A Study of Serum Folate Levels in Patients With Treated With Olaparib.
Phase: PHASE4
Conditions: Ovarian Cancer, Breast Cancer, Folic Acid Deficiency
Sponsor: Rush University Medical Center

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Olaparib - ESR-18-13807 
 
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Clinical Study Protocol  
 
Drug Substance 
Olaparib 
 
Study Code 
ESR-18-13807 
 
Version 
6 
 
Date 
August 16, 2021 
 
 
A study of serum folate levels in patients with solid tumors treated with 
olaparib   
Shammo JM1 MD, FACP, FASCP, Usha L1 MD, Richardson K1 MD, Bitterman P2 MD, 
Ramos J2 MD, and Basu S3. 
  
1Department of Internal Medicine, Division of Hematology and Oncology and Cell 
Therapy, 2Department of Pathology, 3Department of Preventive Medicine, Rush University 
Medical Center, Chicago, IL. 
 
 
Sponsor:  
 
 
 
Regulatory Agency Identifying Number(s):  
 
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VERSION HISTORY 
Version 3,  January 4, 2019 
Version 4, June 16, 2020 
Version 5, December 06, 2020 
Version 6, August 16, 2021 
 
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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................... 1 
VERSION HISTORY ............................................................................................. 2 
TABLE OF CONTENTS ........................................................................................ 3 
1. 
PROTOCOL SUMMARY ...................................................................................... 7 
1.1 
Schedule of Activities (SoA) ................................................................................... 7 
1.1.1 
Table of Schedule of Activities ............................................................................... 8 
1.2 
Synopsis................................................................................................................. 10 
1.3 
Schema .................................................................................................................. 10 
INTRODUCTION ................................................................................................................. 12 
1.4 
Study rationale ....................................................................................................... 13 
1.5 
Background ........................................................................................................... 14 
2. 
OBJECTIVES AND ENDPOINTS....................................................................... 14 
3. 
STUDY DESIGN .................................................................................................. 16 
3.1 
Overall design........................................................................................................ 16 
3.2 
Scientific rationale for study design ...................................................................... 16 
3.3 
Justification for dose ............................................................................................. 16 
3.4 
End of study definition .......................................................................................... 16 
4. 
STUDY POPULATION........................................................................................ 17 
4.1 
Inclusion criteria .................................................................................................... 17 
4.2 
Exclusion criteria ................................................................................................... 19 
4.3 
Lifestyle restrictions .............................................................................................. 22 
4.3.1 
Meals and dietary restrictions................................................................................ 22 
4.3.2 
Activity .................................................................................................................. 22 
4.4 
Screen failures ....................................................................................................... 22 
5. 
STUDY TREATMENTS ...................................................................................... 22 
5.1 
Treatments administered ....................................................................................... 22 
5.2 
Preparation/handling/storage/accountability ......................................................... 24 
5.3 
Measures to minimise bias: randomisation and blinding ...................................... 24 
5.4 
Treatment compliance ........................................................................................... 24 
5.5 
Concomitant therapy ............................................................................................. 25 
5.5.1 
Other concomitant treatment ................................................................................. 28 
5.6 
Dose modification ................................................................................................. 28 
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5.7 
Treatment after the end of the study ...................................................................... 30 
6. 
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL .. 30 
6.1 
Discontinuation of study treatment ....................................................................... 30 
6.1.1 
Procedures for discontinuation of study treatment ................................................ 30 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 31 
7.1 
Efficacy assessments ............................................................................................. 31 
7.1.1 
Clinical outcome assessments ............................................................................... 31 
7.2 
Safety assessments ................................................................................................ 31 
7.2.1 
Clinical safety laboratory assessments .................................................................. 31 
7.2.1.1 
Coagulation (if clinically indicated) ...................................................................... 32 
7.2.1.2 
Bone marrow or blood cytogenetic samples ......................................................... 32 
7.2.2 
Physical examinations ........................................................................................... 33 
7.2.3 
Vital signs .............................................................................................................. 33 
7.2.4 
Other safety assessments ....................................................................................... 33 
7.2.4.1 
Serum or urine pregnancy test ............................................................................... 33 
7.3 
Collection of adverse events.................................................................................. 33 
7.3.1 
Method of detecting AEs and SAEs ...................................................................... 33 
7.3.2 
Time period and frequency for collecting AE and SAE information .................... 33 
7.3.2.1 
Adverse events after the 30 day follow up period ................................................. 34 
7.3.3 
Follow-up of AEs and SAEs ................................................................................. 34 
7.3.4 
Adverse event data collection................................................................................ 34 
7.3.5 
Causality collection ............................................................................................... 35 
7.3.6 
Adverse events based on signs and symptoms ...................................................... 36 
7.3.7 
Adverse events based on examinations and tests .................................................. 36 
7.3.8 
Hy’s law ................................................................................................................ 36 
7.3.9 
Disease progression ............................................................................................... 36 
7.3.10 
New Cancers.......................................................................................................... 37 
7.3.11 
Lack of efficacy ..................................................................................................... 37 
7.3.12 
Deaths .................................................................................................................... 37 
7.3.13 
Olaparib adverse events of special interest ........................................................... 37 
7.4 
Safety reporting and medical management ........................................................... 38 
7.4.1 
Reporting of serious adverse events ...................................................................... 38 
7.4.2 
Pregnancy .............................................................................................................. 38 
7.4.2.1 
Maternal exposure ................................................................................................. 38 
7.4.3 
Overdose ................................................................................................................ 39 
7.4.4 
Management of adverse events Dose Reductions ................................................. 39 
7.4.4.1 
Management of haematological toxicity ............................................................... 40 
7.4.4.2 
Management of anaemia ....................................................................................... 40 
7.4.4.3 
Management of neutropenia, leukopenia and thrombocytopenia ......................... 41 
7.4.4.4 
Management of prolonged haematological toxicities while on study treatment ... 41 
7.4.4.5 
Management of non-haematological toxicity ........................................................ 42 
7.4.4.6 
Management of new or worsening pulmonary symptom ...................................... 42 
7.4.4.7 
Management of nausea and vomiting .................................................................... 42 
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7.4.4.8 
Interruptions for intercurrent non-toxicity related events ..................................... 43 
7.4.4.9 
Renal impairment .................................................................................................. 43 
7.5 
Biomarkers ............................................................................................................ 44 
7.5.1 
Storage, re-use and destruction of biomarker samples .......................................... 44 
8. 
STATISTICAL CONSIDERATIONS .................................................................. 44 
8.1 
Statistical hypotheses ............................................................................................ 44 
8.2 
Sample size determination..................................................................................... 44 
8.3 
Populations for analyses ........................................................................................ 44 
8.4 
Statistical analyses ................................................................................................. 45 
8.4.1 
Efficacy analyses ................................................................................................... 45 
8.4.2 
Safety analyses ...................................................................................................... 45 
8.5 
Interim analyses ..................................................................................................... 45 
8.5.1 
Data monitoring committee (DMC) ...................................................................... 45 
9. 
REFERENCES ...................................................................................................... 46 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 48 
 
LIST OF TABLES 
 
Table 1 
Study Treatments ..................................................................................... 23 
Table 2 
Prohibited medications............................................................................. 25 
Table 3 
Restricted concomitant medications ........................................................ 26 
Table 4 
Dose reductions for study treatment to manage adverse events .............. 29 
Table 5 
Dose reduction for study treatment if patient develops moderate renal 
impairment ............................................................................................... 29 
Table 6 
Dose reductions for study treatment if patient has to start taking a 
strong or moderate CYP3A inhibitor ....................................................... 29 
Table 7 
Laboratory safety variables ...................................................................... 32 
Table8 
Management of anemia ............................................................................ 40 
Table 9 
Management of neutropenia, leukopenia and thrombocytopenia ............ 41 
Table 10 
Dose reductions for study treatment ........................................................ 43 
 
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LIST OF FIGURES 
Figure 1 
Study design ............................................................................................. 11 
 
LIST OF APPENDICES 
 
 
Appendix A 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ............................................................................ 49 
Appendix B 
Acceptable Birth Control Methods .......................................................... 54 
 
 
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1. 
PROTOCOL SUMMARY 
1.1 
Schedule of Activities (SoA) 
 
1. Participants will be screened for eligibility with medical history, physical exam, prior 
treatment, history of anemia and blood tests including baseline CBC, reticulocyte count, 
ferritin, B-12 and serum folate level 
2. If inclusion criteria are met and after signing a consent form, participants will start olaparib 
300 mg twice daily, commercially approved  
3. Assessment of CBC/serum folate will occur every 2 weeks for the first 3 months and then 
monthly for a total of 6 months from the time of enrollment onto study therapy. If the patient 
develops folate deficiency and requires folate replacement, CBC/serum folate and 
reticulocyte count will occur every 2 weeks for 12 months. 
4. One-time measurement of serum folate to occur one month after completion or 
discontinuation of therapy with olaparib 
5. If folate deficiency is identified (defined as any level below normal) at any time point, the 
following parameters will be assessed in 2 weeks or at the next visit/assessment point: a  
repeat CBC/serum folate level along with B-12, LDH, reticulocyte count, methylmalonic 
acid, and homocysteine. These labs (CBC/serum folate level, B-12, LDH, reticulocyte count, 
methylmalonic acid, and homocysteine) need to be drawn once- 2 weeks after initial folate 
deficiency is identified for confirmation purposes and to rule out co-existing B-12 deficiency 
or other causes of anemia.  
6. Once folate deficiency is confirmed in the setting of hemoglobin (Hgb) less than  12 g/dl but 
above 10.0 g/dl, patients will be randomized to folate supplementation or placebo.  At that 
point, assessment of CBC/reticulocyte count and folate levels will continue every 2 weeks.  
7. If Hgb is above 12.0 g/dl and no folate deficiency is identified, patients will not be 
randomized. Assessment of CBC/serum folate will continue every 2 weeks for the first 3 
months and then monthly for a total of 6 months from the time of enrollment onto the study.  
8. If folate deficiency is identified in setting of Hgb less than 10.0 g/dl, patients will not be 
randomized but will receive folic acid supplementation at 1 mg daily. These patients will 
have weekly assessments of CBC/reticulocyte count and folate levels until Hgb improves to a 
level above 10.0 g/dl. At that point, assessment of CBC/reticulocyte count and folate levels 
will change back to every 2 weeks. However, folic acid replacement will continue as 
initiated. 
9. If a patient is already on folic acid supplements and continues to experience folate deficiency 
with a Hgb less than 10.0 g/dl, then folic acid dose can be increased to 2 mg daily or higher, 
at the discretion of the investigator. These patients will have weekly assessments of 
CBC/reticulocyte count and folate levels until Hgb improves to greater than 10.0 g/dl. At that 
point, assessment of CBC/reticulocyte count and folate levels will change back to every 2 
weeks. However, folic acid replacement will continue at the last dose.   
10. If folate deficiency is identified again in a patient who is already on folic acid 
supplementation, the following parameters will be assessed in 2 weeks or at the next 
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visit/assessment point: a  repeat CBC/serum folate level along with B-12, LDH, reticulocyte 
count, methylmalonic acid, and homocysteine (see item # 5). 
11. Tumor assessment will be performed as per treating physicians decision and would include 
regular clinical exams, tumor marker monitoring, and imaging (body CT scans) at every 3 -6 
month interval 
12. Safety assessments will be performed at every clinic visit 
13. Data on BRCA testing results (if performed as standard of care) will be collected at the time 
of enrollment and updated throughout the study duration. 
 
1.1.1 
Table of Schedule of Activities 
1.1.1 A -  PATIENTS WITH NORMAL FOLATE 
 
SCREENING
CYCLE 
/MONTH#1-
3 
CYCLE / 
MONTH 
#1-3  
BIWEEKLY 
LABS 
 
CYCLE / 
MONTH 
 #4 + 
END OF 
TREATMENT  
(1 MONTH  
POST STUDY 
TREATMENT 
Physical exam 
X 
X 
X 
X 
X 
Medical history
X 
X 
 
 
 
Prior treatment 
X 
X 
X 
 
 
Prior history of 
anemia 
X 
X 
X 
 
 
Con Meds 
X 
X 
X 
X 
X 
Adverse effects X 
X 
X 
X 
X 
CBC w/ diff 
X 
X 
X 
X 
 
CMP 
X 
X 
 
X 
 
Pt/PTT/INR* 
X1 
 
 
 
 
Urinalysis* 
X 1 
 
 
 
 
Urine 
pregnancy test 
X1 
X1 
 
 
 
Reticulocyte 
count 
X 
 
 
 
 
Ferritin 
X 
 
 
 
 
B-12 
X 
 
 
 
 
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Folate 
X 
X 
X 
X 
X 
LDH 
 
 
 
 
 
Methylmalonic 
Acid 
 
 
 
 
 
Homocysteine 
 
 
 
 
 
 
1. If clinically indicated 
 
 
1.1.1 B - PATIENTS WHO DEVELOP FOLATE DEFICIENCY 
 
CYCLE/ 
MONTH X 
DAY X 
+ FOLATE 
DEFICIENCY
IDENTIFIED 
 
RETURN IN 
2 WKS 
CYCLE/ 
MONTH 
X 
DAY #1 
CYCLE/ 
MONTH 
X 
(IF Hgb 
less than 
10.0 g/dl) 
weekly 
CYCLE/ 
MONTH 
X 
Biweekly 
labs  
(IF HGB is 
above 10.0 
g/dl 
END OF 
TREATMENT 
(1 MONTH 
POST STUDY 
TREATMENT)
Physical exam 
 
X 
 
 
X 
Con Meds 
 
X 
 
X 
X 
Adverse 
effects 
 
X 
 
X 
X 
CBC w/Diff 
X 
X 
X 
X 
 
CMP 
 
X 
 
 
 
Folate 
X 
X 
X 
X 
X 
Ferritin 
X 
 
 
 
 
B-12 
X 
 
 
 
 
Reticulocyte  
Count 
X 
X 
X 
X 
 
LDH 
X 
 
 
 
 
Methylmelanic
Acid 
X 
 
 
 
 
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Homocysteine 
X 
 
 
 
 
 
 
 
1.2 
Synopsis 
Protocol Title: A study of serum folate levels in patients treated with olaparib  
Rationale:  
Olaparib as well as other PARP inhibitors are known to cause hematologic toxicity, most 
commonly, macrocytic anemia regardless of the cancer type treated. The development of anemia 
may lead to blood transfusions, dose reductions and delay as well as drug discontinuation1. The 
cause of anemia is poorly understood. We have observed folate deficiency (<7 ng/mL) in 66% of 
patients treated with olaparib in a small group of patients with advanced ovarian and metastatic 
breast cancer occurring within weeks of treatment initiation with olaparib2, 3. Folate deficiency is 
a known cause of macrocytic anemia. However, it has not been previously reported in 
association with olaparib therapy. In our cohort of patients, folic acid replacement allowed us to 
avoid or decrease the need for blood transfusions, olaparib dose reduction and discontinuation of 
therapy. 
Statistical methods: 
A previous study by Rush investigators observed folate deficiency (<7 ng/mL) in 66% of 
patients treated with olaparib2, 3. Under this framework, a sample size of n=60 is calculated using 
one-sided test to have 80% power in detecting more than half (50%) of the patients having folate 
deficiency at 0.05 significance level. Allowing for 20% attrition, we propose a sample size of 
n=75 for this study. The statistical analysis will provide descriptive summaries of the primary 
endpoint of drug-induced folate deficiency as well the endpoint of response rate and other 
secondary endpoints. The significance of the observed percentage of folate-deficient cases will 
be assessed by statistical hypothesis test, as well as by multivariable analysis of the binary 
endpoint of folate deficiency adjusted by important covariates. The secondary endpoint of 
response rate to olaparib will be compared between the group who develop cytopenias, folate 
deficiency, and receive folic acid supplementation and the comparator group by descriptive 
summaries as well as by statistical hypothesis test. Statistical analysis will be performed in the R 
Statistical software. No adjustment for multiplicity will be made. Even though the sample size of 
75 is optimal to achieve primary and secondary objectives, it would be reasonable to initially 
accrue 30 patients and re-evaluate the need for continued accrual based on the percentage of 
patients who develop folate deficiency in this first phase. 
1.3 
Schema 
The general study design is summarised in Figure 1. Please refer to Schedule of Activities 
(Section 1.1) for detailed information about the timing of protocol- required blood draws and 
laboratory tests.  
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Figure 1 
Study design 
 
Prior to  
Enrollment 
 
Visit 1 
 
 
 
Bi-weekly 
Months 1-3 
 
 
Monthly labs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*If patient develops folate deficiency and 
Hgb less than 12 g/dl, but more than 10 
g/dl 
Next assessment in 2 weeks: CBC, folate, 
retic ct., B-12, LDH, methylmalonic acid, 
homocysteine 
Patients will be randomized to folate supplementation versus 
observation alone. 
Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria. Secure commercial approval of olaparib. 
Perform baseline assessment: CBC, reticulocyte count, ferritin, B-12, 
folate. Send tumor tissue if available for folate receptor testing (to be done 
at a later time). 
Begin olaparib 300 mg BID by mouth. 
Assessment: CBC, serum folate* 
Tumor response assessment performed and documented by treating 
physician.
Assessment: CBC, serum folate* 
Tumor response assessment performed and documented by treating 
physician (if clinically indicated). 
Folic acid 1 mg 
daily 
No 
supplementation 
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INTRODUCTION 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB). 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose)] polymerisation (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 agents4. 
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) 5, 6, 7 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 
models in vivo8, 9 and in the clinic5. The mechanism of action for olaparib results from the 
trapping of inactive PARP onto the single-strand breaks preventing their repair10, 11. Persistence 
*If patient develops folate deficiency and 
Hgb less than 10.0 g/dl, regardless of 
initial treatment group assignment 
Folic acid 1 mg 
daily ** 
** If a patient is already on folic acid supplements and continues to experience folate deficiency 
and Hgb less than 10.0 g/dl, folic acid dose can be increased to 2 mg daily or higher, at the 
discretion of the investigator. A hematology consultation can be obtained if necessary.    
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of SSBs during DNA replication results in their conversion into the more serious DNA 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 a stand-alone treatment or in combination with established 
chemotherapies. 
Initially, olaparib has been FDA approved for the treatment of advanced ovarian cancer 12 . Later, 
the indications have expanded. Currently, it is approved for the following indications13 -16 
-First-Line Maintenance BRCAm Advanced Ovarian Cancer (gBRCAm = germline BRCA- 
mutated or sBRCAm = somatic BRCA-mutated)  
-First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with 
Bevacizumab. Homologous recombination deficiency (HRD) positive status defined by either a 
deleterious or suspected deleterious BRCA mutation, and/or genomic instability. 
-Maintenance Recurrent Ovarian Cancer in patients who are in complete or partial 
response to platinum-based chemotherapy. 
-Advanced gBRCAm Ovarian Cancer in patients who have been treated with 3 or more 
prior lines of chemotherapy.  
-gBRCAm, HER2-Negative Metastatic Breast Cancer 
-First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer whose disease has not 
progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen  
-HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer in patients with 
deleterious germline or somatic homologous recombination repair (HRR) gene-mutated 
metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior 
treatment with enzalutamide or abiraterone .  
 
Molecular sequencing of the tumor DNA is increasingly used in clinical practice to identify 
molecularly-targeted agents that can potentially effectively and safely treat patients with 
advanced cancers. Olaparib is used in this setting when solid tumors harbor molecular alterations 
such as germline and somatic mutations in BRCA1 and BRCA2 genes, other genes in 
Homologous DNA Recombination pathway, etc17. A detailed description of the chemistry, 
pharmacology, efficacy, and safety of olaparib is provided in the package insert.  
1.4 
Study rationale 
See Section 1.2. 
We have observed folate deficiency in 66% of patients of patients with advanced ovarian and 
metastatic breast cancer occurring within weeks of treatment initiation with olaparib2, 3. While 
folate deficiency is a known cause of macrocytic anemia, it has not been previously reported in 
association with olaparib therapy. Since macrocytic anemia is a known complication of olaparib 
treatment regardless of the cancer type treated, folate deficiency can occur in these patients too. 
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This study is conducted to assess the prevalence and timing of folate deficiency in patients with 
ovarian, breast, pancreatic, prostate, and other cancers that may benefit from olaparib as 
determined by their treating physicians based on their tumor sequencing or germline results. . 
As folic acid supplementation has not been studied prospectively in this patient population, this 
study will also evaluate, in a randomized fashion, the impact of folic acid supplementation on 
anemia and need for transfusion as compared to a placebo group (i.e. no folic acid 
supplementation while on olaparib).  
 
Background 
Olaparib is generally well tolerated. For instance, in the clinical trial of maintenance olaparib 
monotherapy in patients with platinum-sensitive ovarian cancer who had had 2 or more lines of 
platinum-based chemotherapy (Study 19), adverse reactions led to olaparib dose interruption, 
reduction and discontinuation in 35 %, 26 %, and 6 % of patients, respectively13. Olaparib is 
known to cause hematologic toxicity. In the pooled analysis of multiple clinical trials, the 
following hematologic side effects were observed: anemia in 37% of patients, Macrocytosis 
(elevated mean corpuscular volume) is reported in up to 89% of patients treated with olaparib13. 
The manufacturer recommends monitoring blood counts at baseline and monthly thereafter, 
interrupting treatment until any hematologic toxicity has resolved to ≤ grade 1, with additional 
evaluation if blood counts do not recover after 4 weeks of treatment interruption, including bone 
marrow and cytogenetic analyses5, 6. Little is known about the etiology of olaparib-induced 
hematologic toxicity. 
 
2. 
OBJECTIVES AND ENDPOINTS 
Primary objective:  
To determine the frequency and timing of folate deficiency in patients with solid tumors 
harboring molecular alterations such as germline and somatic mutations in BRCA1 and BRCA2 
genes, other genes in Homologous DNA Recombination Repair (HRR) pathway, genomic 
stability as determined by Homologous Recombination Deficiency (HRD) assay, etc.,   who are 
treated with olaparib. 
Secondary objectives: 
To evaluate the effect of folic acid supplementation on serum folate, hemoglobin level, 
transfusion needs/number of transfusions, and need for olaparib treatment interruption, dose 
reduction and drug discontinuation.  
To assess response rate (RR) to olaparib as it relates to serum folate level and folic acid 
supplementation. 
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To assess progression-free survival (PFS) as it relates to serum folate level and folic acid 
supplementation. 
Exploratory objectives: 
To elucidate the mechanism of folate deficiency in patients treated with olaparib including 
possible interaction with germline BRCA1 and BRCA2 mutations via testing for folate receptors 
using immunohistochemistry on available paraffin embedded tumor samples from enrolled 
patients.  
 
Primary endpoint: 
The primary binary endpoint of the study is the percentage of patients who develop drug-induced 
folate deficiency, defined as serum folate level 7 ng/mL, within three months from start of 
olaparib therapy. 
Secondary endpoints: 
To assess the impact of folic acid supplementation on anemia, need for transfusion, and olaparib 
treatment interruption, dose reduction and drug discontinuation as compared to those who did not 
receive/require folic acid supplementation 
To determine tumor response rate (RR), using treating physician assessment, on olaparib therapy 
in patients who develop folate deficiency and receive folic acid supplementation as compared to 
those who do not receive/require folic acid supplementation. Will also compare RR to historical 
controls (patients with solid tumors treated with olaparib or other approved agents on clinical 
trials). 
To determine progression-free survival (PFS) ), using treating physician assessment based on 
olaparib therapy in patients who develop folate deficiency and receive folic acid supplementation 
as compared to those who do not receive/require folic acid supplementation. Will also compare 
PFS to historical controls (patients with solid tumors treated with olaparib or other approved 
agents on clinical trials) using published data. 
 
Exploratory Endpoints: 
To evaluate association between: 
 BRCA 1, BRCA 2, and other HRR gene status (germline mutation carrier vs non-carrier) 
and the intensity of folate receptor alpha expression in the tumor (50% or 50%) 
 BRCA 1, BRCA 2, and other HRR gene  status (germline mutation carrier vs non-carrier) 
and nadir serum folate level during olaparib treatment  
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 BRCA 1, BRCA 2, and other HRR gene  status (germline mutation carrier vs non-carrier) 
and tumor response in patients receiving folate supplementation as compared to patients 
not receiving folate supplementation and historical controls 
 Folate deficiency and expression of folate receptors in patients’ tumor samples 
3. 
STUDY DESIGN 
3.1 
Overall design 
This is a pilot, multi-center study evaluating the prevalence and timing of folate deficiency in 
patients with advanced solid tumors who are eligible to receive olaparib. 
If patients develop folate deficiency concomitantly with a Hgb less than 12.0 g/dl (grade 1), they 
will then be randomized to receive either a placebo or folate supplementation. 
All randomized patients who develop a Hgb less than 10 g/dl (grade 2) concomitantly with folate 
deficiency will receive folic acid supplementation irrespective of their prior randomization.  If 
such patients were originally randomized to receive folic acid and continue to have  a Hgb less 
than 10 g/dl and folate deficiency despite folate supplementation, folic acid dose will be 
increased to 2 mg daily or higher  at the discretion of the investigator.     
Patients will continue with olaparib until objective disease progression (determined by treating 
physician assessment) as long as in the Investigator’s opinion they are benefiting from treatment 
and they do not meet any other discontinuation criteria. 
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 5.1 Treatments Administered.   
For details on what is included in the efficacy and safety endpoints, see Section 2 Objectives and 
Endpoints.   
3.2 
Scientific rationale for study design 
See Section 1.2. 
3.3 
Justification for dose 
The dose of olaparib used in this study is 300 mg twice daily which is the currently FDA 
approved dose. Starting dose modifications based on the patient’s medical condition, for example 
creatinine clearance, are allowed. 
3.4 
End of study definition 
The end of study is defined as 7 months from enrolment. This is to include the one-month follow 
up physical exam, concomitant medications, adverse effects, and folate level 
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4. 
STUDY POPULATION 
This study will include all patients with solid tumors who can benefit from olaparib therapy for 
the treatment of their malignancy as determined by their primary oncologist. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, may be permitted by the principal investigators. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to assigned/randomised to a study intervention Patients, who do not meet the entry 
requirements are deemed as screen failures, refer to Section 5.4. 
4.1 
Inclusion criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
Informed consent 
1. 
Capable of providing a signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
2. 
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses.  
3. 
For inclusion in the optional biomarker research, patients must fulfil the following 
criteria: 
 
Provision of informed consent for biomarker research prior to collection of sample   
If a patient declines to participate in the optional biomarker research, there will be no penalty or 
loss of benefit to the patient.  The patient will not be excluded from other aspects of the study. 
 
Age 
4. 
Patient must be ≥18 years of age inclusive, at the time of signing the informed 
consent form. 
Type of patient and disease characteristics 
Patients with solid tumors harboring molecular alterations which are likely to respond olaparib, 
such as germline and somatic mutations in BRCA1 and BRCA2 genes, other genes in 
Homologous DNA Recombination Repair (HRR) pathway, genomic stability as determined by 
Homologous Recombination Deficiency (HRD) assay, etc.  Olaparib must be recommended to 
these patients by their treating physician.  
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6. 
Patients must have normal organ and bone marrow function measured within 28 days 
prior to administration of study treatment as defined below: 
 
Haemoglobin ≥ 10 g/dL with no blood transfusion in the past 28 days   
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
 
Platelet count ≥ 100 x 109/L 
 
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
 
Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present in which case they must be ≤ 5x ULN 
 
Patients must have creatinine clearance estimated of ≥51 mL/min using the 
Cockcroft-Gault equation or based on a 24 hour urine test : 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg)    (x F)a 
 
 
 
 
 
serum creatinine (mg/dL) x 72 
a where F=0.85 for females. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status 0-1).  
 
8. 
Patients must have a life expectancy ≥ 16 weeks. 
9. 
Patients with measurable and non-measurable disease are eligible.  
10. 
There is no limit on the number of prior therapy lines. Olaparib can be used in the 
front or a subsequent lines of therapy as well as maintenance. 
11. 
Patients can be enrolled with the lab results outside of the Inclusion criteria range or a 
performance status = 2, if olaparib is recommended by their treating 
oncologist/physician and the olaparib Package Insert is followed for dose 
adjustments. 
Sex 
12. 
Female or male  
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Reproduction 
13. 
Postmenopausal or evidence of non-childbearing status for women of childbearing 
potential: negative urine or serum pregnancy test within 28 days of study treatment 
and confirmed prior to treatment on day 1.  
Postmenopausal is defined as: 
 
Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments 
 
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the 
post-menopausal range for women under 50 
 
radiation-induced oophorectomy with last menses >1 year ago 
 
chemotherapy-induced menopause with >1 year interval since last menses 
 
surgical sterilisation (bilateral oophorectomy or hysterectomy) 
14. 
Advise male patients with female partners of reproductive potential or who are 
pregnant to use effective contraception during treatment and for 3 months following 
the last dose of olaparib and to not donate sperm during this time.  
 
 
4.2 
Exclusion criteria  
Medical conditions 
1. 
Patients with folic acid deficiency, defined as folate <7 ng/mL, or those taking folic 
acid supplementation within 30 days of olaparib initiation.  
2. 
Other malignancy unless curatively treated with no evidence of disease for ≥5 years  
except: adequately treated non-melanoma skin cancer, curatively treated in situ 
cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial 
carcinoma.  Patients with a history of localised triple negative breast cancer may be 
eligible, provided they completed their adjuvant chemotherapy more than three years 
prior to registration, and that the patient remains free of recurrent or metastatic 
disease  
3. 
Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) 
grade 2) caused by previous cancer therapy, excluding alopecia. 
4. 
Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features 
suggestive of MDS/AML. 
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5. 
Patients with 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. 
6. 
Patients considered a poor medical risk due to a serious, uncontrolled medical 
disorder, non-malignant systemic disease or active, uncontrolled infection.  Examples 
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. 
7. 
Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
8. 
Immunocompromised patients, e.g., patients who are known to be serologically 
positive for human immunodeficiency virus (HIV). 
9. 
Patients with known active hepatitis (i.e. Hepatitis B or C).  
 
Active hepatitis B virus (HBV) is defined by a known positive HBV surface 
antigen (HBsAg) result.  Patients with a past or resolved HBV infection 
(defined as the presence of hepatitis B core antibody and absence of 
HBsAg) are eligible. 
 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
10.  
Patients with the history of COVID19 are eligible only after two consecutive negative 
tests for COVID19. 
11. 
Any exceptions to the eligibility criteria may be discussed with the Principal 
Investigator on a case by case basis. 
 
Prior/concomitant therapy 
12. 
Any previous treatment with PARP inhibitor, including Olaparib, are allowed. 
13. 
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment. Exceptions may be discussed with 
the Principal Investigator. 
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14. 
 Patients receiving maintenance Bevacizumab as a single agent prior to the study and 
/or are planning to receive concomitant Bevacizumab with Olaparib are allowed. 
Patients who are receiving anti-hormonal  therapy or bone protecting agents are 
allowed. Exceptions may be discussed with the Principal Investigator. 
15. 
Patients who start Olaparib in combination with Bevacizumab are allowed.  
16. 
Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, 
indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A 
inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The 
required washout period prior to starting olaparib is 2 weeks. 
17. 
Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required 
washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital 
and 3 weeks for other agents. 
18. 
Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
19. 
Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
20. 
Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable). 
Prior/concurrent clinical study experience 
21. 
Participation in another clinical study with an investigational product administered in 
the last 1 month 
22. 
Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product. 
23. 
Patients with a known hypersensitivity to folic acid or any of the excipients of the 
product. 
 
Other exclusions 
24. 
Involvement in the planning and/or conduct of the study 
25. 
Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
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26. 
Previous enrolment in the present study.  
27. 
Breast feeding women.  
 
4.3 
Lifestyle restrictions 
4.3.1 
Meals and dietary restrictions 
It is prohibited to consume grapefruit juice, Seville oranges while on olaparib therapy. 
 
4.3.2 
Activity 
Contraception 
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination. This should be started from 
the signing of the informed consent and continue 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 . 
Men who are sexually active with women of childbearing potential must also agree to the terms 
listed above. 
For details of acceptable methods of contraception refer to Appendix B Acceptable Birth Control 
Methods. 
4.4 
Screen failures 
Screen failures are defined as patients who signed the informed consent form to participate in the 
clinical study but are not subsequently entered in the study.  Minimal information includes 
demography, screen failure details, eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.   
5. 
STUDY TREATMENTS 
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) intended to be administered to a study participant according to the 
study protocol. Study treatment in this study refers to olaparib and folic acid supplementation. 
5.1 
Treatments administered 
 
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Table 1 
Study Treatments 
 
Treatment 1 
Treatment 2 
Study treatment name 
 
Olaparib 
Folic acid 
Dosage formulation 
300 mg BID 
1 mg daily  
 
 
 
 
Route of administration  
Oral 
Oral 
Dosing instructions 
 
Olaparib tablets 
should be taken at 
the same time each 
day, approximately 
12 hours apart with 
one glass of water.  
The tablets should 
be swallowed whole 
and not chewed, 
crushed, dissolved 
or divided. Olaparib 
tablets can be taken 
with or without 
food. 
Folic acid 
supplementation 
should be taken at 
the same time 
each day, with 
one glass of 
water. The tablets 
should be 
swallowed whole 
and not chewed, 
crushed, 
dissolved or 
divided. Can be 
taken with or 
without food.  
Packaging and labelling 
 
Study treatment will 
be prescribed by 
provider. Each 
container will be 
labelled in 
accordance with 
Good 
Manufacturing 
Practice (GMP) 
Annex 13 and per 
country regulatory 
requirement. 
Olaparib will be 
commercially 
supplied. 
Study treatment 
will be prescribed 
by provider.  
 
If vomiting occurs shortly after the olaparib or folic acid tablets are swallowed, the dose should 
only be replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled 
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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 that scheduled dose time.  If greater than 2 hours after the scheduled dose time, the 
missed dose is not to be taken and the patient should take their allotted dose at the next scheduled 
time. 
 
5.2 
Preparation/handling/storage/accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only patients enrolled in the study may receive study treatment and only authorised site staff 
may dispense study treatment.  At site, all study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are 
provided. 
 
5.3 
Measures to minimise bias: randomisation and blinding 
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused.  Withdrawn patients will not be replaced  
 
5.4 
Treatment compliance  
Patients should be given clear instructions on how and when to take their study treatment.  
Patients will self-administer olaparib and folic acid. Patients will be given a medication calendar 
to document the olaparib and (if applicable) folate doses taken. Study site staff will review the 
calendar monthly with the patient and discuss reasons for missed doses, if any. Patients will be 
instructed to notify study site personnel of missed doses.   
Any change from the dosing schedule, does interruptions, dose reductions, and dose 
discontinuations should be recorded in eCRF. 
The Investigational Product Storage Manager is responsible for managing the Investigational 
Medicinal Product (IMP) from receipt by the study site until the destruction or return of all 
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unused IMP.  The Investigator(s) is responsible for ensuring that the patient has returned all 
unused IMP. 
 
5.5 
Concomitant therapy 
The use of any natural/herbal products or other 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 along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency 
The information on vitamin intake will be collected at the baseline and throughout the duration 
of the study. Patients will be discouraged to take folate-containing vitamin supplements for at 
least three months after starting olaparib therapy. However, if they have been on them before the 
enrolment and decline holding them, they are still eligible to participate.  
Anti-emetics/Anti-diarrheals 
From screening onwards, should a patient develop nausea, vomiting and / or diarrhea, then these 
symptoms should be reported as AEs (see Section 8.3) and appropriate treatment of the event 
given. 
Medications that may NOT be administered 
Table 2 
Prohibited medications 
Prohibited medication/class of drug: 
 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Radiotherapy (except palliative) 
Biological therapy 
Other novel agents 
Not permitted while the patient is receiving study 
medication 
 
 
*Hormone Replacement Therapy (HRT) is acceptable 
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*Anti-hormonal agents such as aromatase inhibitors are acceptable. 
 
Restricted concomitant medications 
 
Table 3 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
 
 
Strong CYP3A inhibitors: 
itraconazole, telithromycin, clarithromycin, 
boosted protease inhibitors, indinavir, 
saquinavir, nelfinavir, boceprevir, 
telaprevir 
 
Moderate CYP3A inhibitors: 
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil  
 
Strong or moderate CYP3A inhibitors should not 
be taken with olaparib.  If there is no suitable 
alternative concomitant medication then the dose 
of olaparib should be reduced for the period of 
concomitant administration. The dose reduction 
of olaparib should be recorded in the CRF with 
the reason documented as concomitant CYP3A 
inhibitor use.  
• 
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. 
 
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Table 3 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Strong inducers: 
phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s 
Wort 
 
Moderate CYP3A inducers: 
 bosentan, efavirenz and modafinil 
Strong or moderate CYP3A inducers should not 
be taken with olaparib. 
If the use of any strong or moderate CYP3A 
inducers are considered necessary for the 
patient’s safety and welfare this could diminish 
the clinical efficacy of olaparib. 
If a patient requires use of a strong or moderate 
CYP3A inducer then they must be monitored 
carefully for any change in efficacy of olaparib. 
 CYP3A4 substrates: hormonal 
contraceptive, simvastatin, 
cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, 
sirolimus, tacrolimus and 
quetiapine 
 CYP2B6 substrates: bupropion, 
efavirenz 
 OATP1B1substrates: bosentan, 
glibenclamide, repaglinide, statins 
and valsartan 
 OCT1, MATE1 and MATE2K 
substrates:  metformin 
 OCT2 substrates: serum creatinine 
 OAT3 substrates: furosemide, 
methotrexate 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may 
increase the exposure to substrates of CYP3A4, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and 
MATE2K. 
 Based on limited in vitro data, olaparib may 
reduce the exposure to substrates of 2B6. 
Caution should be observed if substrates of these 
isoenzymes or transporter proteins are co-
administered. 
 
Anticoagulant therapy 
Patients who are taking warfarin may participate 
in this trial; however, it is recommended that 
international normalised ratio (INR) be 
monitored carefully at least once per week for 
the first month, then monthly if the INR is stable. 
Subcutaneous heparin and low molecular weight 
heparin are permitted. 
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Table 3 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Palliative radiotherapy 
Palliative radiotherapy may be used for the 
treatment of pain at the site of bony metastases 
that were present at baseline, provided the 
investigator does not feel that these are indicative 
of clinical disease progression during the study 
period.  Study treatment should be discontinued 
for a minimum of 3 days before a patient 
undergoes therapeutic palliative radiation 
treatment.  Study treatment should be restarted 
within 4 weeks as long as any bone marrow 
toxicity has recovered.   
Administration of other anti-cancer agents 
 
Patients must not receive any other concurrent 
anti-cancer therapy, including investigational 
agents, while on study treatment. Patients may 
continue the use of bisphosphonates or 
denosumab for bone disease and corticosteroids 
for the symptomatic control of brain metastases 
provided the dose is stable before and during the 
study and they were started at least 4 weeks prior 
to beginning study treatment.  
 
 
 
 
 
5.5.1 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the CRF. 
In addition, any unplanned diagnostic, therapeutic or surgical procedure performed during the 
study period must be recorded in the CRF. 
5.6 
Dose modification 
 
Dose Reductions  
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In case a dose reduction is necessary, the Study treatment will be administered as follows:  
Table 4 
Dose reductions for olaparib 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 
250 mg twice daily 
200 mg twice daily 
150 mg twice daily 
200 mg twice daily 
150 mg twice daily 
100 mg twice daily 
 
 
Table 5 
Dose reduction for olaparib 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 
If starting dose is 200 mg twice daily, and patient develops renal impairment, dose modification 
will be determined by the treating physician. 
Table 6 
Dose reductions for olaparib if patient has to start taking a strong or 
moderate CYP3A inhibitor 
Initial Dose 
Strong CYP3A inhibitor 
Moderate CYP3A inhibitor 
300 mg twice daily 
100 mg twice daily 
150 mg twice daily 
If starting dose is 200 mg twice daily, and patient is required to take a strong or moderate 
CYP3A inhibitor, dose modification will be determined by the treating physician. 
For guidance on dose reductions for management of AEs (including renal impairment) refer to 
Section 8.4.4. 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors cannot 
be avoided see Section 6.5. 
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 (see Section 8.4.4), or one 150 mg tablet twice 
daily or one 100 mg tablet twice daily (see Section 6.5). 
Folic Acid dose modification: 
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Patients with folate deficiency will start folic acid supplementation at 1 mg daily.  If they 
continue to have  a Hgb less than 10 g/dl (grade 2) and folate deficiency despite folate 
supplementation, folic acid dose can  be increased to 2 mg daily or higher at the discretion of the 
investigator.     
 
5.7 
Treatment after the end of the study 
Not applicable - please see Section 4.1 for details of treatment after the study database has been 
closed.   
6. 
DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL 
6.1 
Discontinuation of study treatment  
Patients may be discontinued from investigational product (IP) in the following situations. Note 
that discontinuation from study treatment is NOT the same thing as a complete withdrawal from 
the study 
 
Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
 
Adverse Event 
 
Severe non-compliance with the Clinical Study Protocol  
 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukaemia (AML) 
6.1.1 
Procedures for discontinuation of study treatment 
The investigator should instruct the patient to contact the site before or at the time if Study 
treatment is stopped.  A patient that decides to discontinue Study treatment will always be asked 
about the reason(s) and the presence of any AEs.  The date of last intake of Study treatment 
should be documented in the CRF (electronic or paper).  All Study treatment should be returned 
by the patient at their next on-site study visit or unscheduled visit.  Patients permanently 
discontinuing Study treatment should be given locally available standard of care therapy, at the 
discretion of the Investigator. 
Any patient discontinuing investigational product should be seen post discontinuation for the 
evaluations and sample collections outlined in the study schedule.  
After discontinuation of the study medication at any point in the study, all ongoing AEs or SAEs 
must be followed until resolution unless, in the Investigator’s opinion the condition is unlikely to 
resolve due to the patients underlying disease, or the patient is lost to follow up (see Section 7.2). 
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All new AEs and SAEs occurring during the 30 calendar days after the last dose of study 
medication must be reported (if SAEs, they must be reported within 24 hours as described in 
Section 8.4.1) and followed to resolution as above. Patients should be seen at least 30 days after 
discontinuing study medication to collect and / or complete AE information. For guidance on 
reporting adverse events after the 30 day follow up period see Section 7.3.2.1. 
Discontinuation of Study treatment, for any reason, does not impact on the patient´s participation 
in the study.  The patient should continue attending subsequent study visits and data collection 
should continue according to the study protocol.  If the patient does not agree to continue in-
person study visits, a modified follow-up must be arranged to ensure the collection of endpoints 
and safety information.  This could be a telephone contact with the patient, a contact with a 
relative or treating physician, or information from medical records.  The approach taken should 
be recorded in the medical records.  A patient that agrees to modified follow-up is not considered 
to have withdrawn consent or to have withdrawn from the study. 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
 
7.1 
Efficacy assessments  
7.1.1 
Clinical outcome assessments 
Evaluate the percentage of patients who develop drug-induced folate deficiency while on 
olaparib, defined as serum folate level 7 ng/mL.  
Determine the impact of folic acid supplementation on anemia, need for transfusion, and dose 
modification of olaparib as compared to those who did not receive/require folic acid 
supplementation. 
Tumor assessment will be performed as per treating physician’s decision and would include 
regular clinical exams, tumor marker monitoring, and imaging (body CT scans) at every 3 -6 
month interval.  Tumor response will be evaluated according to treating physician assessment. 
Response rate is defined as achievement of complete response (CR) or partial response (PR). 
Progression free survival, PFS, is defined as time from enrolment until disease progression or 
death. Patients who withdrew from olaparib before disease progression or death will be censored 
at the date of their last tumor assessment.  
 
7.2 
Safety assessments  
Planned time points for all safety assessments are provided in the SoA. 
7.2.1 
Clinical safety laboratory assessments 
 
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Table 7 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin (Hgb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Absolute neutrophil count 
S/P-Alkaline phosphatise (ALP) 
B-Absolute lymphocyte count 
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT) 
B-Mean cell volume (MCV) 
S/P-Albumin 
S/P-Potassium 
S/P-Calcium, total 
 
S/P-Sodium 
Urinalysis (dipstick, if clinically indicated for) 
S/P-Urea or Blood Urea Nitrogen (BUN) 
U-Hgb/Erythrocytes/Blood  
S/P-Total Protein 
U-Protein/Albumin  
 
U-Glucose  
 
NB. In case a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN 
please refer to Appendix A ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions. 
7.2.1.1 
Coagulation (if clinically indicated) 
· 
activated partial thromboblastin time {APTT} will be performed if clinically indicated   
· 
international normalised ratio {INR} will be performed if clinically indicated. Patients 
taking warfarin may participate in this study; however, it is recommended that INR be monitored 
carefully at least once per week for the first month, then monthly if the INR is stable. 
Each coagulation test result will be recorded in CRF. 
7.2.1.2 
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
haematological toxicities as defined in Section 8.4.4.1.3. 
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. Full reports must be provided by the 
investigator for documentation on the Patient Safety database. These data are not required to be 
entered into CRF. 
 
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7.2.2 
Physical examinations 
Physical exam will be performed and documented at each monthly visit. 
7.2.3 
Vital signs 
Vital signs will be performed and documented at each monthly visit. 
7.2.4 
Other safety assessments 
7.2.4.1 
Serum or urine pregnancy test 
Pregnancy tests on blood or urine samples will be performed for women of childbearing potential 
within 28 days prior to the start of study treatment and on Day 1 of each monthly visit while on 
the study. Tests will be performed by the hospital’s local laboratory. If results are positive the 
patient is ineligible/must be discontinued from study treatment immediately.  Details of the 
pregnancy tests must be recorded in the patient’s medical records. 
7.3 
Collection of adverse events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).   
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
Section 8.3.3.   
7.3.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.   
7.3.2 
Time period and frequency for collecting AE and SAE information  
Adverse Events will be collected from time of enrolment throughout the treatment period and 
including the follow-up period until the last contact. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the investigator may notify the sponsor. 
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The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in CRF. 
7.3.2.1 
Adverse events after the 30 day follow up period  
For Pharmacovigilance purposes and characterisation, any SAE of MDS/AML or new primary 
malignancy occurring after the 30 day follow up period should be reported to AstraZeneca 
Patient Safety regardless of investigator’s assessment of causality or knowledge of the treatment 
arm.  Investigators will be asked during the regular follow up for overall survival if the patient 
has developed MDS/AML or a new primary malignancy and prompted to report any such cases.   
At any time after a patient has completed the study, if an Investigator learns of any SAE 
including sudden death of unknown cause, and he/she considers there is a reasonable possibility 
that the event is causally related to the investigational product (folate), the investigator should 
notify the Principal Investigator. 
If patients who are gaining clinical benefit are allowed to continue study treatment post data cut 
off and/or post study completion then all SAEs must continue to be collected and reported to 
Patient Safety within the usual timeframe. After study treatment completion (i.e. after any 
scheduled post treatment follow-up period has ended) there is no obligation to actively report 
information on new AEs or SAEs occurring in former study patients. This includes new 
AEs/SAEs in patients still being followed up for survival but who have completed the post 
treatment follow up period (30 days). 
7.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient at 
subsequent visits/contacts.  All SAE/non-serious AEs/AEs of special interest, will be followed 
until resolution, stabilization, the event is otherwise explained, or the patient is lost to follow-up  
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF.  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. 
Any SAE or non-serious adverse event that is ongoing at the time of the 30-day follow up, must 
be followed up to resolution unless the event is considered by the investigator to be unlikely to 
resolve, or the patient is lost to follow up. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary 
7.3.4 
Adverse event data collection 
The following variables will be collect for each AE; 
 
AE (verbatim) 
 
The date and time when the AE started and stopped 
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 
CTCAE grade and changes in CTCAE grade 
 
Whether the AE is serious or not 
 
Investigator causality rating against the Investigational Product(s) (no) 
 
Action taken with regard to Investigational Product(s) 
 
AE caused patient’s withdrawal from study 
 
Outcome. 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date Investigator became aware of serious AE 
 
AE is serious due to. 
 
Date of hospitalisation 
 
Date of discharge 
 
Probable cause of death 
 
Date of death 
 
Autopsy performed 
 
Causality assessment in relation to Study procedure(s) 
 
Causality assessment to other medication' 
 
Description of AE 
7.3.5 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in the Clinical Study Protocol. 
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7.3.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you had any health problems since the previous 
visit/you were last asked?’, or revealed by observation will be collected and recorded in the CRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
7.3.7 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs should therefore only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information.  Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study, see Sections 8.3.9 and 8.3.10. 
7.3.8 
Hy’s law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to be 
reported as SAEs.  Please refer to Appendix A for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law 
7.3.9 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE.  Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study. 
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7.3.10 
New Cancers 
The development of a new primary cancer should be reported as an AE (see Section 8.3.13 
Olaparib Adverse Events of Special Interest) and would in most cases meet seriousness criteria 
(with the exception of some non-melanoma skin cancers). New primary malignancies are those 
that are not the primary reason for the administration of the study treatment and have developed 
after the inclusion of the patient into the study.  They do not include metastases of the original 
cancer.  Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as 
they are considered to be disease progression. 
7.3.11 
Lack of efficacy 
When there is deterioration in the cancer, for which the study treatment(s) is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the 
Sponsor or the reporting physician considers that the study treatment contributed to the 
deterioration of the condition, or local regulations state to the contrary, the deterioration should 
be considered to be a lack of efficacy and not an AE. 
7.3.12 
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 CRF but should not be 
reported as an SAE. 
 
Where 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 a SAE within 
24 hours (see Section 8.4.1 for further details).  The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death.  This information can be captured in the 
CRF. 
Deaths with an unknown cause should always be reported as a SAE.  A post mortem maybe 
helpful in the assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to AstraZeneca within the usual timeframes. 
7.3.13 
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. Adverse Events of Special Interest for 
olaparib are the Important Potential Risks of MDS/AML, new primary malignancy (other than 
MDS/AML) and pneumonitis.   
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 
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AESIs that require the use of a questionnaire to help characterise the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
7.4 
Safety reporting and medical management 
7.4.1 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 24 
hours  of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it. 
7.4.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
 
If the pregnancy is discovered before the study patient has received any study drug 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
7.4.2.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, olaparib should be discontinued 
immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication.  Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs.  Elective abortions without complications should not be handled 
as AEs.  The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) occurring from the date of the first dose of 
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study medication until 1 month after the last dose of study medication should be followed up and 
documented even if the patient was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
 
7.4.3 
Overdose 
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 twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and should be 
managed appropriately. 
 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 7.3.2.  
For other overdoses, reporting must occur within 30 days. 
 
7.4.4 
Management of adverse events Dose Reductions 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, for 
a maximum of 4 weeks on each occasion. If the interruption is any longer, the study team must 
be informed. Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 
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mg twice daily as a second step. If the reduced dose of 200 mg twice daily is not tolerable, no 
further dose reduction is allowed, and study treatment should be discontinued.  
Once dose is reduced, escalation is not permitted (except following concomitant treatment with 
CYP3A4 inhibitors – see Section 6.5 
7.4.4.1 
Management of haematological toxicity 
7.4.4.2 
Management of anaemia 
Table 8 
Management of anaemia 
Haemoglobin 
Action to be taken 
Hgb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
First occurrence: 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment 
(e.g., transfusion) or interrupt dose for a maximum of 4 weeks. Study 
treatment can be restarted if Hb has recovered to > 9g/dl. 
Subsequent occurrences: 
If Hgb< 10 but ≥ 9 g/dl investigator judgement to continue olaparib with 
supportive treatment (e.g., transfusion) or dose interrupt (for max of 4 
weeks) and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
If Hgb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 
g/dl and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step).  
Hgb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g., transfusion) and investigate 
causality.  
Interrupt olaparib for a maximum of 4 weeks until improved to Hgb ≥ 9 
g/dl. 
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hgb decrease. 
 
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. For cases where patients develop prolonged 
haematological toxicity (≥2 week interruption/delay in study treatment due to CTC grade 3 (Hgb 
less than 8.0 g/dl) or worse anemia and/or development of blood transfusion dependence), refer 
to guidance later in this section for the management of this.  
 
 
 
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7.4.4.3 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 9 
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 4 weeks; appropriate supportive treatment 
and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 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 
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 CTC 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. 
For cases where patients develop prolonged haematological toxicity (≥2 week interruption/delay 
in study treatment due to CTC grade 3 or worse), refer to guidance later in this section for the 
management of this.  
 
7.4.4.4 
Management of prolonged haematological toxicities while on study treatment 
If a patient develops prolonged haematological toxicity such as: 
 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia 
and/or development of blood transfusion dependence 
 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
neutropenia (ANC < 1 x 109/L) 
 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 
50 x 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient 
should be referred to haematologist for further investigations. Bone marrow analysis and/or 
blood cytogenetic analysis should be considered at this stage according to standard 
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haematological practice. Study treatment should be discontinued if blood counts do not recover 
to CTC gr 1 or better within 4 weeks of dose interruption. 
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. 
7.4.4.5 
Management of non-haematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. 
If the interruption is any longer than this the study monitor must be informed.  Where toxicity 
reoccurs following re-challenge with study treatment, and where further dose interruptions are 
considered inadequate for management of toxicity, then the patient should be considered for dose 
reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice 
daily as a second step (see section 5.6 for more information on dose modification guidance). 
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. 
7.4.4.6 
Management of new or worsening pulmonary symptom 
If new or worsening pulmonary symptoms (e.g., dyspnoea) 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. 
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 Study 
Physician. 
7.4.4.7 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. 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). 
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As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered eg dopamine receptor antagonist, antihistamines or 
dexamethasone. 
7.4.4.8 
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 AZ study physician. 
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 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.  
Table 10 
Dose reductions for study treatment 
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 
250 mg twice daily 
200 mg twice daily 
150 mg twice daily 
200 mg twice daily 
150 mg twice daily 
100 mg twice daily 
 
7.4.4.9 
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 or 
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. 
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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 is it recommended that olaparib be discontinued. 
 
7.5 
Biomarkers 
Optional samples for biomarker research that should be collected from patients in the study 
where possible are the following: 
 
Existing paraffin embedded tissue samples from patients will be collected for 
assessment of folate receptors via immunohistochemical staining as according to the 
previously stated Exploratory Objective/Endpoint.  
Unless otherwise specified in the protocol, biomarker data will not be routinely reported to sites 
unless specifically requested. Frequently, biomarker data are generated retrospectively towards 
the end of the study. Any sample material remaining after completion of analyses to fulfil the 
study objectives may be used for optional exploratory research to develop methods, assays, 
prognostics, and/or companion diagnostics related to cancer, disease process, pathways 
associated with disease state, PARP, and or mechanism of action of olaparib. 
7.5.1 
Storage, re-use and destruction of biomarker samples 
Samples will be stored for a maximum of 10 years from the date of the Last Patient’s Last Visit, 
after which they will be destroyed.  The results of this biomarker research will be reported either 
in the CSR itself or as an addendum, or separately in a scientific report or publication.  The 
results of this biomarker research may be pooled with biomarker data from other studies with the 
study drug to generate hypotheses to be tested in future research. 
8. 
STATISTICAL CONSIDERATIONS  
8.1 
Statistical hypotheses 
 Olaparib-treated patients develop folate deficiency 
 Replacing folic acid in these patients can mitigate olaparib-induced adverse events 
related to its hematologic toxicity (anemia, transfusion needs/number of transfusions, 
dose reductions and drug discontinuation)  
 Folate replacement does not affect an antineoplastic effect of olaparib 
8.2 
Sample size determination  
A previous study by Rush investigators observed folate deficiency (<7 ng/mL) in 66% of 
patients treated with olaparib. A sample size of n=60 is calculated using one-sided test to have 
80% power in detecting more than half (50%) of the patients having folate deficiency at 0.05 
significance level. Allowing for 20% attrition, we propose a sample size of n=75 for this study. 
8.3 
Populations for analyses 
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All enrolled patients who receive at least one dose of olaparib will be included in the analysis 
population to be used to assess the efficacy and safety endpoints.  
8.4 
Statistical analyses 
8.4.1 
Efficacy analyses 
Patients will be monitored for development of anemia and folate deficiency at scheduled time 
points throughout the course of the study, as described in Section 1.1. Patients who develop ≤G2 
cytopenias and folate deficiency will be randomly assigned in a 1:1 ratio to receive folic acid 
supplementation 1 mg daily or no supplementation. Patients who develop G3 or higher 
cytopenias and folate deficiency will be started on folic acid supplementation, thus not included 
in the randomization.  For patients who are randomized, we will assess the impact of folic acid 
supplementation on anemia, need for transfusion, and dose interruption, dose reduction and drug 
discontinuation of olaparib as compared to those who did not receive/require folic acid 
supplementation. Additionally, PFS and RR to olaparib will be compared amongst randomized 
patients relative to folic acid supplementation. 
The statistical analysis will provide descriptive summaries as well as 95% confidence intervals 
for the primary endpoint of drug-induced folate deficiency in addition to response rate and other 
secondary endpoints. Kaplan-Meier methodology will be used to estimate the PFS curve and 
estimate of median PFS and corresponding 95% confidence interval will be provided. The 
significance of the observed percentage of folate-deficient cases will be assessed by statistical 
hypothesis test, as well as by multivariable analysis of the binary endpoint of folate deficiency 
adjusted by important covariates. Covariates will include age, race/ethnic group, previous 
therapy, Hgb prior to olaparib therapy, genetic testing result (BRCA carrier status). RR and PFS 
will be compared to historical controls as a descriptive comparison. Analyses will be reported on 
the entire combined cohort of patients with solid tumors and also separately for each cancer type. 
The statistical analysis of the exploratory endpoint will be specified in the SAP. Statistical 
analysis will be performed in the R Statistical software. No adjustment for multiplicity will be 
made. 
8.4.2 
Safety analyses 
Tabulations and descriptive summaries of adverse events (AEs) and serious adverse events 
(SAEs) will be reported as described in Section 8. Adverse events will be compared among the 
comparator groups of the study.  
8.5  
 Interim analyses 
We consider would be reasonable to initially accrue 30 patients and re-evaluate the need for 
continued accrual based on the percentage of patients who develop folate deficiency in this first 
phase. 
8.5.1 
Data monitoring committee (DMC) 
A data monitoring committee will not be utilized for this study.  The study will be monitored by 
the study investigators and information will be shared with the funder company (Astra/Zeneca). 
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9. 
REFERENCES 
 
1) Lynparza [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP; 2014. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf. Published 
2014.  
2) Shammo JM, Usha L, Richardson K, Elliott E, Dewdney S, Venugopal P, Cobleigh M, 
Kuzel T. Olaparib-induced severe folate deficiency in women with relapsed ovarian 
cancer: First report and case series. J Clin Oncol (ASCO Annual Meeting Abstracts) 
https://meetinglibrary.asco.org/record/163750/abstract Published May 16, 2018. 
3) Shammo JM, Usha L, Richardson K, Elliott E, Venugopal P, Kuzel T, Cobleigh M 
Dewdney S. First report of severe folate deficiency in women treated with olaparib for 
relapsed ovarian cancer. Blood (ASH Annual Meeting Abstracts) 
http://www.bloodjournal.org/content/130/Suppl_1/4748/tab-article-info Published 
December 7, 2017. 
4) Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with 
platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of 
outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-
861. doi:10.1016/S1470-2045(14)70228-1 
5) A two-stage Simon Design Phase II Study for non-BRCA MBC patietns with HRD 
treated with olaparib single agent (NOBROLA). Available from: 
https://clinicaltrials.gov/ct2/show/NCT03367689. NLM identifier: NCT03367689. Last 
accessed January 4, 2019  
6) Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly 
(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 
2009;361(2):123-34. 
7) Olaparib tablets as a treatment for ovarian cancer subjects with different HRD tumor 
status. Available from: https://clinicaltrials.gov/ct2/show/NCT02983799. NLM identifier: 
NCT02983799. Accessed July 24, 2018. 
8) Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al. Poly(ADP-ribose) 
polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary 
tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 
2009;69(9):3850-5.  
9) Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. 
High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 
alone and in combination with platinum drugs. Proc Natl Acad Sci. 2008;105(44):17079-
84. 
10) Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: 
Clearing up the misunderstandings. Molecular Oncology 2011; 5: 387-393. 
11) Murai J, Huang SN, Das BB, Renaud A, Zhnag, Y, Doroshow, JH, et al. Trapping of 
PARP1 and PARP2 by Clinical PARP Inhibitors. AACR; 72(21); 5588–99. 
12) Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier 
W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, 
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Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian 
cancer. N Engl J Med. 2012; 366(15);1382. Epub 2012 Mar 27. 
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14) Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung 
N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast 
Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017; 377(6); 523. 
Epub 2017 Jun 4.  
15) Hammel P, Kindler HL, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, 
Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algül H, O'Reilly 
EM, McGuinness D, Cui KY, Joo S, Yoo HK, Patel N, Golan T, POLO Investigators. 
Health-related quality of life in patients with a germline BRCA mutation and metastatic 
pancreatic cancer receiving maintenance olaparib. Ann Oncol. 2019; 30(12); 1959. 
16) Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, Syndikus I, Ralph C, 
Jain S, Varughese M, Parikh O, Crabb S, Robinson A, McLaren D, Birtle A, Tanguay J, 
Miranda S, Figueiredo I, Seed G, Bertan C, Flohr P, Ebbs B, Rescigno P, Fowler G, 
Ferreira A, Riisnaes R, Pereira R, Curcean A, Chandler R, Clarke M, Gurel B, Crespo M, 
Nava Rodrigues D, Sandhu S, Espinasse A, Chatfield P, Tunariu N, Yuan W, Hall E, 
Carreira S, de Bono JS. Olaparib in patients with metastatic castration-resistant prostate 
cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, 
randomised, phase 2 trial. Lancet Oncol. 2020; 21(1); 162. Epub 2019 Dec 2. 
17) Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña 
J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, 
Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced 
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Nov 3. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
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Appendix A Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law 
A 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries.  Specific guidance on managing liver abnormalities can be found 
in Section 8.4 of the Clinical Study Protocol. 
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 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 (IP).   
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. 
A 2 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication  irrespective of an increase in alkaline phosphatase (ALP).   
Hy’s Law (HL) 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, 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.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur. 
A 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 ≥ 3 × ULN 
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 
AST ≥ 3 × ULN 
 
TBL ≥ 2 × ULN 
When a patient meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (and also to the AstraZeneca 
representative).   
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
 
Notify the AstraZeneca representative 
 
Request a repeat of the test (new blood draw) by the central laboratory 
 
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
 
Determine whether the patient meets PHL criteria (see Appendix A 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results) 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
 
Notify the AstraZeneca representative 
 
Determine whether the patient meets PHL criteria (see Appendix A 2 for definition) by 
reviewing laboratory reports from all previous visits 
 
Promptly enter the laboratory data into the laboratory CRF 
A 4 
Follow-up 
A 4.1 
Potential Hy’s Law criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
 
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
A 4.2 
Potential Hy’s Law criteria met 
If the patient does meet PHL criteria the Investigator will: 
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Determine whether PHL criteria were met at any study visit prior to starting Study treatment 
(See Section 8.4 Safety Reporting) 
 
Notify the AstraZeneca 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: 
 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.   
 
Complete the three Liver CRF Modules as information becomes available  
 
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. 
A 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 Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other patient 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 a SAE: 
 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
 
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.   
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 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
 
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 assumed 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 amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined. 
A 6 
Actions required when potential Hy’s Law criteria are met before and 
after starting study treatment 
This section is applicable to patients with liver metastases who meet PHL criteria on Study 
treatment having previously met PHL criteria at a study visit prior to starting Study treatment. 
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the last 
visit where PHL criteria were met.#  
 
If there is no significant change, no action is required 
 
If there is a significant change, notify the AstraZeneca representative, who will inform 
the central Study Team, then follow the subsequent process described in Appendix A4. 
 
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 may be in consultation with the Study Physician if 
there is any uncertainty. 
A 7 
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. 
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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 found to be the 
disease under study (e.g., chronic or progressing malignant disease, severe infection or liver 
disease), or did the patient meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in Appendix  A 6 
If No: Follow the process described in Appendix A 4.1. 
If Yes: Determine if there has been a significant# change in the patient’s condition 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 Appendix A 4. 
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 may 
be in consultation with the AstraZeneca Physician if there is any uncertainty. 
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Appendix B Acceptable Birth Control Methods 
 
Olaparib is regarded as a compound with medium/high foetal risk. 
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination [as listed below].  This 
should be started from the signing of the informed consent and continue 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/True abstinence: When the patient refrains from any form of sexual intercourse and this 
is in line with their usual and/or preferred lifestyle; this must continue for the total duration 
of the trial and for at least 1 month after the last dose of study drug. [Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods, or declaration of 
abstinence solely for the duration of a trial) 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 (e.g., 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 (e.g., levonorgestrel releasing IUS -Mirena®) PLUS male 
condom  
 Intravaginal device (e.g., EE and etonogestrel) PLUS male condom  
 
 
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