiality and Subject Anonymity 
All information about the nature of the proposed investigation provided by the 
Protocol Chair or their representative to the investigator (with the exception of 
information required by law or regulations to be disclosed to the IRB, the subject or 
the appropriate regulatory authority) must be kept in confidence by the 
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The anonymity of participating subjects must be maintained. Subjects will be 
identified by their initials and an assigned subject number on CRFs and other 
documents retrieved from the site or sent to the Protocol Chair, AstraZeneca, 
McGuff, regulatory agencies, or central laboratories/reviewers. Documents that 
identify the subject (e.g., the signed ICF) must be maintained in strict confidence by 
the investigator, except to the extent necessary to allow auditing by the appropriate 
regulatory authority, the study monitor, Protocol Chair or their representative. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This pilot trial has an exact single-stage design.58 It will evaluate olaparib and IV ascorbate 
in patients with metastatic castration resistant prostate cancer in which a DNA repair 
mutation is absent. The hypothesis of the study is that olaparib will synergize with IV 
ascorbic acid to improve clinical outcomes in this population.  
Primary objective: To estimate the proportion of patients with metastatic castration 
resistant prostate cancer (mCRPC) having a 50% reduction in PSA from baseline (PSA50 
response). 
Secondary objectives: 
1) To evaluate the safety and tolerability of olaparib in combination with IV ascorbic acid 
in patients with mCRPC. 
2) To estimate the median radiographic progression free survival (rPFS) of patients with 
mCRPC receiving olaparib in combination with IV ascorbic acid 
3) To estimate the median time to PSA doubling from baseline of patients with mCRPC  
receiving olaparib in combination with IV ascorbic acid. 
4) To estimate the median PSA progression free survival (PSA PFS) of patients with mCRPC 
receiving olaparib in combination with IV. ascorbic acid 
5) To assess overall survival (OS) in patients with castration resistant prostate cancer. 
Exploratory objectives: Examine correlates that may be predictive of the clinical 
outcomes: PSA50 response and rPFS 
1) To quantify ctDNA and perform mutational analysis in the peripheral blood and 
compare it to any baseline germline or somatic mutations (document prestudy on case 
report form) 
2) To quantify circulating tumor cells (CTCs) in the peripheral blood at baseline, 4 weeks, 
12 weeks, and upon progression and assess γH2AX foci in CTCs 
3) Optional γH2AX foci FFPE biopsy tissues 
4) To measure F2-isoprostanes in the urine as a pharmacodynamic measure of oxidant 
injury at baseline, 4 weeks, 12 weeks, and upon progression. 
5) To measure 8-oxo-2’-deoxyguanosine as a measure of oxidative stress in the urine at 
baseline, 4 weeks, 12 weeks, and upon progression. 
 


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13.2 
Primary Endpoint Definition  
The primary endpoint in this study is based on PSA50 response.  PSA50 response will be 
defined as a decrease in the PSA to 50% less than the baseline PSA upon enrollment in the 
trial.  The decrease must be confirmed by a second measurement at least 4 weeks apart.   
PSA values will be measured monthly during the trial.   
13.3 
Secondary Endpoint Definitions 
• 
Safety and tolerability will be defined by frequency of the drug-related adverse events by 
grade as assessed by the NCI CTCAE Version 5.0, lab measurements, and vital signs. 
• 
Radiographic progression will be defined as soft tissue disease progression by modified 
RECIST criteria 1.1 (baseline LN size must be >1.0 cm to be considered target or evaluable 
lesion) or by development of two or more new bone lesions not consistent with tumor 
flair for prostate cancer working group 3.  Radiographic progression free survival (rPFS) 
is defined as the number of months from initiation of therapy to date of first radiographic 
progression, death from any cause, or last patient evaluation.  Patients who have not 
progressed or died will be censored at the last date they were assessed and deemed 
progression-free.   
• 
Time to PSA doubling from baseline is a time-to-event outcome.  Time is measured from 
the initiation of therapy until the PSA has increased to 200% of baseline value, and 
confirmed with another measurement at least 4 weeks later, or death.  The date of PSA 
doubling will be the first value recorded (not the confirmatory value).   
• 
PSA PFS is defined as time to first PSA failure (two consecutive increases in PSA of 50% 
and ≥5 ng/mL above nadir) or death.  
• 
OS is defined as the number of months from initiation of therapy to death due to any 
cause.   
 
13.4 
Correlative Endpoint Definitions 
• 
Circulating tumor DNA (ctDNA) will be measured in peripheral blood to evaluate 
changes in mutation patterns, which will be correlated to therapeutic outcomes and 
compare to any prior noted mutations in germline or somatic sequencing 
• 
γH2AX foci in CTCs and optional FFPE biopsy tissue 
• 
F2-isoprostane levels will be evaluated in urine as a measure of oxidative injury and 
will be correlated to therapeutic outcomes and toxicities. 
• 
8-oxo-2’-deoxyguanosine will be evaluated in urine as a measure of oxidative stress 
and correlated to therapeutic outcomes. 
13.5 
Sample Size/Accrual Rate 
Accrual to this study is expected to be one patient per month.  For this combination to be 
considered for further study a PSA50 response of 23% or more would be desirable.  Our 
null hypothesis of 3% is based on the low PSA50 response rate, 3% (1 of 33), reported by 
Mateo et al.22 for this patient population.  This single-stage design has a 95% chance (α = 
0.05) of rejecting the therapy if the true percentage of patients with some benefit from 
treatment is less than or equal to 3% and an 80% chance of concluding the therapy is 
beneficial if the true percentage is 23% or more.  Twelve patients, will be assessed for 6 
months and if 2 or more achieve a PSA50 response, the therapy will be considered for a 
larger study. Patients enrolled who never receive any study related therapy will be 


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replaced.  Enrollment would be allowed to continue, up to a maximum of 15 patients, to 
replace those patients that drop-out early.   
13.6 
Futility and Safety Monitoring Plan 
Given the small number of patients and the importance of obtaining correlative data to 
consider during the final evaluation of the study results, there will be no futility monitoring 
for efficacy during this pilot study.  The trial will however employ a standard safety 
monitoring plan for adverse events.  In addition, if any patient is diagnosed with an adverse 
event of special interest: myelodysplastic syndrome, acute myeloid leukemia, new primary 
malignancy (other than MDS/AML) or pneumonitis during the trial, the trial will be paused 
for a safety review. 
 
Toxicity will be monitored continuously for grade 3-4 adverse events that do not resolve to 
grade 2 following four-weeks drug discontinuation (per section 8.1). The stopping rule is 
based on the posterior probability that the combination of treatments is too toxic.  If the 
rate of these toxicities convincingly exceeds 30%, the study PI will hold enrollment if the 
posterior probability of risk greater than 0.30 is 65% or higher.  The prior for this toxicity 
monitoring rule is beta (2,6).  This corresponds to assuming our prior guess for the toxicity 
rate is 25%, and there is 90% probability that this proportion is between 5% and 52%.   
 
Table 9.  Monitoring rule for safety. 
Stop if safety events are seen 
2 
3 
4 
5 
in N patients 
2 
3-6 
7-9 
10-12 
 
 
The operating characteristics of the stopping rule shows the percent of the time that the 
monitoring rule would pause the study under different hypothetical risks of toxicity, 
along with the average sample size (based on 5000 simulations).  
 
Table 10. Operating Characteristics for Safety 
Risk of safety event 
0.15 
0.25 
0.30 
0.35 
0.40 
0.45 
0.50 
% of Time Study Stops 
7.4% 
26.5% 
39.8% 
52.3% 
67.8% 
78.6% 
86.3% 
Expected Sample Size 
11.5 
10.4 
9.6 
8.7 
7.7 
6.9 
6.1 
 
13.7 
Analysis of Primary Endpoint 
The primary endpoint is based on PSA50 response. All patients who receive at least one dose 
of olaparib and IV ascorbic acid will be evaluable for the primary objective. If patients do not 
have adequate PSA data after the initiation of therapy due to stopping for toxicity or 
withdrawing consent, then they will be considered unevaluable.  The PSA50 response will be 
calculated as a proportion with 90% confidence intervals.   
PSA50 response will be defined as a decrease in the PSA to 50% less than the baseline PSA 
upon enrollment in the trial. Patients must receive at least one dose of olaparib and IV 
ascorbic acid to be considered evaluable. After the initial measurement showing a >50% 
decrease in PSA compared to baseline, a second measurement must confirm the decrease, 


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and the measurements must be at least 4 weeks apart. PSA50 response rate will be 
calculated as a proportion with 90% confidence intervals. 
13.8 
Analysis of Secondary Endpoints 
 
The safety analysis will be performed in all subjects receiving combination olaparib and IV 
ascorbic acid. AE data will be listed individually and incidence of AEs summarized by 
system organ class and preferred terms within a system organ class for each treatment 
group. When calculating the incidence of AEs, each AE (based on preferred terminology 
defined by Medical Dictionary for Regulatory Activities (MedDRA; Version 13.1, or later) 
will be counted only once for a given subject.  In analyses of grade and causality, if the same 
AE occurs on multiple occasions, the highest grade and strongest relationship to study drug 
will be assumed.  If 2 or more AEs are reported as a unit, the individual terms will be 
reported as separate experiences. Changes in vital signs, hematology and clinical chemistry 
parameters from baseline to the end of the study will be examined.  Toxicity will be 
tabulated by type and grade. Toxicities will be characterized according to the CTCAE 
version 5.0 Treatment-emergent changes from normal to abnormal values in key laboratory 
parameters will be identified.   
 
Radiographic progression-free survival (rPFS) is defined as the number of months from 
initiation of therapy (cycle 1, day 1) to date of first radiographic progression, death from 
any cause, or last patient evaluation. Patients must receive at least one dose of olaparib and 
IV ascorbic acid to be considered evaluable. Radiographic progression will be determined 
by modified RECIST criteria 1.1 by development of two or more new bone lesions not 
consistent with tumor flair for prostate cancer working group 2. Patients who have not 
progressed or died will be censored at the last date they were assessed and deemed 
progression-free. rPFS will be summarized and six month estimates for rPFS will be 
reported using the Kaplan-Meier method with 90% confidence intervals.  
 
 
PSA doubling time from baseline is a time-to-event outcome.  Time in months is measured 
from the initiation of therapy (cycle 1, day 1) until the PSA has increased to 200% of 
baseline value after a minimum of 12 weeks of therapy and has been confirmed with 
another measurement at least 4 weeks later, or death.  The date of PSA doubling will be the 
first value recorded (not the confirmatory value). Patients must receive at least one dose of 
olaparib and IV ascorbic acid to be considered evaluable. PSA doubling time will be 
summarized using the Kaplan-Meier method with 90% confidence intervals. 
 
Prostate-specific antigen progression-free survival (PSA PFS) is defined as the number of 
months from initiation of therapy (cycle 1, day 1) to first PSA failure (two consecutive 
increases in PSA of 50% at least 4 weeks apart and ≥5 ng/mL above nadir) or death. 
Patients must receive at least one dose of olaparib and IV ascorbic acid to be considered 
evaluable. Patients who do not experience PSA failure or die will be censored at the last date 
of PSA measurement. PSA PFS will be summarized using the Kaplan-Meier method with 
90% confidence intervals. 
 
OS is defined as the number of months from the initiation of therapy to death due to any 
cause.  Patients who are alive or lost to follow up as of the data analysis cutoff date will be 


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censored at the last date they were assessed.  OS will be summarized using the Kaplan 
Meier method with 90% confidence intervals.  
 
13.9 
Exploratory/Correlative Analysis 
The additional correlative analyses will be primarily descriptive in nature.  Plots (e.g. 
histograms, scatter and spaghetti plots) and summary statistics (medians, ranges, counts, 
proportions) will be used to summarize patterns over time and compare outcomes. 
Comparisons in the pre- and post-treatment responses will be compared using paired t-
tests (or Wilcoxon signed rank tests if appropriate) for continuous variables and McNemar’s 
tests for dichotomous or categorical variables. Peripheral blood samples will be analyzed 
for ctDNA, CTCs and γH2AX foci in CTCs at serial time points during the study in order to 
identify therapeutic targets, biomarkers, and predictors of response. Additionally, urine 
samples will be analyzed for F2-isoprostane and 8-oxo-2’-deoxyguanosine levels at serial 
time points during the study in order to identify the impact of study therapy on oxidative 
toxicities, which will be correlated to therapeutic outcomes. 
Genomic sequencing library construction, whole genome/exome sequencing, whole 
transcriptome sequencing, microbial sequencing, neoepitope prediction, mutation burden, 
and bioinformatic analysis will be performed either at an on-campus laboratory or at an off-
campus sequencing service. All the samples will be de-identified before sending to any 
laboratory for sequencing.  The FASTQ files, BAM files and VCF files will be generated and 
analyzed.  Genomic sequencing data will be stored and computations conducted using a JH 
IT managed subscription of Azure. 
Results from the sequencing studies will not be released to the patients. These studies are 
for research purposes only and are not using a clinically validated platform 
 
 
 
 
 


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retinol, and 15-isoprostane F2t in serum or urine with prostate cancer risk: The multiethnic 
cohort [Internet]. Cancer Causes Control 20:1161–1171, 2009[cited 2020 Oct 2] Available 
from: /pmc/articles/PMC2725220/?report=abstract 
56. Dimeski G, Jones BW, Tilley V, et al: Glucose meters: Evaluation of the new formulation 
measuring strips from Roche (Accu-Chek) and Abbott (MediSense) [Internet]. Ann Clin 
Biochem 
47:358–365, 
2010[cited 
2020 
Jul 
22] 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/20592335/ 
57. Vasudevan S, Hirsch IB: Interference of intravenous vitamin C with blood glucose testing 
[Internet]. 
Diabetes 
Care 
37, 
2014[cited 
2020 
Jul 
22] 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/24757251/ 
58. A’Hern RP: Sample size tables for exact single-stage phase II designs [Internet]. Stat Med 


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20:859–866, 
2001[cited 
2020 
Oct 
7] 
Available 
from: 
https://pubmed.ncbi.nlm.nih.gov/11252008/ 
 
 
 


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


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APPENDIX B: Serious Adverse Event Reporting Form 
 
Please notify: Channing Paller, MD within 24 hours (email: cpaller1@jhmi.edu) 
Monitor/Harry Cao within 24 hours 
(emails: hcao7@jhmi.edu, kdaughe5@jhmi.edu)  
AstraZeneca within 24 hours (email: TrialTCS@astrazeneca.com; fax: 302-886-4114) 
McGuff within 24 hours (email: ooviedo@mcguff.com 
 
Protocol Title: 
Phase II Study of PARP Inhibitor Olaparib and IV Ascorbate in Metastatic 
Castration Resistant Prostate Cancer 
Protocol Number: 
Signature of PI: 
Principal Investigator: 
Dr. Channing Paller 
Date of Report: 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all that 
apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Other Important Medical Event 
 Cancer 
 Overdose 
 Other:______________________ 
Hospital Admission Date: 
Date Event 
Discovered: 
Hospital Discharge Date:   
SAE ID: 
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
Cause of death (if 
applicable): 
Event Outcome: 
 Not Recovered 
 Recovering 
 Recovered 
 Recovered with 
sequelae 
 Death 
 Unknown 
Event Onset Date (or Date of Death): 
 
Event End Date: 
Section C: Study Drug Information 
Investigational Product:  
Olaparib 300 mg BID 
IV Ascorbic Acid (1 g/kg, 2x per week)  
Indication: Castration Resistant Prostate Cancer (CRPC) 


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Number of Total Cycles: 
Action taken with the study drug: 
None 
 Interrupted 
 Delayed  
 Discontinued  
Date of First Dose: 
Date of Last Dose prior to Event: 
 
Relationship to: 
Olaparib 
IV Ascorbic Acid 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event: 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
Additional Documents: 
 Please specify 
 
 
 
 
 
 


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APPENDIX C: Contraception  
 
Olaparib is regarded as a compound with medium/high fetal risk. Subjects with partners of 
childbearing potential, who are sexually active, must agree to the use of TWO highly effective 
forms of contraception in combination [as listed below], throughout the period of taking 
study treatment and for at least 1 month after last dose of study drug(s), or they must 
totally/truly abstain from any form of sexual intercourse (see below). 
 
Acceptable Non-hormonal birth control methods include: 
• 
Total sexual abstinence. Abstinence must continue for the total duration of study 
treatment and for three months after the last dose for male patients. Periodic 
abstinence (e.g. calendar ovulation, sympothermal, post ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
• 
Vasectomised sexual partner PLUS male condom with participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom 
• 
IUD PLUS male condom. Provided coils are copper-banded 
 
Acceptable hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom 
• 
Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly 
efficacious progesterone based pill. 
• 
Hormonal shot or injection (eg., Depo-Provera) PLUS male condom 
• 
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom 
• 
Norelgestromin / EE transdermal system PLUS male condom 
• 
Intrauterine system [IUS] device (eg., levonorgestrel releasing IUS -Mirena®) PLUS 
male condom 
• 
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom 
 
 
 
 
 
 
 
 


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APPENDIX D: Actions required in cases of combined increase of Aminotransferase 
and Total Bilirubin – Hy’s Law 
 
1. INTRODUCTION 
During the course of the study, the investigator will remain vigilant for increases in 
liver biochemistry. The investigator is responsible for determining whether a patient 
meets potential Hy’s Law (PHL) criteria at any point during the study. The 
Investigator participates, together with AstraZeneca and McGuff clinical project 
representatives, in review and assessment of cases meeting PHL criteria to agree 
whether Hy’s Law (HL) criteria are met. HL criteria are met if there is no alternative 
explanation for the elevations in liver biochemistry other than Drug Induced Liver 
Injury (DILI) caused by the Investigational Medicinal Product (IMP). The Investigator 
is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of 
the review and assessment in line with standard safety reporting processes. 
 
2. DEFINITIONS 
Potential Hy’s Law (PHL) 
• 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 3x 
Upper Limit of Normal (ULN) and Total Bilirubin (TBL) >2xULN at any point 
during the study irrespective of an increase in Alkaline Phosphatase (ALP). 
• 
The elevations do not have to occur at the same time or within a specified time 
frame. 
Hy’s Law (HL) 
 
• 
AST or ALT > 3x ULN and TBL >2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g. elevated ALP 
indicating cholestasis, viral hepatitis, another drug. 
• 
The elevations do not have to occur at the same time or within a specified time 
frame 
 
3. IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
In order to identify cases of PHL it is important to perform a comprehensive review 
of laboratory data for any patient who meets any of the following identification 
criteria in isolation or in combination: 
• 
ALT > 3xULN 
• 
AST > 3xULN 
• 
TBL > 2xULN 
The Investigator will without delay review each new laboratory report and if the 
identification criteria are met will: 


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• 
Determine whether the patient meets PHL criteria (see Section 2 of this 
Appendix for definition) by reviewing laboratory reports from all previous 
visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
 
4. FOLLOW-UP 
Potential Hy’s Law Criteria not met: 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
Potential Hy’s Law Criteria met: 
 
If the patient does not meet PHL criteria the Investigator will: 
• 
Notify the AstraZeneca and McGuff representative who will then inform the 
central study team. 
• 
The Study Physician contacts the Investigator, to provide guidance, discuss and 
agree an approach for the study patients’ follow-up and the continuous review of 
data. Subsequent to this contact the Investigator will: 
o Monitor the patient until liver biochemistry parameters are appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long 
as medically indicated 
o Investigate the etiology of the event and perform diagnostic 
investigations as discussed with the Study Physician 
o Complete the three Liver CRF Modules as information below becomes 
available 
o If at any time (in consultation with the Study Physician) the PHL case 
meets serious criteria, report it as an SAE using standard reporting 
procedures 
 
5. REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this Section should be followed for all cases where PHL criteria 
are met. No later than 3 weeks after the biochemistry abnormality was initially 
detected, the Study Physician contacts the Investigator in order to review available 
data and agree on whether there is an alternative explanation for meeting PHL 
criteria other than DILI caused by the IMP. The AstraZeneca Medical Science Director 
and Global Safety Physician will also be involved in this review together with other 
subject matter experts as appropriate. According to the outcome of the review and 
assessment, the Investigator will follow the instructions below. 
 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation 
on the appropriate CRF 


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• 
If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
o The ‘Medically Important’ serious criterion should be used if no other 
serious criteria apply 
o As there is no alternative explanation for the HL case, a causality 
assessment of ‘related’ should be assigned 
If there is an unavoidable delay of over 3 weeks in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is 
assessed that there is no alternative explanation until such time as an informed 
decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met. Update the SAE report according to 
the outcome of the review 
 
6. ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’s LAW 
This section is applicable when a patient meets PHL criteria on study treatment and 
has already met PHL criteria at a previous on study treatment visit. 
 
The requirement to conduct follow-up, review and assessment of a repeat 
occurrence(s) of PHL is based on the nature of the alternative cause identified for the 
previous occurrence. The investigator should determine the cause for the previous 
occurrence of PHL criteria being met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being 
met chronic or progressing malignant disease? 
o If No: follow the process described in Section 4 of this appendix 
o If Yes: Determine if there has been a significant change in the patient’s 
condition when compared with when PHL criteria were previously 
met 
 
If there is no significant change no action is required 
 
If there is a significant change follow the process described in 
Section 4 of this appendix  
• 
A ‘significant’ change in the patient’s condition refers 
to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or total 
bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms. The 
determination of whether there has been a significant 
change will be at the discretion of the Investigator, this 


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may be in consultation with the Study Physician if 
there is any uncertainty. 
 
7. REFERENCES 
 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical 
evaluation’:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/UCM174090.pdf 
 
 


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APPENDIX E: Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors 
 
RECIST version 1.1 will be used in this study for assessment of tumor response.  While either 
CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in 
this study.   
The RECIST 1.1 criteria have been modified specifically for this study so a lymph node will be 
considered pathological if it measures >20 mm in the short axis as opposed to the standard 
>15 mm cut off. 
Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-
ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable unless there is evidence of progression in the irradiated site. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >20 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <20 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 


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sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is added 
into the sum.  The baseline sum diameters will be used as reference to further characterize 
any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or more 
new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
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The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
Reference 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1).  Eur J Cancer. 2009 Jan;45(2):228-47. 


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APPENDIX F: Adverse Event of Special Interest Reporting Form 
 
Please notify: Channing Paller, MD within 24 hours (email: cpaller1@jhmi.edu) 
Monitor/Harry Cao within 24 hours 
(emails: hcao7@jhmi.edu, kdaughe5@jhmi.edu)  
AstraZeneca within 24 hours (email: TrialTCS@astrazeneca.com; fax: 302-886-4114) 
McGuff within 24 hours (email: ooviedo@mcguff.com) 
 
Protocol Title: 
 
 
Phase II Study of PARP Inhibitor Olaparib and IV Ascorbate in Metastatic 
Castration Resistant Prostate Cancer 
Protocol 
Number: 
 
Signature of PI: 
 
 
 
Principal Investigator: 
 
 
Date of Report: 
 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Addendum to: 
 
Event Onset Date: 
 
Event End Date: 
Date Event 
Discovered: 
Section A: Subject Information 
Subject ID: 
Subject Gender: 
Male 
Female 
 
Subject Age: 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
Event Outcome: 
 Not Recovered 
 Recovering 
 Recovered 
 Recovered with sequelae 
 Death 
 Unknown 
Section C: Study Drug Information 
 
Investigational Product:  
Olaparib 300 mg BID 
IV Ascorbic Acid (1 g/kg, 2x per week)  
Indication: Castration Resistant Prostate Cancer (CRPC) 
Number of Total Cycles: 
 
Action taken with the study drug: 
 
None 


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Date of First Dose: 
 
Date of Last Dose prior to 
Event: 
 
 Interrupted 
 Delayed  
 Discontinued  
Drug(s) discontinued: 
Relationship to: 
Olaparib 
IV Ascorbic Acid 
Underlying Disease 
Unrelated 
 
 
 
Related 
 
 
 
Section D: Brief Description of the Event: 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop 
Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
 
Additional Documents: 
 Please specify