Clinical trial NCT03840200
Conditions: Breast Cancer Prostate Cancer Ovarian Cancer
Sponsor: Hoffmann-La Roche
Start date: 2019-06-12; Completion date: 2022-01-04
Enrollment: 51 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a study in participants with advanced breast, ovarian, or prostate cancer to investigate the dose, safety, pharmacokinetics, and preliminary efficacy of ipatasertib in combination with rucaparib. The study consists of two parts: a Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer and a Dose-Expansion Phase (Part 2) in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).

Detailed description:
There are two parts in the study. A Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer. There will be a 7-day run-in period with ipatasertib alone prior to Cycle 1, Day 1. After the completion of the ipatasertib run-in period, participants will begin Cycle 1, Day 1 of the ipatasertib and rucaparib combination treatment. Each cycle has 28 days. Participants will be split into 4 cohorts: Dose Level 1 group - 300 mg ipatasertib once daily (QD) + 400 mg rucaparib twice daily (BID), Dose Level 2a: 300 mg ipatasertib QD + 600 mg rucaparib BID, Dose Level 2b: 400 mg ipatasertib QD + 400 mg rucaparib BID, Dose Level 3: 400 mg ipatasertib QD + 600 mg rucaparib BID

A Dose-Expansion Phase (Part 2) - The recommended dose identified in Part 1 (highest dose level of ipatasertib and rucaparib with an acceptable safety profile and less than one-third of participants experience a dose limiting toxicity) will be evaluated in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).

Enrollment in Cohort 3 in dose escalation phase was not opened as one-third of Dose Limiting Toxicity (DLT) evaluable participants receiving the highest dose of rucaparib in Cohort 2a experienced a DLT.

Arms: arm 1: Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 milligrams (mg), orally, once daily (QD) for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 400 mg, orally twice daily (BID) in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first. arm 2: Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 600 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first. arm 3: Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 400 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 400 mg, orally QD, and rucaparib, 400 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first. arm 4: Participants with advanced breast cancer, ovarian cancer, or prostate cancer are planned to receive ipatasertib 400 mg orally QD for 7 days (run-in period prior to Cycle 1). Participants will then receive ipatasertib 400 mg orally QD and rucaparib 600 mg, orally BID in 28 days cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first. arm 5: The recommended dose (ipatasertib and rucaparib) identified in Part 1 will be evaluated in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).
Interventions: intervention 1: Ipatasertib intervention 2: Rucaparib
Intervention descriptions: intervention 1: Ipatasertib will be administered orally. intervention 2: Rucaparib will be administered orally.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase Ib, Open-Label, Multicenter Study Evaluating the Safety and 
Efficacy of Ipatasertib in Combination With Rucaparib in Patients With 
Advanced Breast, Ovarian, or Prostate Cancer 
NCT Number: 
NCT03840200 
Document Date: 
Protocol Version 2: 09-Nov-2018 
 
 




Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
2/Protocol BO40933, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol BO40933 has been amended to modify the hyperglycemia management plan 
associated with ipatasertib according to fasting glucose levels.  In addition, the protocol 
has been amended to reflect updated safety and efficacy information related to rucaparib.  
Changes to the protocol, along with a rationale for each change, are summarized below:

Section 1.1.1 has been updated with the rationale for including patients with ovarian 
clear cell carcinoma.  

Section 1.1.3 has been modified to include recent data showing the benefit of 
rucaparib monotherapy in selected patients with prostate cancer.

Section 1.2.2 has been updated to include all approved indications for rucaparib in 
ovarian cancer and to provide updated data on rucaparib treatment in prostate 
cancer. 

Section 2.2.3 has been revised to remove the clinical benefit rate from the list of 
efficacy surrogates to be compared with PI3K pathway alterations as it does not 
bring additional value compared with the objective response rate. In addition, this 
section has been updated to reflect analysis of exploratory efficacy analysis in a 
subgroup of patients with prostate cancer with BRCA1 and BRCA2 mutations.

Section 3.1.2 has been updated to clarify the definition of dose-limiting toxicities 
related to ALT and AST elevations.

Section 3.2 has been revised to clarify the definition of the end of study. 

Section 4.1.1 has been updated to allow enrollment of patients with 
platinum-resistant ovarian cancer and clear cell ovarian cancer as these patients 
have high unmet medical need and may benefit from this novel combination.  In 
addition, the minimum number of slides submitted for tumor tissue analysis has 
been increased from 10 to 12 slides to improve the yield of biomarker data and to 
strengthen the exploratory efficacy analyses.  

Section 4.3.2.2 has been amended to state that rucaparib may be taken with or 
without food which is consistent with the Rucaparib Investigator's Brochure.  

Section 4.4.1 has aligned the contraceptive language with the Rucaparib 
Investigator's Brochure.

Section 4.3.1.1, Table 2, has been modified to correct the number of ipatasertib 
tablets supplied to all patients participating in Study BO40933.

Section 4.3.1.2, Table 4, has been updated to include the possibility that patients 
receiving the 600-mg dose of rucaparib may receive three 200-mg tablets or two 
300-mg tablets. 

Sections 5.1.1 and 5.1.2 were updated for consistency with the identified risks and 
reported adverse events in the current version of the Rucaparib Investigator's
Brochure.


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
Section 5.1.4.4, Table 6, has been revised to replace any reference to 
hyperglycemia grading according to fasting glucose levels in the recommendations 
for the management of hyperglycemia.

Section 5.1.4.6 has been revised to describe photosensitivity related to rucaparib
and provide recommendation for prevention consistent with guidance in the 
Rucaparib Investigator's Brochure.

Section 5.1.4.8, Table 10, has been updated to be consistent with National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5, for 
hepatotoxicity.

Section 5.4.3.3 has been amended regarding the reporting of spontaneous 
abortions and therapeutic or elective abortions performed because of an underlying 
maternal or embryofetal toxicity as serious adverse events.

Section 6.6 and Appendix 2 have been updated for additional pharmacokinetic 
assessments to better define potential drugdrug interactions between ipatasertib 
and rucaparib.

Section 10, References, has been revised.

An error with a sampling timepoint in Appendix 2 has been corrected. The Cycle 1,
Day 1 timepoint has been revised to Cycle 1, Day 7.  A clarification has also been 
added in the footnote that the PK sample is for analysis of coproporphyrin I (CPI)
and CPIII levels at baseline as described in Section 3.3.4.
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.




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3.3.2
Rationale for Patient Population ...................................................... 35
3.3.3
Rationale for Biomarker Assessments............................................. 36
3.3.3.1
Rationale for the Collection of Tumor Tissue for 
Examining Alterations in the HR and PI3K-AKT
Signaling Pathway ................................................................. 36
3.3.3.2
Rationale for Collection of Blood Samples for Non-
Invasive Disease Monitoring.................................................. 37
3.3.3.3
Rationale for Collection of DNA (Blood) for 
Exploratory Whole Genome Sequencing............................... 37
3.3.3.4
Rationale for Optional Collection of Tumor Biopsies 
for Exploratory Purposes ....................................................... 38
3.3.4
Rationale for the Pharmacokinetic Evaluation Schedule ................. 38
4.
MATERIALS AND METHODS ..................................................................... 39
4.1
Patients .............................................................................................. 39
4.1.1
Inclusion Criteria.............................................................................. 39
4.1.2
Exclusion Criteria............................................................................. 42
4.2
Method of Treatment Assignment....................................................... 44
4.3
Study Treatment and Other Treatments Relevant to the 
Study Design ......................................................................... 44
4.3.1
Study Treatment Formulation, Packaging, and Handling ................ 44
4.3.1.1
Ipatasertib..................................................................................... 44
4.3.1.2
Rucaparib ..................................................................................... 45
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 46
4.3.2.1
Ipatasertib..................................................................................... 46
4.3.2.2
Rucaparib ..................................................................................... 47
4.3.3
Investigational Medicinal Product Accountability ............................. 47
4.3.4
Continued Access to Ipatasertib or Rucaparib .................................. 47
4.4
Concomitant Therapy ......................................................................... 48
4.4.1
Permitted Therapy........................................................................... 48
4.4.2
Cautionary Therapy......................................................................... 49
4.4.2.1
Medications Given with Precaution due to Effects 
Related to Cytochrome P450 Enzymes................................. 49
4.4.2.2
Herbal Therapies.......................................................................... 50
4.4.3
Prohibited Therapy .......................................................................... 50


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4.4.4
Prohibited Food ............................................................................... 51
4.5
Study Assessments............................................................................ 51
4.5.1
Informed Consent Forms and Screening Log.................................. 51
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 51
4.5.3
Physical Examinations..................................................................... 51
4.5.4
Vital Signs........................................................................................ 52
4.5.5
ECOG Performance Status ............................................................. 52
4.5.6
Tumor and Response Evaluations................................................... 52
4.5.7
Other Disease-Specific Assessments.............................................. 54
4.5.8
Laboratory, Biomarker, and Other Biological Samples.................... 54
4.5.9
Electrocardiograms.......................................................................... 57
4.5.10
Post-Treatment Follow-Up............................................................. 57
4.5.11
Samples for Whole Genome Sequencing...................................... 58
4.5.12
Optional Tumor Biopsies ............................................................... 59
4.5.13
Optional Samples for Research Biosample Repository................. 59
4.5.13.1
Overview of the Research Biosample Repository....................... 59
4.5.13.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 60
4.5.13.3
Sample Collection....................................................................... 60
4.5.13.4
Confidentiality............................................................................. 60
4.5.13.5
Consent to Participate in the Research Biosample 
Repository ............................................................................. 61
4.5.13.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 61
4.5.13.7
Monitoring and Oversight............................................................ 62
4.6
Treatment, Patient, Study, and Site Discontinuation .......................... 62
4.6.1
Study Treatment Discontinuation..................................................... 62
4.6.2
Patient Discontinuation from Study.................................................. 63
4.6.3
Study Discontinuation...................................................................... 63
4.6.4
Site Discontinuation......................................................................... 63
5.
ASSESSMENT OF SAFETY........................................................................ 64
5.1
Safety Plan ......................................................................................... 64
5.1.1
Risks Associated with Ipatasertib .................................................... 64


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5.1.2
Risks Associated with Rucaparib..................................................... 64
5.1.3
Risks Associated with Ipatasertib and Rucaparib............................ 65
5.1.4
Management of Patients Who Experience Adverse 
Events.................................................................................... 65
5.1.4.1
General Management of Rucaparib-Related Adverse 
Events.................................................................................... 65
5.1.4.2
Management of Rucaparib Treatment-Emergent 
Creatinine Elevations............................................................. 66
5.1.4.3
Management of Treatment-Emergent Diarrhea............................ 66
5.1.4.4
Fasting Hyperglycemia ................................................................. 67
5.1.4.5
Nausea and/or Vomiting ............................................................... 69
5.1.4.6
Rash............................................................................................. 70
5.1.4.7
Pneumonitis.................................................................................. 71
5.1.4.8
Hepatotoxicity............................................................................... 72
5.1.4.9
Dose Modifications ....................................................................... 74
5.1.4.10
Treatment Interruption ................................................................ 76
5.2
Safety Parameters and Definitions ..................................................... 76
5.2.1
Adverse Events ............................................................................... 76
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor).......................................................................... 77
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 78
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters................................................................. 78
5.3.1
Adverse Event Reporting Period ..................................................... 78
5.3.2
Eliciting Adverse Event Information................................................. 79
5.3.3
Assessment of Severity of Adverse Events ..................................... 79
5.3.4
Assessment of Causality of Adverse Events ................................... 80
5.3.5
Procedures for Recording Adverse Events...................................... 81
5.3.5.1
Diagnosis versus Signs and Symptoms ....................................... 81
5.3.5.2
Adverse Events that are Secondary to Other Events ................... 82
5.3.5.3
Persistent or Recurrent Adverse Events....................................... 82
5.3.5.4
Abnormal Laboratory Values ........................................................ 82
5.3.5.5
Abnormal Vital Sign Values .......................................................... 83
5.3.5.6
Abnormal Liver Function Tests..................................................... 84


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5.3.5.7
Deaths.......................................................................................... 84
5.3.5.8
Preexisting Medical Conditions..................................................... 85
5.3.5.9
Lack of Efficacy or Worsening of Cancer...................................... 85
5.3.5.10
Hospitalization or Prolonged Hospitalization............................... 85
5.4
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 86
5.4.1
Emergency Medical Contacts.......................................................... 86
5.4.2
Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest................................. 87
5.4.2.1
Events that Occur prior to Study Drug Initiation............................ 87
5.4.2.2
Events that Occur after Study Drug Initiation................................ 87
5.4.3
Reporting Requirements for Pregnancies........................................ 88
5.4.3.1
Pregnancies in Female Patients................................................... 88
5.4.3.2
Pregnancies in Female Partners of Male Patients........................ 88
5.4.3.3
Abortions ...................................................................................... 88
5.4.3.4
Congenital Anomalies/Birth Defects ............................................. 89
5.4.4
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 89
5.5
Follow-Up of Patients after Adverse Events ....................................... 91
5.5.1
Investigator Follow-Up..................................................................... 91
5.5.2
Sponsor Follow-Up.......................................................................... 91
5.6
Adverse Events that Occur after the Adverse Event 
Reporting Period.................................................................... 91
5.7
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics 
Committees ........................................................................... 92
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN........................ 92
6.1
Determination of Sample Size ............................................................ 93
6.2
Summaries of Conduct of Study......................................................... 93
6.3
Summaries of Demographic and Baseline Characteristics................. 94
6.4
Efficacy Analyses ............................................................................... 94
6.4.1
Primary Efficacy Endpoint for Patients with Prostate 
Cancer................................................................................... 94
6.4.2
Secondary Efficacy Endpoints for Patients with 
Prostate Cancer..................................................................... 94


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6.4.3
Exploratory Efficacy Endpoints........................................................ 95
6.5
Safety Analyses.................................................................................. 95
6.6
Pharmacokinetic Analyses ................................................................. 96
6.7
Biomarker Analyses............................................................................ 96
6.8
Interim Analyses................................................................................. 96
7.
DATA COLLECTION AND MANAGEMENT ................................................ 97
7.1
Data Quality Assurance...................................................................... 97
7.2
Electronic Case Report Forms ........................................................... 97
7.3
Source Data Documentation .............................................................. 97
7.4
Use of Computerized Systems ........................................................... 98
7.5
Retention of Records.......................................................................... 98
8.
ETHICAL CONSIDERATIONS..................................................................... 99
8.1
Compliance with Laws and Regulations............................................. 99
8.2
Informed Consent............................................................................... 99
8.3
Institutional Review Board or Ethics Committee............................... 100
8.4
Confidentiality................................................................................... 101
8.5
Financial Disclosure ......................................................................... 101
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 102
9.1
Study Documentation ....................................................................... 102
9.2
Protocol Deviations........................................................................... 102
9.3
Site Inspections ................................................................................ 102
9.4
Administrative Structure ................................................................... 102
9.5
Dissemination of Data and Protection of Trade Secrets................... 103
9.6
Protocol Amendments ...................................................................... 104
10. REFERENCES ......................................................................................... 105
LIST OF TABLES
Table 1
Dose Levels of Ipatasertib and Rucaparib .......................................... 32
Table 2
Description of Ipatasertib .................................................................... 45
Table 3
Description of Rucaparib..................................................................... 45
Table 4
Doses and Tablets of Rucaparib......................................................... 46


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Table 5
Diarrhea Management Guidelines ...................................................... 67
Table 6
Fasting Hyperglycemia Management Guidelines................................ 69
Table 7
Nausea and Vomiting Management Guidelines.................................. 70
Table 8
Rash Management Guidelines............................................................ 71
Table 9
Pneumonitis Management Guidelines................................................. 72
Table 10
Hepatotoxicity Management Guidelines............................................ 73
Table 11
Dose Reductions for Rucaparib ........................................................ 74
Table 12
Dose Reductions for Ipatasertib........................................................ 75
Table 13
Part 1 and Part 2 Dose Modification.................................................. 76
Table 14
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 80
Table 15
Causal Attribution Guidance ............................................................. 81
Table 16
Estimated PSA Response Rate and Its 95% CI for 30 Patients........ 93
LIST OF FIGURES
Figure 1
Study Schema Part 1......................................................................... 32
Figure 2
Study Flow for Part 1 ......................................................................... 32
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................. 111
Appendix 2
Schedule of Pharmacokinetic Samples (Parts 1 and 2).............. 118
Appendix 3
Schedule of Biomarker Samples (Parts 1 and 2)........................ 120
Appendix 4
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 121
Appendix 5
PSA Progression Eligibility Criteria ............................................ 122
Appendix 6
Criteria for Radiographic Progression per Prostate Cancer 
Working Group 3....................................................................... 123
Appendix 7
Modified Gynecologic Cancer InterGroup (GCIG) Guidelines.... 124
Appendix 8
Response Evaluation Criteria in Solid Tumors:  Excerpt from 
Original Publication................................................................... 125




Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib, OPEN-LABEL, MULTICENTER STUDY EVALUATING 
THE SAFETY AND EFFICACY OF IPATASERTIB IN 
COMBINATION WITH RUCAPARIB IN PATIENTS WITH 
ADVANCED BREAST, OVARIAN, OR PROSTATE CANCER
PROTOCOL NUMBER:
BO40933
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-003293-27
IND NUMBER:
130663
TEST PRODUCT:
Ipatasertib (RO5532961); Rucaparib (CO-338)
PHASE:
Phase Ib
INDICATION:
Advanced breast, ovarian, or prostate cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, efficacy, and pharmacokinetics of ipatasertib administered in 
combination with rucaparib in patients with advanced breast, ovarian cancer, and prostate 
cancer.  Specific objectives and corresponding endpoints for the study are outlined below.
In this protocol “study treatment” refers to ipatasertib, rucaparib, and the combination of both
assigned to patients as part of this study.
Primary Safety Objective
The safety objective for this study is to evaluate the safety of ipatasertib administered in 
combination with rucaparib on the basis of the following endpoints:

To identify a recommended Phase II dose and schedule for ipatasertib and rucaparib
combination

Incidence, nature, and severity of adverse events and laboratory abnormalities, with
severity determined according to National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Incidence and nature of dose-limiting toxicities (DLTs) that determine the
maximum-tolerated dose (MTD) of the ipatasertib and rucaparib combination
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of ipatasertib 
administered in combination with rucaparib in patients with prostate cancer on the basis of the 
following endpoint:

Prostate-specific antigen (PSA) response, defined as the proportion of patients with a
reduction in the PSA level of 50% or more
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of ipatasertib 
administered in combination with rucaparib in patients with prostate cancer on the basis of the 
following endpoints:


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
13/Protocol BO40933, Version 2

Objective response rate (ORR), defined as the proportion of patients with a confirmed 
complete response (CR) or partial response (PR) on two consecutive occasions 4 weeks 
apart, as determined by the investigator per Response Evaluation Criteria in Solid Tumors,
Version 1.1 (RECIST v.1.1)

Duration of objective response (DOR)

rPFS by Prostate Cancer Working Group 3 (PCWG3) criteria

Overall survival (OS)
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is as follows:

To evaluate the potential relationship between the presence of PI3K-AKT or HR pathway 
alterations (e.g., PTEN loss by immunohistochemistry [IHC], PIK3CA/AKT1/PTEN or
BRCA1/BRCA2-altered status by next-generation sequencing [NGS]) and the anti-tumor 
activity of ipatasertib in combination with rucaparib in patients with prostate cancer on the 
basis of the following endpoints:
–
PSA response rate
–
ORR
–
DOR
–
rPFS
–
OS
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the PK profile of ipatasertib, its metabolite G-037720, and rucaparib, when 
administered in combination, on the basis of the plasma concentration of ipatasertib and 
rucaparib at specified timepoints 
Biomarker Objectives
The exploratory biomarker objectives for this study are as follows:

To evaluate possible predictive and prognostic biomarkers in the tissue and plasma based 
on the following endpoint:
–
Exploration of possible relationships between the tissue- and blood-based biomarkers 
and patient clinical features (e.g., baseline features) and outcome (e.g., rPFS)

To evaluate pharmacodynamic effects of ipatasertib and the combination of ipatasertib with 
rucaparib in the tissue based on the following endpoint:
–
Changes in molecular biomarkers in pretreatment and on-treatment tumor tissues

To identify possible mechanisms of resistance to the study treatments through the 
comparative analysis of potential biomarkers in the blood based on the following endpoint:
–
Changes in molecular biomarkers in pretreatment and post-progression plasma and 
blood samples
Study Design
Description of Study
This is a Phase Ib, open-label, non-randomized study in patients with advanced breast, ovarian, 
or prostate cancer to investigate the dose, safety, pharmacokinetics, and preliminary efficacy of 
ipatasertib in combination with rucaparib.
The study consists of two parts:  a Dose-Escalation Phase (Part 1) in patients with previously 
treated advanced breast cancer, ovarian cancer, or prostate cancer and a Dose-Expansion
Phase (Part 2) in patients with advanced prostate cancer who have had at least one line of prior 
therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, 
enzalutamide, apalutamide).
Patients must have fresh or archival tumor tissue samples available for submission for 
biomarker analyses for IHC (e.g., PTEN loss) and NGS methodologies 
(e.g., PIK3CA/AKT1/PTEN or BRCA1/BRCA2-altered status).


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Dose-Escalation Phase (Part 1)
The Dose-Escalation Phase, Part 1, will determine the recommended dose of ipatasertib in 
combination with rucaparib in patients with advanced breast, ovarian, or prostate cancers.  
There will be a 7-day run-in period with ipatasertib alone prior to Cycle 1, Day 1 to allow for PK 
assessment of ipatasertib monotherapy versus that in combination with rucaparib.  After the completion 
of the ipatasertib run-in period, patients will begin Cycle 1, Day 1 of the ipatasertib and 
rucaparib combination treatment.
Two dose levels of rucaparib administered orally (PO) BID will be evaluated with two dose 
levels of ipatasertib in 28-day cycles.  There will be approximately 6 patients per dose level.  
The highest dose level of each agent with an acceptable safety profile and with a minimum of 
6 patients, at which, less than one-third of patients experience a DLT, will be declared the 
recommended Phase II dose (RP2D).  Preliminary assessment of the anti-tumor activity and 
biomarkers of response or resistance to combined ipatasertib and rucaparib will also be 
conducted in Part 1.  
All patients will continue to receive study treatment until disease progression (according to 
RECIST v1.1 for breast and ovarian cancer or PCWG3 criteria for prostate cancer), unacceptable 
toxicity, death, or patient or investigator decision to withdraw, whichever occurs first.
Dose-Expansion Phase (Part 2)
In the Dose-Expansion Phase, Part 2, the potential RP2D of combined ipatasertib and rucaparib 
identified in Part 1 will be further evaluated for safety, pharmacokinetics, and preliminary efficacy 
in patients with advanced prostate cancer who have been treated with at least one line of 
second-generation androgen-receptor targeted therapy.  There will be no run-in phase for the 
ipatasertib monotherapy.  Approximately 30 patients will be enrolled, of whom approximately 
70% are expected to have HR-intact tumors, and approximately 50% are expected to have 
PTEN-loss tumors based on the prevalence previously described in castration-resistant prostate 
cancer (CRPC).  Enrollment may be extended to ensure at least 15 patients with HR-intact 
features are enrolled.  A patient with a homologous recombination (HR)-deficient tumor is 
considered a patient with one of the following molecular features defined by the FoundationOne 
NGS assay:

Deleterious alteration in at least one of the following genes:  ATM, BRCA1, BRCA2, BARD1, 
BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, 
RAD54L
Mandatory archival or fresh tissue will be collected at the time of enrollment and optional fresh 
tumor biopsies on study treatment will be collected.  In addition, plasma and blood samples may be 
analyzed for deleterious alterations and further classification of mutational status.
All patients will continue to receive study treatment until disease progression (according to 
RECIST v1.1 or PCWG3 criteria), unacceptable toxicity, death, or patient or investigator 
decision to withdraw, whichever occurs first.
Number of Patients
Approximately 54 patients will be enrolled in this study:  approximately 24 patients will be 
enrolled in Part 1 (Dose-Escalation Phase) and approximately 30 patients will be enrolled in 
Part 2 (Dose-Expansion Phase).
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

A life expectancy of at least 3 months

Ability to swallow oral study drug

Have adequate organ and marrow function as confirmed by the laboratory values listed 
below, obtained within 28 days prior to the first dose of study treatment


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Bone marrow function assessments (without transfusion within 28 days prior to receipt of 
study treatment)
–
ANC 1500 cells/L (1.5109/L) without granulocyte-colony stimulating factor support
–
Platelet count 100.0109/L
–
Hemoglobin 9 g/dL (or 5.6 mmol/L)
Chemistry panel assessments
–
AST and ALT 1.5upper limit of normal (ULN); if liver metastases, 2.5ULN
–
Bilirubin 1.5ULN (3ULN if hyperbilirubinemia is due to Gilbert’s syndrome)
–
Serum albumin 3.0 g/dL
–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min
–
Fasting glucose 150 mg/dL and hemoglobin A1c 7.5%

Resolved or stabilized toxicities resulting from previous therapy to Grade 1 (except for 
alopecia and neuropathy).
An ongoing, Grade 2, non-hematologic toxicity related to the most recent treatment 
regimen may be permitted with approval from the Medical Monitor
Cancer-Related Inclusion Criteria

Have a histologically confirmed diagnosis of ovarian (Part 1 only), breast (Part 1 only) or 
prostate cancer (Part 1 and Part 2)

Disease must be either metastatic or locally advanced disease that cannot be treated with 
curative intent

For patients with ovarian cancer (Part 1 only): 
–
High-grade (2 or 3) serous or endometrioid or clear cell epithelial ovarian, fallopian tube, 
or primary peritoneal cancer (PPC)  
If the tumor is of mixed histology, 50% of the primary tumor must be confirmed to 
be high-grade serous, endometrioid, or clear cell.
–
Must have received at least one prior platinum-based therapy and may have platinum-
sensitive disease (i.e., documented radiologic disease progression 6 months following 
the last dose of the platinum treatment administered) or platinum-resistant disease
–
Have a CA-125 level that is 2ULN
–
Must have measurable disease by RECIST v1.1

For patients with breast cancer (Part 1 only):  must be human epidermal growth factor 
receptor 2 negative (HER2) (estrogen receptor [ER]/progesterone positive or negative)
–
ER/progesterone-positive patients must have received and progressed on at least one 
endocrine therapy (adjuvant or metastatic) 
–
ER/progesterone-negative/HER2(triple-negative breast cancer [TNBC]) patients must 
have received at least one prior line of chemotherapy for metastatic breast cancer
–
Must not have received more than two prior lines of chemotherapy for metastatic breast 
cancer
–
Must have measurable disease by RECIST v1.1

For patients with prostate cancer: 
–
Adenocarcinoma of the prostate without small cell or neuroendocrine features 
–
Surgical or medical castration with testosterone 50 ng/dL (1.7 nM) 
–
Patients treated with luteinizing hormone-releasing hormone analogs must have initiated 
therapy at least 4 weeks prior to the first dose of study treatment and continue 
throughout the study treatment 


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–
Progression of prostate cancer either via PSA progression (two rising PSA levels 
measured 1 week apart, with second result 1 ng/mL) or radiographic progression 
with or without PSA progression 
–
Must have received at least one prior line of second-generation androgen receptor 
targeted therapy (e.g., abiraterone, enzalutamide, apalutamide)
–
Patients with prostate cancer must have either measurable disease by RECIST v1.1 or 
bone lesions by bone scan, or both.

Submission of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or a minimum 
of 12 freshly cut, unstained, serial tumor slides from the most recently collected tumor tissue 
for central molecular analysis (retrospective NGS testing for HR and PI3K-AKT pathway 
status and for other protocol-mandated secondary and exploratory assessments).  
Cytologic or fine needle aspirate samples are not acceptable.  Tumor tissue from bone 
metastases is not acceptable.
–
If the specimen is either insufficient or unavailable, the patient may still be eligible if the 
patient is willing to consent to and undergo an additional pretreatment core or excisional 
biopsy of the non-target lesion (if it is assessable and the biopsy can be safely 
obtained).  In general, a minimum of three core biopsies for NGS testing are required.

For women of childbearing potential:  be abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating eggs, as defined 
below:
Women must be abstinent or use contraceptive methods with a failure rate of 1% per 
year during the treatment period and for at least 28 days after the final dose of 
ipatasertib or 6 months after the last dose of rucaparib, whichever occurs later.  
Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of progesterone-only 
injectable or implantable contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices, and copper intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method plus 
spermicide.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.

For men:  be abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must be abstinent or use a condom 
plus an additional contraceptive method that together result in a failure rate of 1% 
per year during the treatment period and for 28 days after the last dose of ipatasertib 
or for 6 months after last dose of rucaparib whichever occurs later.  Men must refrain 
from donating sperm during this same period.
With pregnant female partners, men must be abstinent or use a condom during the 
treatment period and for 28 days after the last dose of ipatasertib or rucaparib to avoid 
exposing the embryo.
Examples of contraceptive methods with a failure rate of 1% per year, when used 
consistently and correctly, include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion, 
male sterilization, intrauterine hormone releasing system, and sexual abstinence. 


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The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
28 days after the final dose of ipatasertib or 6 months after the final dose of rucaparib
Women of childbearing potential must have a negative serum pregnancy test result 
within 3 days prior to initiation of study drug.

Prior treatment with a PARP inhibitor, AKT inhibitor, or PI3K inhibitor 

Treatment with investigational therapy within 14 days prior to initiation of study drug

Symptomatic and/or untreated CNS metastases
Patients with asymptomatic previously treated CNS metastases are eligible provided 
they have been clinically stable for at least 4 weeks.
Patients with leptomeningeal carcinomatosis will be excluded. 

Uncontrolled tumor-related pain 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomization.  Patients should be recovered (e.g., to Grade 1 or resolved) from the 
effects of radiation prior to study enrollment.  There is no required minimum recovery 
period beyond the 7 days required for radiation therapy. 
Asymptomatic metastatic lesions whose further growth would likely cause functional
deficits or intractable pain (e.g., epidural metastasis that is not presently associated 
with spinal cord compression) should be considered for loco-regional therapy if 
appropriate prior to randomization. 

Nonstudy-related minor surgical procedures 5 days or major (invasive) surgical 
procedure 14 days prior to first dose of study treatment
Patient must be sufficiently recovered from surgery and stable, and wound healing 
must have occurred.

Patients with active hepatitis C virus (HCV)
Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
is negative for HCV RNA.

Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B 
surface antigen (HBsAg) test or a positive quantitative HBV DNA test
If a patient has a negative HBsAg test and a positive total hepatitis B core antibody 
(HBcAb) test, a quantitative HBV DNA test must be performed. 
Patients receiving anti-viral therapy for HBV are not eligible.

Known HIV infection

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Malabsorption syndrome or other condition that would interfere with enteral absorption

Serious infection requiring antibiotics within 14 days of first dose of study treatment

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an equivalent 
dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic 
disease


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
History of another malignancy within 5 years prior to randomization, except for either 
adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma
in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta, 
and low-grade T1 tumors), or other malignancies where the patient has undergone 
potentially curative therapy with no evidence of disease and are deemed by the treating 
physician to have a recurrence rate of 5% at 5 years. 

History of clinically significant cardiovascular dysfunction, including the following:
–
History of stroke or transient ischemic attack within 6 months prior to enrollment
–
History of myocardial infarction within 6 months prior to first dose of study drug 
–
New York Heart Association Class III or IV cardiac disease
–
Unstable arrhythmias or unstable angina

Presence of any other condition that may have increased the risk associated with study 
participation or may have interfered with the interpretation of study results, and, in the 
opinion of the investigator, would have made the patient inappropriate for entry into the 
study
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following criteria specific to ipatasertib will be excluded from 
study entry:

Type 1 or Type 2 diabetes mellitus requiring insulin at study entry
However, patients who are on a stable dose of oral diabetes medication 4 weeks 
prior to initiation of study treatment may be eligible for enrollment.  Patients must meet 
the laboratory eligibility criteria for fasting blood glucose and hemoglobin A1c as 
outlined in the inclusion criteria.

History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), active 
bowel inflammation (e.g., diverticulitis)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 4 weeks or five
elimination half-live of the inhibitors, whichever is longer, prior to initiation of study drug 
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical efficacy analysis or safety follow-up is received 
from the last patient, whichever occurs later.
For an individual patient, the last visit is defined as the end of treatment visit or the time of disease 
progression whichever occurs the last.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 36 months.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are ipatasertib (RO5532961) and 
rucaparib (CO-338).  The dose levels of ipatasertib and rucaparib to be used in this study are as 
follows:

Dose Level 1:
300 mg ipatasertib once daily (QD)400 mg rucaparib twice daily (BID)

Dose Level 2a: 300 mg ipatasertib QD600 mg rucaparib BID

Dose Level 2b: 400 mg ipatasertib QD400 mg rucaparib BID

Dose Level 3:
400 mg ipatasertib QD600 mg rucaparib BID
Both IMPs will be administered orally (tablets).
Non-Investigational Medicinal Products
Not applicable.


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Statistical Methods
Primary Analysis
The safety analyses will include all patients who received at least one dose of any study drug, 
and will be analyzed and summarized separately for the Part 1 and Part 2; data will not be 
combined across phases.
Adverse events, deaths, change in laboratory test results, change in vital signs, and exposure to 
components of study treatment will be assessed to determine the safety of treatment regimen.
For safety-evaluable patients, study drug administration data will be tabulated or listed by arm, 
and any dose modifications will be flagged.  Descriptive statistics will be used to summarize the 
total dose of ipatasertib and rucaparib received.
Verbatim descriptions of adverse events will be mapped to appropriate thesaurus terms.  All 
adverse events occurring on or after treatment Day 1 will be summarized by the mapped term, 
appropriate thesaurus levels, and NCI CTCAE v5.0 toxicity grade.  In addition, adverse events 
leading to treatment withdrawal or death, and serious adverse events will be listed with more 
detailed information, such as the day of onset of an adverse event, duration of adverse event, 
toxicity grade, and so on.
Relevant laboratory and vital signs (heart rate, blood pressure, and temperature) and ECG data 
will be displayed by time post-dose, with NCI CTCAE Grade 3 and 4 values identified where 
appropriate.  Additionally, changes in laboratory data will be summarized by grade using the 
NCI CTCAE toxicity grade.  Selected vital signs and selected laboratory data will be 
summarized by visit.
The extent of study drug exposure (dose and duration) will be examined to determine the 
degree of treatment tolerability.  In addition to study treatment duration and total dose received, 
any dose modification of study drugs will also be summarized.
Determination of Sample Size
There is no formal hypothesis testing planned.  The determination of sample size for each part 
is described below.
For Part 1 (Dose-Escalation Phase), approximately 24 patients are planned to be enrolled 
based on the dose-escalation rules.
For Part 2 (Dose-Expansion Phase), approximately 30 patients with advanced prostate cancer 
who have had at least one line of prior therapy with second-generation AR-receptor targeted 
agents (e.g., abiraterone, enzalutamide, apalutamide) are planned to be enrolled.  No formal 
statistical hypothesis testing is planned.  Instead, the analysis here is for hypothesis generation, 
and the emphasis is on estimations.  To evaluate the primary endpoint of PSA response rate, 
the analyses will be based on patients enrolled in Part 2.  Thirty patients provide reasonably 
reliable estimates for hypothesis generation.
Interim Analyses
An interim analysis for safety (including DLTs) will be performed by the Sponsor prior to dose 
expansion (Part 2)
Given the hypothesis-generating nature of this study, the Sponsor may conduct an interim 
analysis of efficacy in Part 2.  The decision to conduct such an interim analysis and its timing 
will be documented in the Sponsor’s study master file prior to the conduct of the interim 
analysis.  The Clinical Study Report will also document that such an interim analysis occurred.  
The interim analysis, should it occur, will be performed and interpreted by members of Roche's 
study team and management.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
aCGH
array comparative genome hybridization
ADP
adenosine diphosphate
AKT
protein kinase B
AR
androgen receptor
AUC0-t
area under the concentration–time curve from Time 0 to Time t
BID
twice daily
BRCA1 (2)
breast cancer gene 1 (2)
Cmax
maximum plasma concentration
CP I (III)
coproporphyrin I (III)
CR
complete response
CRO
contract research organization
CRPC
castration-resistant prostate cancer
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
DLT
dose-limiting toxicity
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EOC
epithelial ovarian cancer
ER
estrogen receptor
ET
endocrine therapy
FDA
(U.S.) Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FMI
Foundation Medicine, Inc.
g
germline
GCIG
Gynecologic Cancer InterGroup
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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Abbreviation
Definition
HER2
human epidermal growth factor receptor 2
HER2-
human epidermal growth factor receptor 2 negative
HIPAA
Health Insurance Portability and Accountability Act
HR
hormone receptor positive
HR
homologous recombination
ICH
International Council for Harmonisation
ICR
Immunologic Constant of Rejection
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITT
intent to treat
IV
intravenous
LFT
liver function test
mCRPC
metastatic castration-resistant prostate cancer
mPFS
median progressive-free survival
MRI
magnetic resonance imaging
MTD
maximum-tolerated dose
mTOR
mammalian target of rapamycin
NCI
National Cancer Institute
NGS
next-generation sequencing
OATP
organic-anion-transporting polypeptide
ORR
objective response rate
OS
overall survival
PARP
poly (adenosine diphosphate ribose) polymerase
PCR
polymerase chain reaction
PCWG3
Prostate Cancer Working Group 3
PD-L1
programmed deathligand 1
PFT
pulmonary function test
PFS
progression-free survival
PI3K
phosphoinositide 3-kinase
PK
pharmacokinetic
PO
orally
popPK
population pharmacokinetic
PPC
primary peritoneal cancer
PR
partial response


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Abbreviation
Definition
PSA
prostate-specific antigen
PTEN
phosphatase and tensin homolog
QD
once daily
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase II dose
rPFS
radiographic progression-free survival
s
somatic
SD
stable disease
Tmax
time to maximum concentration
TNBC
triple-negative breast cancer
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing


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1.
BACKGROUND
1.1
BACKGROUND ON OVARIAN, BREAST, AND 
PROSTATE CANCER
1.1.1
Background on Ovarian Cancer
Ovarian cancer is the second most common gynecologic malignancy worldwide and the 
leading cause of death attributed to gynecological cancer (Morgan et al. 2011; U.S. 
Cancer Statistics Working Group 2013).  Globally, epithelial ovarian cancer (EOC) 
affects 238,719 women annually and results in 140,200 cancer-related deaths, with an 
annual incidence of 65,584.  EOC, fallopian tube cancer, and primary peritoneal cancer 
comprise tumors of Müllerian origin.  They share common clinical and biological 
behavior and are typically grouped together in treatment paradigms and clinical 
investigations (Levanon et al. 2008; Salvador et al. 2008; Flesken-Nikitin et al. 2013).
The standard of care for ovarian cancer at initial diagnosis includes primary tumor 
reduction surgery, followed by platinum (carboplatin) and taxane (paclitaxel) systemic 
chemotherapy and bevacizumab (McGuire et al. 1996; Piccart et al. 2000; Ozols et al. 
2003; Ledermann et al. 2013; Burger et al. 2018).  After initial therapy, most women with 
advanced disease will have a progression-free interval of approximately 1.52 years, 
depending on the extent of post-operative residual disease and response to 
chemotherapy (Cannistra 2004).  Relapse following initial treatment is common and only 
10%30% of women experience long-term survival (Cannistra 2004). 
The choice of treatment for relapsed disease is based on the treatment-free interval 
relative to the last therapy administered and chemotherapy agents used.  As many 
patients experience multiple relapses, prognosis and response to therapy decrease as 
the interval between last chemotherapy exposure and disease relapse shortens.  The 
treatment-free interval, or specifically the platinum-free interval, provides further 
prognostic information for patients, as therapeutic options lessen and survival shortens 
as a patient’s tumor becomes less responsive to platinum-based therapy.
Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor monotherapy 
has elicited objective responses in patients with platinum-sensitive disease, as well as in 
patients with platinum-resistant disease.  However, response rates are higher in the 
former population (Gelmon et al. 2011; Kaye et al. 2012; Sandhu et al. 2013).  Although 
initially PARP inhibitors were thought to be active only in BRCA-mutated tumors, more 
recent studies have shown that their efficacy can be extended to include a larger group 
of ovarian cancer patients with BRCA wild-type tumors (Mirza et al. 2016; Coleman et al. 
2017; Swisher et al. 2017).
The phosphoinositide 3-kinase (PI3K)-AKT pathway is frequently deregulated in ovarian 
cancer.  Array comparative genomic hybridization (aCGH) studies have identified this 
pathway as the most frequently altered in ovarian cancer (Huang et al. 2011).  In 
particular, this pathway is dysregulated in 30%40% of ovarian clear cell carcinoma, which is an 


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aggressive subtype. Inhibitors of this pathway continue to be evaluated in ovarian cancer 
although currently none are approved for this indication (Gasparri et al. 2017).
1.1.2
Background on Breast Cancer
Breast cancer is the most frequent cancer diagnosed in women, with an estimated global 
incidence of 1.67 million new cases reported in 2012 (Ferlay et al. 2013). It accounts for 
approximately 15% (approximately 522,000 cases) of all cancer deaths.  Breast cancer 
is a genetically heterogeneous and biologically diverse disease that can be clinically 
subdivided into subgroups that guide therapeutic intervention, which is based on the 
expression of estrogen receptor (ER), progesterone receptor, and human epidermal 
growth factor receptor 2 (HER2). Triple-negative breast cancer (TNBC) accounts for 
about 20% of breast cancers diagnosed worldwide.  Patients with metastatic TNBC 
exhibit a particularly poor clinical outcome, generally with rapid progression and a 
median overall survival (OS) rate of approximately 16 months (Rodler et al. 2010). 
Although TNBC may respond to chemotherapy, including taxanes, there are no 
approved first-line regimens for patients with this specific subtype of breast cancer.  
While olaparib is the first targeted-therapy approved for this subtype, it is limited to 
patients with germline mutations in BRCA.  Hormone receptor positive 
(HR)/HER2-negative (HER2) breast cancer (hereafter referred to as HRbreast 
cancer) accounts for over 70% of all breast cancer subtypes.  Patients with metastatic 
HRbreast cancer may be treated with endocrine therapy (ET), either alone or in 
combination with a targeted therapy such as CDK4/6 inhibitor or mammalian target of 
rapamycin (mTOR inhibitor), or with chemotherapy.  
Approximately 5% of unselected patients with breast cancer carry a germline BRCA
mutation (Kurian et al. 2009) and such mutations are more likely to be present in 
patients with a strong family history of breast cancer and patients who have TNBC
(Mavaddat et al. 2012).  In a recent study of olaparib versus chemotherapy in HER2
patients with germline BRCA mutations, median progression-free survival (mPFS) was 
significantly longer in the olaparib group than in the chemotherapy group (Robson et al. 
2017).  Activity in patients without germline mutations is still being evaluated.
Overall, PIK3CA/AKT1/PTEN-altered tumors are frequently observed in breast cancer, 
and are reported in approximately 35% of TNBC patients and in approximately 50% of 
HR/HER2breast cancers (Cancer Genome Atlas Network 2012).  To date, the 
relationship between PI3K-AKT pathway activation and prognosis in early breast cancer 
is mixed, with some data demonstrating association with favorable outcomes, some data 
with poor prognosis, and a number of studies showing insignificant results (Yang et al. 
2016).  Information demonstrating significant differences in the prevalence of these gene 
alterations between primary and metastatic tumor tissues is limited, while enrichment in 
metastatic patients is probable (Millis et al. 2015). For patients with metastatic 
HR/HER2breast cancer, everolimus (a mTOR inhibitor) in combination with 
exemestane is an approved therapy during the endocrine-sensitive phase of disease 


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(Baselga et al. 2012).  Other inhibitors of this pathway are being actively explored in both 
HR/HER2breast cancer and TNBC (Dey et al. 2017).
1.1.3
Background on Prostate Cancer
Prostate cancer is the most commonly diagnosed cancer in men and the second leading 
cause of death in men in the Western world (Ferlay et al. 2015).  Although most men are 
diagnosed with localized disease, progression to metastatic disease of the bones and 
visceral organs leads to significant morbidity and mortality (Logothetis et al. 2012; 
Basch et al. 2014).  In the United States, prostate cancer is the most common non-skin 
cancer diagnosed, with over 180,890 new cases and 26,120 deaths (American Cancer 
Society 2016).  Likewise, in Europe, prostate cancer leads male cancer diagnoses with 
approximately 417,000 new cases, and 92,000 deaths (Ferlay et al. 2013).
Androgen deprivation therapy constitutes the mainstay of treatment for advanced 
prostate cancer.  Two novel androgen-receptor (AR) targeting agents, abiraterone, and 
enzalutamide have had a significant impact in changing the treatment landscape of 
prostate cancer.  Both agents initially showed overall survival benefit in men with 
castration-resistant prostate cancer (CRPC) following progression on docetaxel 
chemotherapy (de Bono et al. 2011; Scher et al. 2012).  Subsequently both agents 
demonstrated improvement in radiographic progression free survival (rPFS) and OS
when used as front-line therapy for males with metastatic CRPC (mCRPC) and who had 
minimal or no symptoms and no prior chemotherapy (Ryan et al. 2013; Beer et al. 2014).  
Abiraterone has also demonstrated survival benefit in an earlier disease state, hormone 
sensitive prostate cancer (Fizazi et al. 2017), and enzalutamide and apalutamide have 
demonstrated metastasis-free survival benefit in nonmetastatic CRPC (Smith et al. 2018; 
Hussain et al. 2018).  
As these agents are being used in earlier disease states, there is a high unmet need in 
patients who have disease progression on novel AR-targeting agents.  Cross-resistance 
occurs between the abiraterone and enzalutamide; the rate of response to abiraterone 
therapy after treatment with enzalutamide is less than 10%, whereas the response rate 
for enzalutamide after abiraterone is 15-30% (Smith et al. 2017; Noonan et al. 2013; 
Schrader et al. 2014).  The benefit of taxanes appears to be diminished after treatment 
with abiraterone or enzalutamide, as compared with benefit in patients who have not 
received such treatments, although taxanes remain active (de Bono et al. 2017).  Novel 
therapies for these patients are needed.
Olaparib has demonstrated strong signal for anti-tumor activity in patients with somatic 
and germline homologous recombination (HR) repair defects (HR-deficient) (Mateo et al. 
2015).  Patients without homologous HR defects (HR-intact) had minimal benefit from 
olaparib monotherapy.  Early data from a combination of olaparib and durvalumab 
similarly showed benefit largely limited to patients with HR-deficient tumors (Karzai 
abstract GU ASCO 2018).  Olaparib in combination with abiraterone has also been 
reported showing potential benefit in an all-comer population although tumor was


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evaluable for HR-status in only 27% of patients (Clarke et al. 2018). Rucaparib has 
received breakthrough designation by the U.S. Food and Drug Administration (FDA) in 2018 
based on results from the TRITON2 study, which showed significant single-agent disease activity 
of rucaparib in patients with metastatic CRPC with BRCA1 and BRCA2 germline or somatic 
mutations (Abida et al. 2018).
Other treatments with novel mechanisms of action, such as PI3K inhibitors, may also 
have a role in the future treatment landscape of prostate cancer.  The PI3K-AKT
pathway is one of the most frequently activated pathways in prostate cancer, with 
genomic alterations occurring in approximately 50% of cases with genetic loss of 
phosphatase and tensin homolog (PTEN) as the most common cause (Robinson et al. 
2015).  Deregulation of this pathway results in activation of downstream targets 
(e.g., PRAS40, mTOR, GSK3b, FOXO, etc.) involved in survival, proliferation, cell-cycle 
progression, growth, migration, and angiogenesis (Yuan and Cantley 2008).  Activation 
of the PI3K-AKT pathway is physiologically relevant as it compensates for AR 
downregulation and provides a means for receptor blockade escape; in a similarly 
reciprocal manner, blockade of the PI3K-AKT pathway leads to increased stability and 
activity of the AR, demonstrating the cooperative action of both pathways to enable 
prostate cancer progression (Carver et al. 2011; Mulholland et al. 2011).  
Clinical studies have consistently demonstrated that low PTEN expression and PTEN
loss (together referred to as PTEN loss hereafter) are associated with worse prognosis 
(Yoshimoto et al. 2007; Reid et al. 2010; Antonarakis et al. 2012; Chaux et al. 2012; 
Zafarana et al. 2012; Cuzick et al. 2013; Barnett et al. 2014; Ferraldeschi et al. 2015; 
Kim et al. 2015), regardless of whether patients are newly diagnosed, receiving 
treatment for localized disease, or have late-line advanced metastatic castration-
resistant disease. Collectively, these results suggest that activation of the PI3K-AKT
pathway is an important driver for prostate cancer and that the pathway is a relevant 
target for treatment.
1.2
BACKGROUND ON IPATASERTIB AND RUCAPARIB 
1.2.1
Background on Ipatasertib
Ipatasertib is a potent, highly selective, small-molecule inhibitor of all three isoforms of
the serine/threonine kinase AKT.  Ipatasertib is being developed by Genentech/Roche 
as a single agent and in combination with other therapies for the treatment of cancers in 
which activation of the PI3K-AKT-mTOR pathway may be relevant for tumor growth or 
therapeutic resistance.
In nonclinical models with high levels of phosphorylated AKT or PI3K-AKT pathway 
activity (i.e., PIK3CA mutation, PTEN alterations), sensitivity to ipatasertib has been 
observed across different tumor models, including ovarian, breast, and prostate cancers 
(Lin et al. 2013).  In vivo efficacy studies support the use of ipatasertib as a single agent 


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or in combination with chemotherapeutic, hormonal, or targeted agents for the treatment 
of patients with advanced or metastatic solid tumors.
Clinical studies in a variety of tumor types have been conducted with ipatasertib both as 
monotherapy and in combination.  Combination partners have included hormonal 
therapies (i.e., abiraterone and enzalutamide), MEK inhibitor, chemotherapy, and 
immunotherapy.  Randomized studies with ipatasertib have been conducted in breast, 
prostate, and gastric cancer.  
The randomized Phase Ib/II study GO27983 was conducted in patients with mCRPC
post-docetaxel.  Ipatasertib (400-mg dose) when added to abiraterone and 
prednisone/prednisolone showed improved rPFS benefit compared with abiraterone and 
prednisone/prednisolone in the all-comer population and in patients with PTEN-loss 
tumors (hazard ratio0.75 for all-comer; hazard ratio0.39 for PTEN-loss by 
Immunologic Constant of Rejection [ICR] immunohistochemistry [IHC] assay).  There is 
an ongoing randomized Phase III study CO39303 evaluating 400 mg ipatasertib when 
added to abiraterone and prednisone/prednisolone compared to abiraterone and 
prednisone/prednisolone in front-line mCRPC.
The randomized Phase II study, GO29227, evaluated the addition of ipatasertib to 
paclitaxel in front-line metastatic TNBC patients and those with a PTEN loss (by IHC) 
and separately, patients with PIK3CA/AKT1/PTEN-altered tumors. Results from this 
study showed improvement in median PFS in the intent-to-treat (ITT) population (hazard 
ratio0.60; 6.2 months in the ipatasertib arm compared with 4.9 months in the control 
arm); and more pronouncedly in the pre-specified patient population with 
PIK3CA/AKT1/PTEN-altered tumors (hazard ratio0.44; 9 months vs. 4.9 months).  
There is an ongoing randomized Phase III study CO40016 evaluating 400 mg ipatasertib 
when added to paclitaxel compared to paclitaxel in first-line TNBC and HR/HER2
breast cancer for patients with PIK3CA/AKT1/PTEN-altered tumors.  
Refer to the Ipatasertib Investigator's Brochure for details on nonclinical and clinical 
studies.
1.2.2
Background on Rucaparib
Rucaparib is a PARP inhibitor approved for the treatment of women with BRCA-mutated 
ovarian cancer who have been treated with two or more lines of chemotherapy and as 
maintenance therapy for women with ovarian cancer (regardless of BRCA-mutational status) 
who have either a complete or partial response to platinum-based therapy.  Nonclinical 
evaluation has demonstrated exquisite sensitivity of BRCA1 and BRCA2 homozygous 
mutant cell lines to rucaparib, which is attributed to PARP inhibition alone, and provides 
a rationale for the clinical assessment of rucaparib as monotherapy in patients with 
hereditary (germline [g]) and acquired (somatic [s]) deficiencies of BRCA1 and BRCA2.  
Clinical data indicate that benefit from treatment with a PARP inhibitor includes patients 
with a gBRCA or sBRCA mutation, and may extend to patients with other HR-deficient 


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alterations.  Rucaparib received breakthrough designation by the FDA in 2018 based on results 
from the TRITON2 study, which showed significant single-agent disease activity of rucaparib in 
patients with metastatic CRPC with BRCA1 and BRCA2 germline or somatic mutations (Abida 
et al. 2018).  This supports the investigation of PARP inhibitors, such as rucaparib, in a 
broader group of tumors with HR-deficiency (inclusive of sBRCA and BRCA-like, as well 
as other non-BRCA mutations involved in HR-deficiency). Additional Phase II and 
Phase III clinical studies with oral rucaparib monotherapy are ongoing in patients with 
ovarian, prostate, or bladder cancer.  Clinical trials investigating oral rucaparib in combination 
with other anti-cancer therapies are also planned or ongoing.  
Refer to the Rucaparib Investigator’s Brochure for details on nonclinical and clinical 
studies of rucaparib.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
HR-deficient tumors are dependent on PARP-mediated DNA repair and have profound 
sensitivity to PARP inhibitor (Tutt et al. 2010; Fong et al. 2009; McCabe et al. 2006).  In 
contrast, the clinical activity of PARP inhibitor in HR-intact tumors has been limited 
(Esteller et al. 2000).  Preclinical data suggests that PI3K-AKT pathway inhibition can be 
exploited to induce HR deficiency in HR-intact cells and promote sensitization to PARP 
inhibition (Ibrahim et al. 2012).  Combining a PI3K inhibitor with a PARP inhibitor has 
also demonstrated synergistic activity in a genetically engineered BRCA1-deficient 
mouse model as well as in humans for BRCA1-mutated breast cancer patient-derived 
xenograft tumors suggesting potential relevance of the combination even in HR-deficient 
tumors (Juvekar et al. 2012).  PARP inhibitor can promote PI3K-AKT pathway activation, 
which can cause resistance to cytostatic agents (Szanto et al. 2009), and concurrent
inhibition of both pathways can prevent this salvage pathway.  
A Phase I study has evaluated the combination of a PARP inhibitor with an AKT inhibitor 
in breast, ovarian, and endometrial cancer (Westin et al. 2017).  The combination was 
well tolerated and there was preliminary evidence of durable tumor activity all three 
tumor types. Response was independent of BRCA1/2 status, but possibly associated 
with PI3K-AKT activation.  Patients with prostate cancer were not included in the study 
population but high prevalence of PTEN-loss and HR deficiency in mCRPC provides 
strong rationale for extending exploration of this combination in prostate cancer.
Despite recent advances, metastatic ovarian, breast, and prostate cancer remain
incurable diseases, and there is a need to develop improved anti-cancer therapies.  
PI3K inhibitors have demonstrated activity in later-line settings for patients in all three 
tumor types but activity has largely been limited to HR-deficient tumors.  There is strong 
preclinical and early clinical data to support combining ipatasertib and rucaparib to 
expand disease activity to tumors regardless of HR status.  In prostate cancer, the 
combination has high relevance as novel mechanisms of action are needed following 
progression on AR-targeted therapies due to mechanisms of cross-resistance with other 
AR-targeted therapies and with docetaxel.  Patients with HR-deficient tumors that were 


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previously treated with AR-targeted therapies have shown response to PI3K inhibitors 
suggesting that this pathway remains an active and relevant target.  Combining with 
ipatasertib can potentially bring this benefit to HR-intact patients and enhance the benefit 
in HR-deficient patients.
The study design including dose-escalation and dose-expansion intends to minimize risk 
to patients by allowing for thorough safety review.  There are limited overlapping 
toxicities between ipatasertib and rucaparib.  Dose-expansion in prostate cancer will 
provide an opportunity to assess early signals for disease activity in a patient population 
of high unmet need. The Sponsor has assessed that the potential benefit-risk profile of 
ipatasertib in combination with rucaparib justifies the initiation of the proposed clinical 
study with the initial Dose-Escalation Phase.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, efficacy, and pharmacokinetics of ipatasertib 
administered in combination with rucaparib in patients with advanced breast, ovarian 
cancer, and prostate cancer.  Specific objectives and corresponding endpoints for the 
study are outlined below.
In this protocol “study treatment” refers to ipatasertib, rucaparib, and the combination of 
both assigned to patients as part of this study.
2.1
PRIMARY SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of ipatasertib administered in 
combination with rucaparib on the basis of the following endpoints:

To identify a RP2D and schedule for ipatasertib and rucaparib combination

Incidence, nature, and severity of adverse events and laboratory abnormalities, with
severity determined according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)

Incidence and nature of dose-limiting toxicities (DLTs) that determine the MTD of 
the ipatasertib and rucaparib combination
2.2
EFFICACY OBJECTIVES
2.2.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of ipatasertib 
administered in combination with rucaparib in patients with prostate cancer on the basis 
of the following endpoint:

Prostate-specific antigen (PSA) response, defined as the proportion of patients with 
a reduction in the PSA level of 50% or more


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2.2.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of ipatasertib 
administered in combination with rucaparib in patients with prostate cancer on the basis 
of the following endpoints:

Objective response rate (ORR), defined as the proportion of patients with a 
confirmed complete response (CR) or partial response (PR) on two consecutive 
occasions 4 weeks apart, as determined by the investigator per Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1)

Duration of objective response (DOR)

rPFS by Prostate Cancer Working Group 3 (PCWG3) criteria

OS
2.2.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is as follows:

To evaluate the potential relationship between the presence of PI3K-AKT or HR
pathway alterations (e.g., PTEN loss by IHC, PIK3CA/AKT1/PTEN- or 
BRCA1/BRCA2-altered status by next-generation sequencing [NGS]) and the 
anti-tumor activity of ipatasertib in combination with rucaparib in patients with 
prostate cancer on the basis of the following endpoints:
–
PSA response rate
–
ORR
–
DOR
–
rPFS
–
OS
2.3
PHARMACOKINETIC OBJECTIVES
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the PK profile of ipatasertib, its metabolite G-037720, and rucaparib,
when administered in combination, on the basis of the plasma concentration of 
ipatasertib and rucaparib at specified timepoints as listed in Appendix 2
2.4
BIOMARKER OBJECTIVES
The exploratory biomarker objectives for this study are as follows:

To evaluate possible predictive and prognostic biomarkers in the tissue and plasma
based on the following endpoint:
–
Exploration of possible relationships between the tissue- and blood-based 
biomarkers and patient clinical features (e.g., baseline features) and outcome 
(e.g., rPFS)

To evaluate pharmacodynamic effects of ipatasertib and the combination of 
ipatasertib with rucaparib in the tissue based on the following endpoint:


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–
Changes in molecular biomarkers in pretreatment and on-treatment tumor 
tissues

To identify possible mechanisms of resistance to the study treatments through the 
comparative analysis of potential biomarkers in the blood based on the following 
endpoint:
–
Changes in molecular biomarkers in pretreatment and post-progression plasma 
and blood samples
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study
This is a Phase Ib, open-label, non-randomized study in patients with advanced breast, 
ovarian, or prostate cancer to investigate the dose, safety, pharmacokinetics, and 
preliminary efficacy of ipatasertib in combination with rucaparib.
The study consists of two parts: a Dose-Escalation Phase (Part 1) in patients with 
previously treated advanced breast cancer, ovarian cancer, or prostate cancer and a 
Dose-Expansion Phase (Part 2) in patients with advanced prostate cancer who have had 
at least one line of prior therapy with second-generation AR-targeted agents 
(e.g., abiraterone, enzalutamide, apalutamide).
Approximately 24 patients will be enrolled in Part 1 (Dose-Escalation Phase) and 
approximately 30 patients will be enrolled in Part 2 (Dose-Expansion Phase).  Patients 
must have fresh or archival tumor tissue samples available for submission for biomarker 
analyses for IHC (e.g., PTEN loss) and NGS methodologies (e.g., PIK3CA/AKT1/PTEN
or BRCA1/BRCA2-altered status).
3.1.1.1
Dose-Escalation Phase (Part 1)
The Dose-Escalation Phase, Part 1, will determine the recommended dose of ipatasertib 
in combination with rucaparib in patients with advanced breast, ovarian, or prostate 
cancers.  There will be a 7-day run-in period with ipatasertib alone prior to Cycle 1,
Day 1.  After the completion of the ipatasertib run-in period, patients will begin Cycle 1,
Day 1 of the ipatasertib and rucaparib combination treatment.  The study schema for 
Part 1 is presented in Figure 1, and the study flow for Part 1 is presented in Figure 2.
Two dose levels of rucaparib administered orally (PO) BID will be evaluated with two 
dose levels of ipatasertib in 28-day cycles.  There will be approximately 6 patients per 
dose level.  The highest dose level of each agent with an acceptable safety profile and 
with a minimum of 6 patients, at which, less than one-third of patients experience a DLT,
will be declared the RP2D.  Preliminary assessment of the anti-tumor activity and 
biomarkers of response or resistance to combined ipatasertib and rucaparib will also be 
conducted in Part 1.  The dose levels of ipatasertib and rucaparib to be used in this 
study are listed in Table 1.


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All patients will continue to receive study treatment until disease progression (according 
to RECIST v1.1 for breast and ovarian cancer or PCWG3 criteria for prostate cancer), 
unacceptable toxicity, death, or patient or investigator decision to withdraw, whichever 
occurs first.
Table 1
Dose Levels of Ipatasertib and Rucaparib
Dose Level
Ipatasertib (mg)
Rucaparib (mg)
1
300 mg QD
400 mg BID
2a
300 mg QD
600 mg BID
2b
400 mg QD
400 mg BID
3
400 mg QD
600 mg BID
BIDtwice daily; QDonce daily.
Figure 1
Study Schema Part 1
BIDtwice daily; DLTs dose-limiting toxicities; Ipatipatasertib; Rucaprucaparib; QDonce 
daily.
Figure 2
Study Flow for Part 1
CCycle; DDay.
3.1.1.2
Dose-Expansion Phase (Part 2)
In the Dose-Expansion Phase, Part 2, the potential RP2D of combined ipatasertib and 
rucaparib identified in Part 1 will be further evaluated for safety, pharmacokinetics, and 
preliminary efficacy in patients with advanced prostate cancer who have been treated 
with at least one line of second-generation AR-targeted therapy.  There will be no run-in 
phase for the ipatasertib monotherapy.  Approximately 30 patients will be enrolled, of 
whom approximately 70% are expected to have HR-intact tumors, and approximately 


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50% are expected to have PTEN-loss tumors based on the prevalence previously 
described in CRPC (Robinson et al. 2015).  Enrollment may be extended to ensure at 
least 15 patients with HR-intact features are enrolled. A patient with a HR-deficient
tumor is considered a patient with one of the following molecular features defined by the 
FoundationOne NGS assay:

Deleterious alteration in at least one of the following genes:  ATM, BRCA1, BRCA2, 
BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, 
RAD51C, RAD51D, RAD54L
Mandatory archival or fresh tissue will be collected at the time of enrollment and optional 
fresh tumor biopsies on study treatment will be collected.  In addition, plasma and blood 
samples may be analyzed for deleterious alterations and further classification of mutational status.
All patients will continue to receive study treatment until disease progression (according 
to RECIST v1.1 or PCWG3 criteria), unacceptable toxicity, death, or patient or 
investigator decision to withdraw, whichever occurs first.
3.1.2
Definition of Dose-Limiting Toxicity
A DLT will be defined as any of the following adverse events related to study treatments 
occurring during the DLT reporting period, which corresponds to the first cycle of study 
treatment (i.e., from Cycle 1, Day 7 to Day 28; Cycle 1 has 35 days):

Any death related to study treatment

Grade 4 neutropenia lasting for 7 days

Grade 3 neutropenia complicated by fever 38C or infection

Grade 4 thrombocytopenia lasting for 7 days

Grade 3 thrombocytopenia complicated by hemorrhage or that requires 
transfusion

Study treatment-related Grade 3 non-hematologic toxicity (graded according to the 
NCI CTCAE, v5.0) except for the following:
–
Grade 3 fatigue, asthenia, fever, anorexia, or constipation
–
Grade 3 nausea, vomiting, or diarrhea that responds to maximal supportive 
care within 72 hours
–
Grade 3 rash that resolves to Grade 1 within 7 days with maximal supportive 
care
–
Grade 3 hyperglycemia that is controlled with subcutaneous insulin
–
Grade 3 ALT or AST elevation that is not accompanied by a concurrent increase in 
bilirubin (i.e., greater than the upper limit of normal [ULN]) 
–
Any other Grade 3 laboratory abnormality that is asymptomatic and is deemed 
not to be clinically significant by the investigator


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Patients who miss seven or more doses of either ipatasertib or rucaparib during the 
DLT-evaluation period for reasons other than a DLT will be replaced.  In addition, 
patients who are discontinued from the study prior to completing the DLT-evaluation 
period for reasons other than a DLT (e.g., disease progression, consent withdrawn) will 
also be replaced.  If a patient experiences a DLT, study treatment will be interrupted 
immediately for that individual and a safety assessment will be conducted.
The NCI CTCAE v5.0 will be used to characterize the toxicity profile of the study 
treatments for all patients.
An interim analysis for safety (including DLTs) will be performed by the Sponsor prior to 
the Dose-Expansion Phase (Part 2) to assess data from all patients in the 
Dose-Escalation Phase (Part 1).  The interim analysis will be completed after the last 
evaluable patient in Part 1 has competed the first cycle of treatment.  The combination 
dose levels demonstrating acceptable safety will be carried forward to the 
Dose-Expansion Phase (Part 2) of the study.
3.1.3
Tumor-Response Assessment
For all patients with breast and ovarian cancer, tumor response will be evaluated 
according to RECIST v1.1.  For patients with ovarian cancer, CA-125 response will be 
assessed according to Gynecologic Cancer InterGroup (GCIG) criteria. For patients with 
prostate cancer, tumor response and PSA response will be evaluated according to 
PCWG3 criteria.  
3.1.4
Internal Safety Monitoring
The Study Team, including the Study Medical Monitor and Safety Scientist, will monitor 
patient safety throughout the study.  In addition to the ongoing assessments of the 
incidence, nature, and severity of adverse events, serious adverse events, deaths, and 
laboratory abnormalities performed by the investigators and the Medical Monitor, the 
Study Team will review all necessary cumulative data at regular intervals during the 
study. Assessment of safety and all available PK data for the Dose-Escalation Phase 
(Part 1) will be performed by the Study Team prior to opening enrollment for 
Dose-Expansion Phase (Part 2).
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical efficacy analysis or safety 
follow-up is received from the last patient, whichever occurs later.
For an individual patient, the last visit is defined as the end of treatment visit or the time of 
disease progression, whichever occurs later.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 36 months.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Study Treatment Dose and Schedule
Based on preclinical and limited clinical studies, the combination of ipatasertib and 
rucaparib may have synergistic anti-tumor activity.  This study is designed to assess the 
safety and preliminary efficacy of the two drugs in combination.
The starting dose for ipatasertib in Part 1 will be 300 mg PO QD, and the starting dose 
for rucaparib in Part 1 will be 400 mg PO BID.  The highest potential dose for ipatasertib 
is 400 mg QD, which is the current dose of ipatasertib being studied in combination with 
abiraterone in prostate cancer and with paclitaxel in breast cancer.  Ipatasertib is given 
continuously with abiraterone; it is given for 21 days of every 28-day cycle with paclitaxel.  
The highest potential dose for rucaparib is 600 mg BID given continuously, which is the 
approved dose for rucaparib monotherapy. Since ipatasertib has not been administered 
with rucaparib before, the Dose-Escalation Phase includes different dose combinations 
in cohorts of approximately 6 patients each.  Additional dose de-escalation levels for 
ipatasertib or rucaparib (or both) may be explored during Part 1 if the frequency of DLT 
is 33%.
In Part 1, there is a 7-day run-in period for ipatasertib alone prior to Cycle 1.  The 
rationale for the run-in is to allow for PK assessment of ipatasertib monotherapy after the 
run-in phase for comparison with the pharmacokinetics in combination with rucaparib.  Based 
on available information to date, there could be a potential for increased exposure to 
ipatasertib when given in combination with rucaparib due to CYP3A inhibition by rucaparib.  
PK sampling of ipatasertib monotherapy at steady-state and following addition of 
rucaparib at steady state will add to PK data for drugdrug interaction evaluation and aid 
in determining the RP2D for both agents when administered in combination. Trough
rucaparib concentrations will also be evaluated and compared with published single-agent data. 
Based on prior Phase I data with an AKT inhibitor combined with a PARP inhibitor
(Westin et al. 2017), the overlapping toxicities are expected to be limited.  Given the 
available clinical safety data, ipatasertib 300 mg QD and rucaparib 400 mg BID are 
considered appropriate starting doses to evaluate the combination.
3.3.2
Rationale for Patient Population
The combination will be evaluated in Part 1 in patients with advanced breast, ovarian, 
and prostate cancer.  PARP inhibitors have previously demonstrated single-agent 
activity in these tumor types (see Section 1.1), but activity has been most pronounced in
patients with HR-deficient tumors.  There remains potential to expand and extend clinical 
benefit of PARP inhibitors to patients with HR-intact tumors with the addition of 
ipatasertib.  This study is designed to explore the simultaneous inhibition of PARP and 
AKT, thereby targeting the tumor in a multifactorial fashion that may enhance the 
efficacy of PARP and PI3K-AKT inhibition by inducing an HR-deficient phenotype 
regardless of tumor HR-status by germline/somatic mutation.  Based on the distribution 


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of genetic alterations in HR and PI3K-AKT pathways in prostate cancer, this tumor type 
provides a unique opportunity to explore the combined activity of two different biomarker 
segments.  In addition, there exists a high unmet need in patients who have previously 
received AR-targeted therapies and this population is expected to grow as these 
therapies are moving up in use to earlier lines of therapy.
3.3.3
Rationale for Biomarker Assessments
An exploratory objective of this study is to evaluate biomarkers (including the HR and 
PI3K pathway, and immune-related biomarkers) in tumor tissue and in plasma that will 
be used to help understand the response or resistance in patients treated with 
ipatasertib plus rucaparib. In addition, tissue and blood-based samples will be assessed 
for additional biomarkers in an effort to identify factors that may correlate with the safety 
and efficacy of the study treatments, are associated with progression to a more severe 
disease state, are associated with acquired resistance to study drug, or can increase the 
knowledge and understanding of disease biology through the use of NGS, whole 
genome sequencing (WGS), and/or other methods.
3.3.3.1
Rationale for the Collection of Tumor Tissue for Examining 
Alterations in the HR and PI3K-AKT Signaling Pathway
Activation of PI3K-AKT signaling frequently occurs in prostate cancer primarily through 
loss of PTEN expression, which occurs in approximately 45% of patients with prostate 
cancer and is associated with worse outcomes (Ferraldeschi et al. 2015).  In the 
Phase II study GO27983, a pre-specified patient population with PTEN-loss tumors, as 
identified using archival or newly obtained biopsy tissue, demonstrated an improved 
mPFS benefit from ipatasertib treatment (de Bono et al. 2017). In addition, patients with 
prostate cancer who had defects in their DNA-repair genes experienced a high-response 
rate to the PARP inhibitor, olaparib (Mateo et al. 2015).
These considerations support the use of archival tissue (i.e., sample from primary 
prostate tumor) or a newly obtained biopsy to determine the PI3K-AKT pathway 
alterations and HR status of the disease, thus evaluating for a patient population with a 
higher probability of having a clinically meaningful response to ipatasertib combined with 
rucaparib.  In the current study, PTEN-tumor status will be determined using an IHC 
assay and HR pathway status will be determined using an NGS assay (e.g., Foundation 
Medicine, Inc. [FMI]).  Additional alterations in the PI3KAKT-signaling pathway will also 
be assessed using NGS assay.  Review of PI3KAKT-pathway alterations and HR
status in tumor tissue and response measures will be performed on an ongoing basis.  
In addition, in the cohorts in the Dose-Expansion Phase, enrollment may be restricted to 
patients with tumors demonstrating an intact HR pathway.
To obtain the most accurate reflection of the patient’s current disease while minimizing 
burden, a specimen from the most recently obtained tumor tissue will be requested.


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3.3.3.2
Rationale for Collection of Blood Samples for Non-Invasive 
Disease Monitoring
Circulating-tumor DNA (ctDNA) can be detected in the blood of patients with epithelial 
cancers and may have diagnostic and therapeutic significance (Schwarzenbach et al. 
2011).  For example, the mutational status of tumor cells may be obtained through the 
isolation of ctDNA (Maheswaran et al. 2008), and ctDNA has been used to monitor 
treatment effectiveness in melanoma (Shinozaki et al. 2007).  In the current study, blood 
samples will be collected at screening, at the time of first tumor assessment, and at the 
study completion/early termination visit in order to evaluate oncogenic genetic alterations 
at baseline and to assess for the possible emergence of new alteration after treatment 
with ipatasertib and rucaparib.  Genetic alterations will be evaluated in relevant genes in 
the HR and PI3K pathway.  Identifying potential discordances in the HR and 
PI3K-pathway status between tumor samples and ctDNA may help generate hypotheses 
regarding the prognostic and predictive significance of these alterations in the enrolled 
patients that can be further tested in a future pivotal study.
3.3.3.3
Rationale for Collection of DNA (Blood) for Exploratory 
Whole Genome Sequencing 
Genomics is increasingly informing researchers' understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in the identification of important pathways, guiding the development of new targeted 
agents.
Genetic variants of drug-metabolizing enzymes and transporters can alter the 
pharmacokinetics of drugs, affecting their safety and efficacy.  For example, patients
who carry defective alleles of the gene encoding UGT1A1, which facilitates the 
metabolism and excretion of SN-38 (the active metabolite of irinotecan), are at higher 
risk for adverse events associated with the use of standard doses of irinotecan (O’Dwyer 
and Catalano 2006).  Preliminary results from in vitro metabolism studies suggest that 
ipatasertib is primarily metabolized by the CYP450 enzyme CYP3A, with a minor 
contribution by CYP2D6.  Although in vitro studies can help elucidate the roles of 
enzymes in the metabolism of the drug, these results are not always predictive of in vivo 
metabolism for a number of reasons, including differences in drug concentrations that 
the enzymes encounter in vitro and in vivo.  For this reason, a blood sample for DNA 
isolation will be collected from all patients in this study for potential pharmacogenetic 
analysis of genes or biomarkers that may affect the pharmacokinetics of ipatasertib and 
its metabolite G-037720.  The decision to analyze the samples will be based on a review 
of the PK data.  For example, if a patient in a given cohort has substantially higher 
ipatasertib plasma levels than other patients in that cohort, he or she may carry a 
defective allele of a gene important in the metabolism or transport of ipatasertib.  The 


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genotyping efforts would be guided by results from in vitro metabolism studies and by 
results from ongoing clinical studies with ipatasertib.
The pharmacogenetic analysis, if needed, will be performed on identifiable (referring to 
the blinded clinical trial number assigned to the patient at the time of enrollment and not 
to the actual name or other protected health information of the patient) DNA samples, 
because it is necessary to link a patient’s PK data with genotype.  This analysis will be 
restricted to the evaluation of genes that may be involved in the pharmacokinetics of 
ipatasertib and its metabolite G-037720 (e.g., drug metabolism, disposition, 
or elimination genes, or genes influencing these processes).
In addition, tumor DNA can contain both reported and unreported chromosomal 
alterations resulting from the tumorigenesis process.  To help control for sequencing 
calls in previously unreported genomic alterations, the blood sample will help determine 
whether an observed alteration identified in the tumor tissue is somatic throughout the 
evaluation of the DNA isolated in peripheral blood using WGS or similar assay techniques.
This sample for WGS will be collected if approved locally.
3.3.3.4
Rationale for Optional Collection of Tumor Biopsies for 
Exploratory Purposes 
Pre- and during-treatment tumor tissue may be collected from patients for DNA and/or 
RNA extraction for exploratory NGS or other research on non-inherited biomarkers 
(including, but not limited to, cancer-related genes and biomarkers associated with 
common molecular and biological pathways).  These tumor tissue samples will be 
collected from patients who sign an Optional Research Biosample Repository Informed 
Consent Form, and whose tumor biopsies can be obtained on study as described in 
Appendix 1 with minimal risk and discomfort.  These samples will be used to assess 
pharmacodynamic biomarkers in order to evaluate evidence of biologic activity of the 
study treatments.  In addition these biopsies may provide insights into the tumor 
immunobiology, stromal markers, and critical signaling targets of HR and PI3K signaling 
cascades.
3.3.4
Rationale for the Pharmacokinetic Evaluation Schedule
Plasma samples for PK characterization of ipatasertib, its metabolite G-037720, and 
rucaparib, will be collected as outlined in Appendix 2. The sampling schedule is 
designed to enable characterization of ipatasertib PK using non-compartmental analysis 
and/or population PK (popPK) methodology. In addition, the PK data will allow 
comparison of ipatasertib exposure with single-agent ipatasertib data from the Phase I 
clinical trial (Study PAM4743g) and with ipatasertib data from other trials to evaluate 
whether ipatasertib exposures are altered in combination with rucaparib, which is a mild 
CYP3A4 inhibitor.


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Rucaparib is metabolized by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4.  
Given that ipatasertib is a mild-to-moderate inhibitor of CYP3A4 (see the Ipatasertib 
Investigator’s Brochure) and is not an inhibitor of CYP2D6 and CYP1A2, ipatasertib is 
not expected to alter rucaparib exposure in a clinically significant manner. Therefore, 
only trough concentrations of rucaparib will be evaluated in this study and compared to 
historical data in the literature.
Prior to start of any drug treatment in Part 1, a PK biomarker sample may be collected to 
measure baseline levels of coproporphyrin (CP) I and III, which are putatively 
transported into the liver by uptake transporters OATP1B1 and OATP1B3.
The levels of these endogenous substrates of organic-anion-transporting polypeptide 
(OATP) transporters, if warranted, will be measured in an exploratory way prior to and 
on ipatasertib treatment to understand the impact of ipatasertib on OATP functionality.  If 
the analysis is conducted, remaining plasma samples from PK analysis will be used for 
assessing on-treatment effect on CPI and CPIII levels.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 54 patients will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years at time of signing Informed Consent Form

Ability to comply with the study protocol, in the investigator's judgment

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

A life expectancy of at least 3 months

Ability to swallow oral study drug

Have adequate organ and marrow function as confirmed by the laboratory values 
listed below, obtained within 28 days prior to the first dose of study treatment
Bone marrow function assessments (without transfusion within 28 days prior to 
receipt of study treatment)
–
ANC 1500 cells/L (1.5109/L) without granulocyte-colony stimulating factor 
support
–
Platelet count 100.0109/L
–
Hemoglobin 9 g/dL (or 5.6 mmol/L)
Chemistry panel assessments
–
AST and ALT 1.5ULN; if liver metastases, 2.5ULN


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–
Bilirubin 1.5ULN (3ULN if hyperbilirubinemia is due to Gilbert’s syndrome)
–
Serum albumin 3.0 g/dL
–
Serum creatinine 1.5ULN or creatinine clearance 50 mL/min
–
Fasting glucose 150 mg/dL and hemoglobin A1c (HbA1c) 7.5%

Resolved or stabilized toxicities resulting from previous therapy to Grade 1 (except 
for alopecia and neuropathy).
An ongoing, Grade 2, non-hematologic toxicity related to the most recent
treatment regimen may be permitted with approval from the Medical Monitor
Cancer-Related Inclusion Criteria

Have a histologically confirmed diagnosis of ovarian (Part 1 only), breast (Part 1 
only) or prostate cancer (Part 1 and Part 2)

Disease must be either metastatic or locally advanced disease that cannot be 
treated with curative intent

For patients with ovarian cancer (Part 1 only): 
–
High-grade (2 or 3) serous or endometrioid or clear cell epithelial ovarian, 
fallopian tube, or primary peritoneal cancer (PPC)  
If the tumor is of mixed histology, 50% of the primary tumor must be 
confirmed to be high-grade serous, endometrioid, or clear cell.
–
Must have received at least one prior platinum-based therapy and may have 
platinum-sensitive disease (i.e., documented radiologic disease progression 
6 months following the last dose of the platinum treatment administered) or 
platinum-resistant disease
–
Have a CA-125 level that is 2ULN
–
Must have measurable disease by RECIST v1.1

For patients with breast cancer (Part 1 only): must be HER2-(ER/progesterone
positive or negative)
–
ER/progesterone-positive patients must have received and progressed on at 
least one endocrine therapy (adjuvant or metastatic) 
–
ER/progesterone-negative/HER2(TNBC) patients must have received at least 
one prior line of chemotherapy for metastatic breast cancer
–
Must not have received more than two prior lines of chemotherapy for 
metastatic breast cancer
–
Must have measurable disease by RECIST v1.1

For patients with prostate cancer: 
–
Adenocarcinoma of the prostate without small cell or neuroendocrine features 
–
Surgical or medical castration with testosterone 50 ng/dL (1.7 nM) 


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–
Patients treated with luteinizing hormone-releasing hormone analogs must have 
initiated therapy at least 4 weeks prior to the first dose of study treatment and 
continue throughout the study treatment 
–
Progression of prostate cancer either via PSA progression (two rising PSA 
levels measured 1 week apart, with second result 1 ng/mL) or radiographic 
progression with or without PSA progression (see Appendix 5 for guidance)
–
Must have received at least one prior line of second-generation androgen 
receptor targeted therapy (e.g., abiraterone, enzalutamide, apalutamide)
–
Patients with prostate cancer must have either measurable disease by 
RECIST v1.1 or bone lesions by bone scan, or both.

Submission of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or a 
minimum of 12 freshly cut, unstained, serial tumor slides from the most recently 
collected tumor tissue for central molecular analysis (retrospective NGS testing for 
HR and PI3K-AKT pathway status and for other protocol-mandated secondary and 
exploratory assessments).  Cytologic or fine needle aspirate samples are not 
acceptable.  Tumor tissue from bone metastases is not acceptable.
–
If the specimen is either insufficient or unavailable, the patient may still be 
eligible if the patient is willing to consent to and undergo an additional 
pretreatment core or excisional biopsy of the non-target lesion (if it is 
assessable and the biopsy can be safely obtained).  In general, a minimum of 
three core biopsies for NGS testing are required.

For women of childbearing potential:  be abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures, and agreement to refrain from donating 
eggs, as defined below:
Women must be abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for at least 28 days after the final dose 
of ipatasertib or 6 months after the last dose of rucaparib, whichever occurs 
later.  Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, and established proper use of 
progesterone-only injectable or implantable contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method 
plus spermicide.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  


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Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  be abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must be abstinent or use a 
condom plus an additional contraceptive method that together result in a failure 
rate of 1% per year during the treatment period and for 28 days after the last 
dose of ipatasertib or for 6 months after last dose of rucaparib whichever occurs 
later.  Men must refrain from donating sperm during this same period.
With pregnant female partners, men must be abstinent or use a condom during 
the treatment period and for 28 days after the last dose of ipatasertib or 
rucaparib to avoid exposing the embryo.
Examples of contraceptive methods with a failure rate of 1% per year, when 
used consistently and correctly, include combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation, 
progestogen-only hormonal contraception associated with inhibition of ovulation, 
bilateral tubal occlusion, male sterilization, intrauterine hormone releasing 
system, and sexual abstinence. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or
within 28 days after the final dose of ipatasertib or 6 months after the final dose of 
rucaparib
Women of childbearing potential must have a negative serum pregnancy test 
result within 3 days prior to initiation of study drug.

Prior treatment with a PARP inhibitor, AKT inhibitor, or PI3K inhibitor

Treatment with investigational therapy within 14 days prior to initiation of study drug

Symptomatic and/or untreated CNS metastases
Patients with asymptomatic previously treated CNS metastases are eligible 
provided they have been clinically stable for at least 4 weeks.
Patients with leptomeningeal carcinomatosis will be excluded. 

Uncontrolled tumor-related pain 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
randomization.  Patients should be recovered (e.g., to Grade 1 or resolved) 


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from the effects of radiation prior to study enrollment.  There is no required 
minimum recovery period beyond the 7 days required for radiation therapy. 
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to randomization. 

Nonstudy-related minor surgical procedures 5 days or major (invasive) surgical 
procedure 14 days prior to first dose of study treatment
Patient must be sufficiently recovered from surgery and stable, and wound 
healing must have occurred.

Patients with active hepatitis C virus (HCV)
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA.

Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test or a positive quantitative HBV DNA test
If a patient has a negative HBsAg test and a positive total hepatitis B core 
antibody (HBcAb) test, a quantitative HBV DNA test must be performed. 
Patients receiving anti-viral therapy for HBV are not eligible.

Known HIV infection

Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's 
judgment

Malabsorption syndrome or other condition that would interfere with 
enteral absorption

Serious infection requiring antibiotics within 14 days of first dose of study treatment

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study

Need for chronic corticosteroid therapy of 10 mg of prednisone per day or an 
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants 
for a chronic disease

History of another malignancy within 5 years prior to randomization, except for either 
adequately treated non-melanomatous carcinoma of the skin, adequately treated 
melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of 
the bladder (Tis, Ta, and low-grade T1 tumors), or other malignancies where the 
patient has undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to have a recurrence rate of 5% at 5 years. 

History of clinically significant cardiovascular dysfunction, including the following:
–
History of stroke or transient ischemic attack within 6 months prior to enrollment
–
History of myocardial infarction within 6 months prior to first dose of study drug 


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–
New York Heart Association Class III or IV cardiac disease
–
Unstable arrhythmias or unstable angina

Presence of any other condition that may have increased the risk associated with 
study participation or may have interfered with the interpretation of study results, 
and, in the opinion of the investigator, would have made the patient inappropriate for 
entry into the study.
Ipatasertib-Specific Exclusion Criteria
Patients who meet any of the following criteria specific to ipatasertib will be excluded 
from study entry:

Type 1 or Type 2 diabetes mellitus requiring insulin at study entry
However, patients who are on a stable dose of oral diabetes medication 
4 weeks prior to initiation of study treatment may be eligible for enrollment. 
Patients must meet the laboratory eligibility criteria for fasting blood glucose 
and HbA1C as outlined in the inclusion criteria.

History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), 
active bowel inflammation (e.g., diverticulitis)

Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 4 weeks or 
five elimination half-live of the inhibitors, whichever is longer, prior to initiation of 
study drug 
4.2
METHOD OF TREATMENT ASSIGNMENT  
This is an open-label study; the investigational products will not be blinded or masked.  
All patients enrolled will receive oral rucaparib and oral ipatasertib.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are ipatasertib (RO5532961) 
and rucaparib (CO-338).
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Ipatasertib
Ipatasertib will be supplied by the Sponsor as 100-mg and 200-mg tablets in packaged 
bottles.  For information on the formulation and handling of ipatasertib, see the 
Ipatasertib Investigator’s Brochure.  A brief description of the investigational product is 
provided in Table 2.


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Table 2
Description of Ipatasertib
Drug Name:
GDC-0068, RO5532961
INN:
Ipatasertib 
Formulation:
Tablet; film coated
200 mgoval, brownish pink, embossed with ROCHE on one side
100 mgoval, light or pale or grayish yellow, embossed with ROCHE on 
one side
How Supplied:
200 mg and/or 100 mg (as hydrochloride salt) strength, 30 count in 
high-density polyethylene bottles with desiccant and child-resistant 
screw cap
Storage Conditions:
Do not store above 25°C; protect from moisture
INNInternational Nonproprietary Name.
4.3.1.2
Rucaparib
Rucaparib will be supplied by the Sponsor as 200-mg and 300-mg tablets in packaged 
bottles.  For information on the formulation and handling of rucaparib, see the 
Rucaparib Investigator's Brochure.  A brief description of the investigational product is 
provided in Table 3.
Table 3
Description of Rucaparib
Drug Name:
CO-338
INN:
Rucaparib 
Formulation:
Tablet; film coated
200 mgblue, round, embossed with C2
300 mgyellow, oval, embossed with C3
How Supplied:
200 and/or 300 mg (as free base) strength, 60-count each, in 
high-density polyethylene bottles or equivalent with child-resistant caps 
Storage Conditions:
15°C30°C (59°F86°F)
INNInternational Nonproprietary Name.
All potential doses of rucaparib and the tablets that will be assigned for each dose level 
are described in Table 4.


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Table 4
Doses and Tablets of Rucaparib
Rucaparib Dose a
Tablet
Number of Tablets
600 mg
300-mg tablet
Or
200-mg tablet
2
3
500 mg
300-mg tablet
200-mg tablet
1
1
400 mg
200-mg tablet
2
300 mg
300-mg tablet
1
BIDtwice a day.
a All rucaparib doses are to be prescribed BID.  The number of tablets listed above is for one 
single dose of a BID dosing schedule.
The study drug container for rucaparib will be labeled according to national regulations 
for investigational products and will detail the applicable expiry date.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.4.4.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.
4.3.2.1
Ipatasertib
Patients will self-administer oral ipatasertib QD (approximately 24 hours apart) at the 
cohort-assigned dose throughout the treatment period unless dose reduction is required 
for adverse event management.  Ipatasertib may be taken with or without food. It may be 
taken concurrently with rucaparib on days when the patient is taking both.  If a dose is missed 
(i.e., not taken within 8 hours after the scheduled dosing time), the patient should 
resume dosing with the next scheduled dose. Missed or vomited doses will not be made 
up. 
On PK sampling days, patients will be instructed not to administer ipatasertib study drug 
at home but to bring their bottles of ipatasertib and their dosing diaries to the clinic. 
Patients will be instructed when to take their doses of ipatasertib in the clinic in the 
context of the schedule of activities for the given visit. Time of dose administration will 
be collected on the PK sampling day and for prior dose administered the day before a PK 
sampling visit.  Any incidence of vomiting within 3 hours after drug administration should 
also be recorded for the day of PK sampling.  A sufficient amount of ipatasertib should 


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be provided to the patient to last one treatment cycle.  Patients will be instructed to bring 
their bottles of ipatasertib and their medication diaries to each study visit.
4.3.2.2
Rucaparib 
Patients will self-administer oral rucaparib BID (approximately 12 hours apart) at the
cohort-assigned dose throughout the treatment period unless dose reduction is required
for adverse event management.  In Part 1 only, patients will start rucaparib on the evening of 
Day 1 of Cycle 1 following all PK sampling of ipatasertib on that day.  Patients should take 
rucaparib as directed by the treating physician.  Patients may take rucaparib with or 
without food.  Rucaparib may be taken concurrently with ipatasertib on days when the patient is 
taking both.  Each dose should be taken with at least 8 ounces (240 mL) of water.  
Tablets should be swallowed whole.  Missed doses (i.e., patient does not take dose
within 6 hours of the scheduled time) or vomited doses will not be made up; the patient
should resume rucaparib dosing with the next scheduled dose.
On PK sampling days, patients will be instructed not to administer rucaparib study drug 
at home but to bring their bottles of rucaparib and their dosing diaries to the clinic.  
Patients will be instructed when to take their doses of rucaparib in the clinic in the 
context of the schedule of activities for the given visit.  Time of dose administration will 
be collected on the PK sampling day and for prior doses administered the day before a 
PK sampling visit.  Any incidence of vomiting within 3 hours after drug administration 
should also be recorded for the day of PK sampling.  A sufficient amount of rucaparib 
should be provided to the patient to last one treatment cycle.  Patients will be instructed 
to bring their bottles of rucaparib and their medication diaries to each study visit.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (ipatasertib and rucaparib) will be provided 
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to confirm the 
shipment condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Ipatasertib or Rucaparib
Currently, the Sponsor does not have any plans to provide the Roche IMP ipatasertib or 
any other study treatments or interventions to patients who have completed the study.  


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The Sponsor may evaluate whether to continue providing ipatasertib and/or rucaparib in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 14 days 
prior to initiation of study drug to the study completion/ discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Progesterone only injectable or implantable contraceptives
Of note, a decrease in glucose tolerance has been observed in some patients treated 
with medroxyprogesterone acetate contraceptive injection treatment.
Medroxyprogesterone acetate injection contraception should be used with caution, given 
the potential risk of worsening glycemic control.

Prophylactic anti-emetic and antidiarrheal medications

Prophylactic or therapeutic anticoagulation therapy
Caution should be exercised in patients receiving warfarin (Coumadin®) as 
rucaparib can be an inhibitor of CYP2C9.  Patients taking warfarin should have their 
INR monitored regularly per standard clinical practice.

Inactivated vaccinations

Bisphosphonates or denosumab

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
After Cycle 2, palliative radiotherapy is permitted, provided it does not interfere with 
the assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Rucaparib may be continued during palliative 
radiotherapy.  Treatment with ipatasertib should be suspended for at least 7 days 
before and after the procedure.  For single-day radiotherapy, the ipatasertib hold 
may be shorter, if approved in advance by the Medical Monitor.
Premedication with antihistamines, antipyretics, and/or analgesics may be administered
at the discretion of the investigator.
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  


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4.4.2
Cautionary Therapy
Use of concomitant corticosteroids with ipatasertib can increase risk of hyperglycemia.  
Patients who require use of systemic corticosteroids 10 mg of prednisone (or an 
equivalent dose of other corticosteroid) should hold ipatasertib during that time period to 
reduce risk of hyperglycemia.
4.4.2.1
Medications Given with Precaution due to Effects Related to 
Cytochrome P450 Enzymes
Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, 
CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicity of these drugs.  
Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically 
indicated.  If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, 
consider increasing the frequency of INR monitoring.
In vitro data suggest that ipatasertib is metabolized by CYP3A and may be a 
time-dependent inhibitor of CYP3A4.  A clinical drug-drug interaction study with 
midazolam (a sensitive CYP3A substrate) showed a 2.2-fold increase in midazolam 
exposures in presence of steady-state ipatasertib dosed at 600 mg QD.  Therefore, 
sensitive CYP3A substrates with narrow therapeutic window should be avoided.  Given 
that ipatasertib is primarily metabolized by CYP3A, there is a high potential for drug-drug 
interactions of ipatasertib with any medication that strongly inhibits or induces CYP3A. 
Data from a clinical study showed that ipatasertib exposures were reduced by 
approximately 50% when co-administered with enzalutamide, a strong CYP3A inducer.  
Strong CYP3A inhibitors are expected to increase ipatasertib exposures.  Therefore, the
following drugs should be avoided while taking ipatasertib:

Strong CYP3A4/5 inhibitors, such as, but not limited to, atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin, and/or voriconazole

Strong CYP3A4/5 inducers, such as, but not limited to, rifampin, carbamazepine,
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin

CYP3A4/5 substrates with a narrow therapeutic index.
Note: Chronic use of strong CYP3A inhibitors or inducers, or sensitive CYP3A 
substrates with a narrow therapeutic window that are deemed not permissible by the 
Medical Monitor are prohibited (see Section 4.4.3)
Patients who require short-term use of a strong CYP3A4/5 inhibitor or inducer or use of
sensitive CYP3A substrates with a narrow therapeutic window for medical treatment
(i.e., an alternative treatment cannot be used) must exercise caution and all study 
treatment should be temporarily held until at least 5 half-lives or 7 days, whichever is 
shorter, after the last dose of these drugs.


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Patients are permitted to take moderate inhibitors of CYP3A4/5 with caution.  Patients 
should be closely monitored.  Refer to the following information for further guidance on 
CYP450-drug interactions and a list of common substrates, inhibitors, and inducers:
Drug Development and Drug Interactions: Table of Substrates, Inhibitors, and Inducers 
(U.S. FDA):
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm
The above lists of medications are not comprehensive.  The investigator should consult
the prescribing information when determining whether a concomitant medication can be
safely administered with study treatment.  In addition, the investigator should contact the
Medical Monitor if questions arise regarding medications not listed above.
For additional information on rucaparib pharmacokinetics and drug interactions please 
refer to Rucaparib Package Insert or Summary of Product Characteristics.
4.4.2.2
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer may be 
used during the study at the discretion of the investigator.  Herbal therapies that require 
caution or are prohibited due to CYP interactions, such as St. John’s wort, are described 
in Section 4.4.2.1.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 14 days prior to initiation of study treatment and during study treatment.

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy) is prohibited for various time periods prior to starting study treatment, 
depending on the agent (see Section 4.1.2), and during study treatment, until 
disease progression is documented and the patient has discontinued study 
treatment, with the exception of palliative radiotherapy and local therapy under 
certain circumstances (see Section 4.4.1 for details).

Quinidine or other anti-arrhythmic agents with a narrow therapeutic index

Chronic use of strong CYP3A inhibitors or inducers, or sensitive CYP3A substrates 
with a narrow therapeutic window that are deemed not permissible by the Medical 
Monitor (refer to the guidance in Section 4.4.2)


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4.4.4
Prohibited Food
Use of the following foods is prohibited as described below:

Consumption of grapefruit juice, a potent CYP3A4 enzyme inhibitor, is prohibited 
during the study and for 10 days after the final dose of study treatment.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study. 
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  Patient re-screening may be considered under 
exceptional circumstances, after approval by the Medical Monitor.  
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, and smoking 
history, will be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.  Race/ethnicity 
will be captured to assess if any differences in safety exist based on this entry.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.


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Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
Height will be recorded at screening only.  Weight will be recorded at screening and on 
Day 1 of each cycle.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure, while the patient is in a seated position, and temperature.
4.5.5
ECOG Performance Status
Performance status will be measured using the ECOG Performance Status scale (see
Appendix 4) and recorded on the eCRF.
4.5.6
Tumor and Response Evaluations
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Disease progression should be determined by 
radiographic means (including computed tomography [CT] scans, magnetic resonance 
imaging [MRI] scans, and bone scans). The same radiographic procedure used to 
assess disease sites at screening should be used throughout the study (e.g., the same 
contrast protocol for CT scans).
For patients with breast and ovarian cancer, overall response at a single timepoint will 
be assessed by the investigator using RECIST v1.1.  For patients with prostate cancer, 
response assessments will be per PCWG3 guidelines (bone lesions will be assessed per
PCWG3 criteria and soft tissue lesions will be assessed per RECIST v1.1).  An 
objective response should be confirmed by repeat assessments 4 weeks after initial 
documentation.  For symptomatic deterioration attributed to disease progression, every 
effort should be made to document progression through use of objective criteria per 
RECIST v1.1.
Baseline CT/MRI assessments should be performed 28 days before starting study 
treatment.  Baseline bone scans (technetium bone scan) should be performed within 
6 weeks of starting study treatment.

CT scans are the preferred imaging modality for tumor assessments in patients with 
breast and ovarian cancer and soft tissue tumor assessments for patients with 
prostate cancer.  Tumor assessments should include a diagnostic quality, 
contrast-enhanced CT scan of the chest, abdomen, and pelvis at baseline.  CT 
scans of the neck should be included if clinically indicated.  To be suitable for 
RECIST assessments, CT scans should have a maximum thickness of 5 mm and 
no gaps.  Subsequent tumor assessments should include CT scans of the chest, 
abdomen, and pelvis, and other known sites of disease


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
In patients for whom a CT scan is contraindicated because of an allergy to 
intravenous (IV) radiographic contrast, both a CT scan of the chest without contrast 
and an MRI scan of the abdomen and pelvis with contrast are recommended.

MRI scans may be performed in lieu of CT scans.  However, an MRI scan of the 
chest may be performed only with the approval of the Medical Monitor.  At screening, 
tumor assessments should include a diagnostic quality, contrast-enhanced MRI 
scan of the chest (if approved), abdomen, and pelvis.  MRI scans of the neck should 
be included if clinically indicated.  To be suitable for RECIST assessments, MRI 
scans should ideally have a maximum thickness of 5 mm and minimal gaps.  
Subsequent tumor assessments should include MRI scans of the chest (if approved),
abdomen, and pelvis as well as other known sites of disease.

For patients with prostate cancer, bone lesions should be assessed by bone scans 
and evaluated by PCWG3 criteria.  For adequate assessment of bone lesions, it is 
expected that the radiologist will adjust window leveling accordingly.  If progressive 
disease is suspected only on the basis of new lesions detected by bone scan, a 
confirmatory bone scan must be performed at least 6 weeks after the initial scan 
which showed disease progression.  Bone scans conducted prior to Week 12 of 
study treatment may show a false positive due to “flare” phenomenon and should 
not be considered a confirmatory scan for disease progression (see Appendix 5 for 
guidance).

For patients with breast and ovarian cancer, a bone scan will be conducted at 
screening.  For patients with known or suspected bone metastases, follow-up bone 
scans should be conducted at the time of tumor assessments and at the study 
treatment discontinuation visit (unless followed by other imaging modalities).
The frequency of tumor assessments for all patients will be approximately every 8 weeks 
(or 2 cycles) 2 weeks after initiation of study treatment for the first 6 months and then 
every 12 weeks (or 3 cycles) thereafter and as clinically indicated.  At the investigator's 
discretion, imaging may be repeated at any time if progressive disease is suspected.  
The frequency of tumor assessments may be further reduced after 1 year with approval 
of the Medical Monitor.  Tumor assessments at the end of treatment visit are not 
required if radiographic disease progression per RECIST v1.1 or PCWG3 criteria (if 
applicable) has been documented previously or if the last tumor assessments were
performed 4 weeks prior to the end of treatment visit.  If an initial CR or PR is noted, 
confirmatory scans should be performed 4 weeks later.  In the case of stable disease 
(SD), follow-up measurements should have met the SD criteria at least once after study 
entry at a minimum interval of no less than 4 weeks.
For patients with prostate cancer, tumor assessments should continue per above 
schedule until radiographically assessed disease progression even if study treatment 
has been discontinued for other reasons.  For patients with breast and ovarian cancer, 
continuation of tumor assessments is preferred but not required.


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4.5.7
Other Disease-Specific Assessments
For patients with prostate cancer:

PSA samples collected will be tested at a central laboratory obtained on Day 1 of 
each cycle starting with Cycle 1.  If medically indicated, additional PSA samples 
may be collected and tested locally. Early increases in PSA levels (before 12 weeks) 
should be disregarded in determining PSA responses per PCWG3.  Treatment 
should be continued in the case of an isolated increase in PSA without radiographic 
or clinical progression.
For patients with ovarian cancer:

CA-125 measurements will be obtained on Day 1 of each cycle starting with Cycle 1.  
All CA-125 measurements will be performed by a local laboratory.  See Appendix 7
for GCIG guidelines for response using CA-125.  If there is an indication of disease 
progression based on CA-125 elevation, further evaluation by an unscheduled 
radiographic assessment may be required.  Treatment should be continued in the 
case of an isolated increase in CA-125 without radiographic or clinical progression.
4.5.8
Laboratory, Biomarker, and Other Biological Samples
Laboratory samples should be drawn according to the schedule of activities (see 
Appendix 1 and Appendix 2).  Results of the following assessments should be available 
for review at the Day 1 visit every cycle to inform dosing decision: hemoglobin, absolute 
neutrophil count, platelet count, fasting glucose, AST, ALT, and pregnancy test.  Fasting 
glucose level results should also be available for review at each visit.
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, BUN or 
urea, creatinine, total protein, albumin, calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, LDH, amylase, and lipase

Coagulation:  INR, aPTT, and PT

Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, 
triglycerides) performed following a 8-hour fast

Fasting and non-fasting blood glucose (fasting defined as following 8 hour fast)

Glycosylated hemoglobin (HbA1c)

Urinalysis: specific gravity, pH, glucose, protein, ketones, and blood

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening and monthly thereafter, and as clinically indicated.  A final pregnancy 
test will be performed at the study treatment discontinuation visit.  


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
Home glucose monitoring: for any patients who initiate home glucose monitoring 
(see Table 6 for management guidelines of fasting hyperglycemia), a glucose log 
will be made available for capturing these results

For patients with prostate cancer: PSA may be done by local laboratory 
assessment at screening if needed for eligibility

For patients with prostate cancer: serum testosterone 

For patients with ovarian cancer: CA-125
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

For patients with prostate cancer: PSA samples on Day 1 of every cycle and at 
study treatment discontinuation to be tested at a central laboratory.
The following samples will be sent to the Sponsor or designee for analysis:

Plasma samples for PK analysis of ipatasertib, G-037720, and rucaparib (see
Appendix 2)

Blood sample (pharmacogenomic sample) for DNA extraction to enable analysis via 
WGS and NGS (if approved by local regulatory authorities)

Biomarker samples (blood, plasma, and tissue) for mandatory exploratory biomarker 
research include, but not limited to, the following assays and assay platforms:
–
Single-nucleotide polymorphisms that may impact exposure or other responses, 
or NGS results interpretation
–
Mutation and copy-number variations by NGS or PCR-based methods in tumor 
tissue and ctDNA
–
Expression analysis (e.g., RNASeq) of genes related to the HR and PI3K-AKT
pathway, immune infiltration/activation, DNA damage repair pathway, apoptosis, 
and cancer biology 
–
IHC-based analysis or quantitative digital IHC of tumor suppressors, such as 
PTEN, and markers of immune infiltration and activation, such as CD8 and 
programmed deathligand 1 (PD-L1)

Archival or newly collected tumor tissue sample obtained at baseline for 
determination of alterations in the HR and PI3K pathway and for exploratory 
biomarker research
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
12 slides containing unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study enrollment.  If fewer 
slides are available, the patient may still be eligible for the study, after Medical 
Monitor approval has been obtained.
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Samples collected via resection, core-needle biopsy (at least three cores, 


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embedded in a single paraffin block), or excisional, incisional, punch, or forceps 
biopsy are acceptable.  Fine-needle aspiration (defined as samples that do not 
preserve tissue architecture and yield cell suspension and/or smears), 
brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable.  Tumor tissue from bone metastases is not acceptable.
If archival tumor tissue is unavailable or is determined to be unsuitable for 
required testing, a pretreatment tumor biopsy is required.  A pretreatment tumor 
biopsy may also be performed if a patient's archival tissue test results do not 
meet eligibility criteria.
Exploratory biomarker research may include, but will not be limited to, evaluation of 
cytokines, chemokines, and potential protein markers of PARP and AKT inhibition.  
Research may involve extraction of DNA, ctDNA, or RNA, analysis of mutations, and 
genomic profiling through use of NGS of a comprehensive panel of genes.  Research 
may aim to distinguish germline mutations from somatic mutations.  NGS methods may 
also include WGS, but only at participating sites (see Section 4.5.11).
NGS may be performed by FMI.  If performed by FMI, the investigator may obtain results 
from these analyses by requesting an NGS report directly from FMI.  If allowed by local 
laws, the investigator may share and discuss the results with the patient, unless the 
patient chooses otherwise.  The NGS report is generated for research purposes and is 
not provided for the purpose of guiding future treatment decisions.  Results may not be 
available for samples that do not meet criteria for testing.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.13), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Plasma and serum samples collected for PK may be needed for additional 
immunogenicity characterization and for PK or immunogenicity assay development 
and validation; therefore, these samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed.

Blood, plasma, serum, and tumor tissue samples collected for study-related 
procedures and biomarker research will be destroyed no later than 5 years after the 
final Clinical Study Report has been completed.

For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 


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samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law (with the exception of the report from FMI).  The 
aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication.
4.5.9
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  
4.5.10
Post-Treatment Follow-Up
After treatment discontinuation, all patients will be followed for survival information 
unless the patient requests to be withdrawn from study survival follow-up; this request 
must be documented in the source file and signed by the investigator.
Post-treatment follow-up information will be collected via telephone calls and/or clinic 
visits, or patients’ medical records, approximately every 3 months until death, loss to 
follow-up, or study termination by the Sponsor.
Patients with prostate cancer who discontinue study treatment in the absence of disease 
progression, per RECIST v1.1 or PCWG3, will return to the clinic for tumor assessment 
follow up visits approximately every 3 months from last tumor assessment (CT or MRI 
scan and bone scan) until radiographically assessed disease progression (see 
Appendix 1).  


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4.5.11
Samples for Whole Genome Sequencing
At participating sites, blood samples will be collected for DNA extraction to enable WGS
to identify mutations that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with acquired resistance to 
study drug, are associated with susceptibility to developing adverse events, can lead to 
improved adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Research may aim to distinguish 
germline mutations from somatic mutations.  The samples may be sent to one or more 
laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's Institutional Review Board or Ethics 
Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for WGS sampling, this section of the protocol (Section 4.5.11) 
will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Patient medical information associated with WGS samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.


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Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.12
Optional Tumor Biopsies
Consenting patients will undergo optional tumor biopsies at baseline or after treatment 
initiation and may undergo additional on-treatment biopsies at any other time at the 
investigator's discretion (if deemed clinically feasible by the investigator).  Samples 
collected via resection, core-needle biopsy (at least three cores preferred), or excisional, 
incisional, punch, or forceps biopsy are preferred.  For sampling procedures, storage 
conditions, and shipment instructions, see the laboratory manual.  
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies.  The investigator should document whether or 
not the patient has given consent to participate and (if applicable) the date(s) of consent, 
by completing the Optional Biopsy Sample Informed Consent eCRF.
Samples may be used for exploratory biomarker research as described in Section 4.5.8.  
Refer to Section 4.5.13.3 for details on sample storage, use of samples after patient 
withdrawal (Section 4.5.13.6), confidentiality standards for data (Section 4.5.13.4), and 
availability of data from biomarker analyses (Section 4.5.13.4).
4.5.13
Optional Samples for Research Biosample Repository
4.5.13.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition


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
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.13.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.13) 
will not be applicable at that site.
4.5.13.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to ipatasertib, rucaparib, the 
HR and PI3K pathway, immune infiltration/activation, apoptosis, and the biology of 
breast, ovarian, and prostate cancer, or drug safety:

Left over blood, serum, plasma, and tumor tissue samples (with the exception 
of remaining archival tissue blocks, which will be returned to sites) and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via WGS, whole exome sequencing (WES), or other genomic 
analysis methods. Genomics is increasingly informing researcher's understanding of 
disease pathobiology.  WGS and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more likely to 
respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.13.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.


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Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.13.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR patient's death or loss of competence, the patient's samples and 
data will continue to be used as part of the RBR research.
4.5.13.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  However, if RBR samples have been tested prior to 
withdrawal of consent, results from those tests will remain as part of the overall research 
data.  If a patient wishes to withdraw consent to the testing of his or her RBR samples 
during the study, the investigator must inform the Medical Monitor in writing of the 
patient's wishes through use of the appropriate RBR Subject Withdrawal Form and must 
enter the date of withdrawal on the RBR Research Sample Withdrawal of Informed 
Consent eCRF.  If a patient wishes to withdraw consent to the testing of his or her RBR 


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samples after closure of the site, the investigator must inform the Sponsor by emailing 
the study number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.13.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Unacceptable toxicity related to study treatment (see Section 5)

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Use of another non-protocol-specified anti-cancer therapy

Disease progression per investigator assessment according to RECIST v1.1 or 
PCWG3
–
Rise in CA-125 or rise in PSA without radiographic disease progression does 
not require treatment discontinuation
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced, with the exception of patients enrolled in Part 1 (Dose-Escalation Phase) who 
are not considered DLT-evaluable (see Section 3.1.2).
Patients will return to the clinic for a treatment discontinuation visit 30 days after the 
final dose of study drug (see Appendix 1 for additional details).


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After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the 
Sponsor terminates the study).  Patients with prostate cancer who discontinue prior to 
radiographic progression should continue tumor assessments until radiographically 
assessed disease progression.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced except for patients in Part 1 who are not considered DLT-evaluable (see 
Section 3.1.2).
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence


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
Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with ipatasertib 
and rucaparib in completed and ongoing studies.  The anticipated important safety risks 
are outlined below (see Section 5.1.1 and Section 5.1.2).  Ipatasertib is not approved, 
and clinical development is ongoing.  Refer to the Ipatasertib Investigator’s Brochure for 
a complete summary of safety information.  Refer to the Rucaparib Investigator’s 
Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.
5.1.1
Risks Associated with Ipatasertib
Ipatasertib has been associated with risks such as the following: nausea, vomiting, 
diarrhea, stomatitis/mucosal inflammation, asthenia/fatigue, hyperglycemia, erythema 
multiforme, and rash.  
Refer to the Ipatasertib Investigator’s Brochure for a detailed description of the 
anticipated safety risks for Ipatasertib.
5.1.2
Risks Associated with Rucaparib
Rucaparib has been associated with risks such as the following: anemia, 
thrombocytopenia, febrile neutropenia, nausea, constipation, vomiting, diarrhea, 
asthenia/fatigue, pyrexia, increased blood creatinine, decreased neutrophil count, and dyspnea. 
Note: AST or ALT elevation is not considered an identified risk in the Rucaparib Investigator’s 
Brochure but has been reported with rucaparib.
Refer to the Rucaparib Investigator’s Brochure for a detailed description of the 
anticipated safety risks for Rucaparib.


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5.1.3
Risks Associated with Ipatasertib and Rucaparib
Ipatasertib and rucaparib have both been associated with the following risks: nausea, 
vomiting, diarrhea, and asthenia/fatigue.
Note: AST or ALT elevation is a potential risk in the Ipatasertib Investigator's Brochure.  AST
or ALT elevation is not considered as a potential or identified risk in the Rucaparib Investigator’s 
Brochure but has been reported with rucaparib.
Refer to the Ipatasertib and Rucaparib Investigator’s Brochure for a detailed description 
of the anticipated safety risks for rucaparib.
5.1.4
Management of Patients Who Experience Adverse Events
Guidelines for managing selected adverse events are provided in this section to improve 
safety and tolerability; however, patients may be treated per institutional practices as 
appropriate.  If any observed toxicity is attributable to only one drug as assessed by the 
investigator, the dose of the other drug may not require modification.  The reasons for 
dose modifications (e.g., interruptions, reduction, and withdrawal) or delays, supportive 
measure taken, and the outcome will be recorded in the eCRF.
5.1.4.1
General Management of Rucaparib-Related Adverse Events
Treatment with rucaparib should be held if any of the following are observed:

Grade 3 or 4 hematologic toxicity

Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, 
diarrhea adequately controlled with systemic antiemetic/antidiarrheal medication 
administered in standard doses according to the study center routines, and Grade 3 
ALT/AST elevations not accompanied by bilirubin ULN or other signs of liver 
dysfunction)

In addition, at the discretion of the investigator, the dose of rucaparib may be held 
and/or reduced for Grade 2 toxicity that is attributed to rucaparib and not adequately 
controlled by concomitant medications and/or supportive care.
Rucaparib should be held until the toxicity resolves to Grade 2.  BID dosing may then
be resumed at either the same dose or a lower dose per investigator discretion.  If
treatment is resumed at the same dose and the patient soon experiences the same
toxicity, the dose should be reduced following resolution of the repeated event to
Grade 2.  If the patient continues to experience the same toxicity, additional dose
reduction steps are permitted down to a minimum dose of 300 mg BID (see Table 11).
Unless otherwise specified, rucaparib dose re-escalation upon resolution of toxicity to
Grade 1 is permitted upon agreement between the investigator and Sponsor.
If a patient continues to experience the same toxicity despite multiple dose reduction 
steps to the lowest allowed dose or if dosing with rucaparib is interrupted for 


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28 consecutive days due to the toxicity, treatment should be discontinued unless 
otherwise agreed between the investigator and the Sponsor.
5.1.4.2
Management of Rucaparib Treatment-Emergent Creatinine 
Elevations
Rucaparib is a potent inhibitor of MATE1 and MATE2-K transporters, which are involved
in active secretion of creatinine.  Rucaparib-mediated creatinine elevation occurs early in
treatment and then stabilizes.  Creatinine elevation is not typically accompanied by
elevations in urea (BUN).  Creatinine elevation resolves with treatment interruption of 
rucaparib and recurs with re-challenge.  Creatinine elevation has not been associated 
with evidence or reports of permanent renal impairment.  The following are guidelines for 
rucaparib dose modifications in the events of Grade 3 creatinine elevations:

For Grade 4 isolated creatinine elevations (BUN ULN), hold rucaparib and 
investigate with ultrasound, urinalysis, and so on for potential alternative etiologies.  
When other reversible causes are treated or ruled out and the event has resolved to 
Grade 1 or better, then resume rucaparib at a reduced dose.

For Grade 3 isolated creatinine elevations (BUN ULN), investigate with ultrasound, 
urinalysis, and so on for potential alternative etiologies.  In the absence of another 
reversible cause (e.g., obstructions or infections) or evidence of renal injury, 
continue rucaparib at the same dose.  Hold rucaparib for other reversible causes 
until the patient is treated and the event has resolved to Grade 1 or better, and then 
resume rucaparib at the same dose.
5.1.4.3
Management of Treatment-Emergent Diarrhea
Diarrhea has been associated with both ipatasertib and rucaparib administration.
For diarrhea occurring after Cycle 2 that persists for more than 5 days, despite treatment 
with an anti-diarrheal agent, a stool culture for infectious workup (i.e., Clostridium difficile, 
enteric bacteria, cytomegalovirus) will be obtained, and diarrhea should be treated with 
the appropriate antibiotic.  


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Table 5
Diarrhea Management Guidelines
Severity of Diarrhea
Management Guideline
Grade 1
Continue study drugs at the current dose level.
Manage with loperamide 4 mg initially, and then 2 mg every 4 hours or 
after every unformed stool until after 12-hour diarrhea-free interval.
Dietary modifications such as avoiding any lactose-containing foods.
Hydration with 810 glasses of clear liquid such as broth and low-calorie 
electrolyte-enhanced drinks per day.
Grade 2
Manage with loperamide as early as possible 4 mg initially, and then 
2 mg every 4 hours or after every unformed stool until after 12-hour 
diarrhea-free interval.
Dietary modifications such as avoiding any lactose-containing foods.  
Hydration with 810 glasses of clear liquid, such as broth and low-calorie 
electrolyte-enhanced drinks, per day.
For non-infectious diarrhea lasting more than 48 hours despite optimal 
loperamide treatment, manage with second-line anti-diarrheal agents, 
including, but not limited to Lomotil®, codeine, or octreotide, or as per 
institutional guidelines.
Interrupt ipatasertib.  Rucaparib may be continued at the investigator’s 
discretion.  If diarrhea persists for 3 days following interruption of 
ipatasertib, rucaparib should also be interrupted.  Ipatasertib and 
rucaparib can be resumed at the same dose or one dose lower per 
investigator evaluation upon improvement to Grade 1 or better.  
Reduce ipatasertib and rucaparib by one additional dose level 
(see Table 3) for recurrent Grade 2 diarrhea.
Grade 3
Rule out infectious etiology.
Treatment per Grade 2 management guidelines and supportive care.
Interrupt ipatasertib and rucaparib until diarrhea improves to Grade 1 or 
better.
Ipatasertib and recaparib should be reduced by one dose level 
(see Table 3 and Table 4 ) when treatment is restarted.  
For recurrent Grade 3 diarrhea, reduce ipatasertib and rucaparib dose by 
one additional dose level (see Table 3), or permanently discontinue 
ipatasertib and rucaparib per investigator discretion.  
Grade 4
Management as per Grade 3 guidelines.  Permanently discontinue 
ipatasertib and rucaparib.
If both study drugs are interrupted, step-wise reintroduction of one agent at a time 
(e.g., ipatasertib monotherapy for several days followed by reintroduction of rucaparib if 
diarrhea remains Grade 1) may be pursued.
5.1.4.4
Fasting Hyperglycemia
Hyperglycemia has been associated with ipatasertib and other agents targeting the 
PI3K/AKT/mTOR pathway but not associated with rucaparib or other PARP inhibitors.  
For this reason, management guidelines will address ipatasertib, only.


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Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours.  
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined in Table 6 and are intended to provide guidance for fasting glucose 
measurements assessed in the clinic.  This table is not meant to inform grading of 
adverse events, which should be conducted per NCI CTCAE v5.0.  Decisions regarding 
study treatment should be made on fasting levels drawn in the clinic whenever possible.
Home glucose measurements may be used to trigger contact between patient and the 
investigative site team and may lead to an unscheduled clinic visit to assess fasting 
glucose.  Guidance for when to call the investigator/site staff (or designated 
endocrinologist, if applicable) should be provided to patients for hypoglycemia 
(e.g., glucose value under 70 mg/dL) and hyperglycemia (e.g., glucose value over 
300 mg/dL).  Alternative thresholds may be selected as clinically indicated per 
investigator discretion or institutional guidance and noted in the source documents.  For 
any patients performing home glucose monitoring, a blood glucose log should be 
reviewed at each clinic visit (and source data retained); entry of results into the patient’s 
eCRF will be limited to values which result in intervention.
In the event of ipatasertib interruption, anti-diabetic medications may need to be held or 
reduced (per investigator judgment) and glucose should be monitored closely to 
minimize the risk of hypoglycemia.


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Table 6
Fasting Hyperglycemia Management Guidelines
Severity of Fasting 
Hyperglycemia
Management Guideline
Fasting glucose value 
ULN to 160 mg/dL
(8.9 mmol/L)

Monitor fasting glucose per protocol.

Consider home glucose monitoring.
Fasting glucose value 
160 to 250 mg/dL
(8.913.9 mmol/L)

Interrupt ipatasertib until the fasting glucose value decreases to 
160 mg/dL.

Initiate home glucose monitoring.

Start oral anti-diabetic medications (e.g., metformin).

If the patient is already on an oral anti-diabetic medication, the 
dose of ipatasertib should be reduced by one dose level (refer to
Table 3).

If the patient previously has not been receiving any oral 
anti-diabetic medication, ipatasertib may be resumed at the 
previous dose level with initiation of oral anti-diabetic medication.
Fasting glucose value 
250 to 500 mg/dL
(13.927.8 mmol/L)

Interrupt ipatasertib until fasting glucose value decreases to 
160 mg/dL.

Initiate home glucose monitoring.

Treat hyperglycemia as per standard of care.

Start (or increase dose of) oral anti-diabetic medications 
(e.g., metformin).

If the patient is already on an oral anti-diabetic mediation, 
ipatasertib should be reduced by one dose level when treatment is 
restarted.

If previously the patient has not been receiving any oral 
anti-diabetic medication, ipatasertib may be resumed at the 
previous dose level with initiation of oral anti-diabetic medication.

If fasting glucose value between 250 and 500 mg/dL recurs, the dose of 
ipatasertib should be reduced by one dose level when treatment is 
restarted.
Severity of Fasting 
Hyperglycemia
Management Guideline
Fasting glucose value 
500 mg/dL
(27.8 mmol/L)

Interrupt until fasting glucose value decreases to 160 mg/dL.

Treat hyperglycemia per standard of care.

Initiate home glucose monitoring.

Start (or increase dose of) oral anti-diabetic medications 
(e.g., metformin).

Assess for volume depletion and appropriate intravenous or oral 
hydration.

Reduced ipatasertib by one dose level when treatment is 
restarted.
If fasting glucose value 500 mg/dL recurs, permanently discontinue 
ipatasertib.
ULNupper limit of normal. 
Note:  For all grades, the patient should receive education on a diabetic diet.
5.1.4.5
Nausea and/or Vomiting 
Nausea and/or vomiting has been associated with both ipatasertib and rucaparib
administration.


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Dose reductions for nausea and/or vomiting should occur only if the symptoms persist 
despite a minimum of two treatments with adequate (combination) anti-emetic 
treatment(s), including ondansetron (or equivalent anti-emetic treatment; see Table 7).
For persistent nausea and/or vomiting attributable to ipatasertib, dosage-modification 
guidelines are outlined in Table 7.
Table 7
Nausea and Vomiting Management Guidelines
Severity of Nausea 
and Vomiting
Management Guideline
Grade 1

Provide maximum supportive care as needed.
Grade 2

Provide maximum supportive care as needed.

Provide ondansetron (or equivalent anti-emetic medication) as 
needed.
Grade 3

Interrupt ipatasertib and rucaparib until nausea or vomiting resolves 
to Grade 2.

Provide maximum supportive care as needed.

Provide ondansetron (or equivalent anti-emetic) as needed.

If Grade 3 nausea or vomiting recurs, ipatasertib and rucaparib 
should be reduced by one dose level (refer to Table 3) when 
treatment is restarted.
If both study drugs are interrupted, step-wise reintroduction of one agent at a time 
(e.g., ipatasertib monotherapy for several days followed by reintroduction of rucaparib if 
nausea/vomiting remains Grade2) may be pursued.
5.1.4.6
Rash
Rash has been associated with ipatasertib administration and skin photosensitivity has been
associated with rucaparib treatment.  
Ipatasertib should be permanently discontinued for rash associated with erythema 
multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, or other suspected 
severe hypersensitivity or allergic reaction.  Dosage modification and symptom 
management guidelines for skin toxicity attributable to study treatment are shown below 
(see Table 8). With respect to skin photosensitivity being related to rucaparib, patients should 
always protect themselves appropriately when exposed to the sun.


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Table 8
Rash Management Guidelines
Severity of Rash
Management Guideline
Grade 1

Continue study drugs.
Consider topical corticosteroids.
Grade 2

Interrupt ipatasertib and rucaparib treatment until resolution to Grade 1 or 
better or the toxicity is no longer clinically significant.

Treat rash with topical corticosteroids.

Consider treatment of rash with oral corticosteroids
Follow above guidance and reduce ipatasertib by one dose level for 
recurrent Grade 2 rash.
Grade3

Interrupt ipatasertib and rucaparib treatment until resolution to Grade 1 or 
better or the toxicity is no longer clinically significant.

Treat rash with topical and systemic corticosteroids. 

Consider dermatological consultation.

If the skin toxicity resolves to Grade 1 or better or is no longer clinically 
significant within 28 days, following completion of the steroid taper, 
ipatasertib and rucaparib may be resumed at one dose level below the 
previous dose (refer to Table 3).
If recovery of the skin toxicity to Grade 1 or better does not occur or skin 
toxicity remains clinically significant continuously for 4 weeks, or Grade 3 
rash recurs, permanently discontinue ipatasertib and rucaparib.
Grade 4
Administration of systemic steroids (oral or intravenous) is recommended.  
Consider dermatological consultation and skin biopsy.  Ipatasertib and 
rucaparib should be permanently discontinued.
If both study drugs are interrupted, step-wise reintroduction of one agent at a time (e.g.,
ipatasertib monotherapy for several days followed by reintroduction of rucaparib if rash 
remains Grade1) may be pursued.
5.1.4.7
Pneumonitis
Pneumonitis is not known to be causally related to any of the study drugs; however, it 
has been observed with other drugs treating pathways similar to ipatasertib.  
As pneumonitis has not been observed with rucaparib, the management guidance will 
address ipatasertib, only.  Every effort should be made to determine the etiology of 
dyspnea and changes in pulmonary function (see Table 9).


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Table 9
Pneumonitis Management Guidelines
Severity of 
Pneumonitis
Management Guideline
Grade 1

Continue study drugs.
Perform CT scan and pulmonary function tests.  Repeat CT scan every 
8 weeks until a return to baseline.
Grade 2

Prescribe corticosteroids if there are clinical symptoms and infectious 
etiology is ruled out.  Interrupt ipatasertib treatment as long as 
corticosteroids are being given. 

Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return 
to baseline.

If pneumonitis resolves to Grade 1 or better after completion of the steroid 
taper, ipatasertib may be resumed at either the previous dose or one 
dose level below the previous dose (see Table 3) per investigator 
assessment.

For recurrent Grade 2 pneumonitis, ipatasertib must be resumed at one 
dose level below the previous dose.

Discontinue ipatasertib if recovery to Grade 1 or better is not evident 
within 28 days.
Grade 3

If infectious etiology is ruled out, prescribe corticosteroids as clinically 
indicated.

Interrupt ipatasertib treatment as long as corticosteroids are being given. 

Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return 
to baseline.  Bronchoscopy is recommended.

If pneumonitis resolves to Grade 1 or better, following completion of the 
steroid taper, continue ipatasertib at one dose level below the previous 
dose (see Table 3).  Discontinue ipatasertib if recovery to Grade 1 or 
better is not evident within 28 days.
For recurrent non-infectious Grade 3 pneumonitis events, ipatasertib 
should be permanently discontinued
Grade 4

If infectious etiology is ruled out, prescribe corticosteroids as clinically 
indicated.

Permanently discontinue ipatasertib.
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return 
to baseline.  Bronchoscopy is recommended.
CTcomputed tomography; PFT pulmonary function test.
5.1.4.8
Hepatotoxicity
Liver enzyme elevations have been associated with both ipatasertib and rucaparib
administration.
Permanently discontinue rucaparib and ipatasertib for any patients who develop a 
concurrent elevation of ALT and/or AST greater than 3baseline and total bilirubin 
greater than 2ULN and/or clinical jaundice in the absence of biliary obstruction or other 


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causes responsible for the concurrent elevation, including patients having abnormal liver 
function tests that meet Hy’s law criteria (see Section 5.3.5.6).
Table 10 Hepatotoxicity Management Guidelines
Severity of LFT Elevation
Management Guideline
Grade 1 AST or ALT 
ULN3.0ULN if baseline was 
normal; 1.53.0baseline if baseline 
was abnormal or total bilirubin 
ULN1.5ULN if baseline was 
normal; 1.01.5baseline if baseline 
was abnormal
Continue study drugs.
Monitor LFTs until values resolve to baseline values.
Grade 2 AST or ALT 
3.05.0ULN if baseline was 
normal; 3.05.0baseline if 
baseline was abnormal or total 
bilirubin 1.53.0ULN if baseline 
was normal; 1.53.0baseline if 
baseline was abnormal

Continue study drugs. 
The frequency of liver function test monitoring should be 
increased as clinically indicated if the investigator judges 
that the laboratory abnormalities are potentially related to 
study medication.
Grade 3 AST or ALT 
5.020.0ULN if baseline was 
normal; 5.020.0baseline if 
baseline was abnormal or total 
bilirubin 3.010.0ULN if baseline 
was normal; 3.010.0baseline if 
baseline was abnormal

Interrupt ipatasertib until improvement of AST/ALT to 
Grade 2.  Treatment may be resumed at previous dose 
level.

Continuation of rucaparib with elevation of AST/ALT up to 
Grade 3 is permitted provided bilirubin is ULN and 
alkaline phosphatase is 3ULN.  If levels do not 
decline within 2 weeks or they continue to rise, treatment 
interruption and improvement to Grade 2 will be 
required before rucaparib can be resumed with reduction 
by one dose level.

Consider hepatology consult.

Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 2 weeks 
for 3 months and monthly thereafter.

If another Grade 3 event occurs, interrupt rucaparib and 
ipatasertib.  On return of LFTs to Grade 2, resume 
ipatasertib, reducing the dose by one level and rucaparib, 
reducing the dose by one level.
Further Grade 3 occurrences must result in permanent 
discontinuation of rucaparib and ipatasertib.
Grade 4 AST or ALT 20.0ULN
if baseline was normal; 
20.0baseline if baseline was 
abnormal or total bilirubin 10.0
ULN if baseline was normal; 10.0
baseline if baseline was abnormal
Permanently discontinue treatment with ipatasertib and 
rucaparib.
LFTliver function test; QD once daily; ULNupper limit of normal.


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If both study drugs are interrupted, step-wise reintroduction of one agent at a time 
(e.g., ipatasertib monotherapy for several days followed by reintroduction of rucaparib if 
liver enzymes remain Grade2) may be pursued.
5.1.4.9
Dose Modifications
Rucaparib Dose Modifications
Potential dose reduction steps for rucaparib based on different current doses of 
rucaparib are shown in Table 11.  In Part 1, during the DLT evaluation period (Cycle 1), 
dose reductions of rucaparib are not allowed for reasons other than a DLT or a decision 
by the Sponsor based on emerging safety data.
In Part 1, during the DLT evaluation period (Cycle 1), dose interruptions of rucaparib are 
not allowed for reasons other than toxicity.  Patients are eligible for safety and DLT 
evaluation of the dose cohort if they receive at least 70% of the planned total dose of 
each study drug within Cycle 1 or they experience a DLT at any time during Cycle 1.  
During the remainder of the study, treatment with rucaparib may be interrupted for up to 
28 days (1 cycle) for toxicity or reasons unrelated to toxicity.  If rucaparib is withheld 
because of adverse events for 28 days, the patient will be discontinued from rucaparib.  
If, however, in the judgment of the investigator, the patient is likely to derive clinical 
benefit from rucaparib after a hold of 28 days, study drug may be restarted with the 
approval of the Medical Monitor.  
Once a RP2D has been established at the end of Part 1, those patients in Part 1 who 
are treated at a dose below the RP2D and are tolerating study drugs may be escalated 
to the RP2D at the discretion of the investigator with approval from the Medical Monitor. 
Table 11 Dose Reductions for Rucaparib
Current Dosage
Dose Reduction
600 mg BID
500 mg BID
500 mg BID
400 mg BID
400 mg BID
300 mg BID
300 mg BID
No further dose reductions allowed
BIDtwice daily.
Ipatasertib Dose Modifications
The ipatasertib dose reduction instructions provided in Table 12 are intended to serve as 
recommended guidelines to allow ongoing treatment for patients without signs or 
symptoms of disease progression while monitoring patient safety.  Guidelines for 
implementing dosage modifications and treatment interruption or discontinuation for 
patients who experience specific adverse events are provided in Section 5.1.1. 


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In Part 1, during the DLT evaluation period (Cycle 1), dose reductions of ipatasertib are 
not allowed for reasons other than a DLT or a decision by the Sponsor based on 
emerging safety data.
In Part 1, during the DLT evaluation period (Cycle 1), dose interruptions of ipatasertib 
are not allowed for reasons other than toxicity.  Patients are eligible for safety and DLT 
evaluation of the dose cohort if they receive at least 70% of the planned total dose of 
each study drug within Cycle 1 or they experience a DLT at any time during Cycle 1.  
During the remainder of the study, treatment with ipatasertib may be interrupted for up to 
28 days (1 cycle) for toxicity or reasons unrelated to toxicity.  If ipatasertib is withheld 
because of adverse events for 28 days, the patient will be discontinued from ipatasertib.  
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
ipatasertib after a hold of 28 days, study drug may be restarted with the approval of the 
Medical Monitor.  
Once a RP2D has been established at the end of Part 1, those patients in Part 1 who
are treated at a dose below the RP2D and are tolerating study drugs may be escalated
to the RP2D at the discretion of the investigator with approval from the Medical Monitor.  
Table 12 Dose Reductions for Ipatasertib
Current Dosage
Dose Reduction
400 mg QD
300 mg QD
300 mg QD
200 mg QD
200 mg QD
No further dose reductions allowed
QDonce daily.
No more than two dose reductions are allowed, and dose re-escalation is not permitted.
Summary of Study Drug Modifications for Both Treatments
A summary of dose modification allowances is shown in Table 13.


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Table 13 Part 1 and Part 2 Dose Modification
Part 1, Cycle 1
Part 1, Cycle 2+ and Part 2
Dose reduction
Only for DLT or Sponsor decision
For toxicity (see Table 11 and 
Table 12 for dose reductions)
Dose hold
For toxicity; must receive 70% 
doses to be evaluable for DLT
For up to 28 days a for toxicity or 
reasons unrelated to toxicity 
DLT dose-limiting toxicity.
a If a longer hold is required for slowly resolving toxicity, Sponsor approval is required.
5.1.4.10
Treatment Interruption
Ipatasertib and/or rucaparib treatment may be temporarily suspended in patients who 
experience toxicity considered to be related to study drug(s).  If either drug has been 
withheld for 28 days because of toxicity, the patient should be discontinued from that 
drug, unless resumption of treatment is approved following investigator discussion with
the Medical Monitor.  Patients discontinuing ipatasertib because of treatment-related 
toxicity may continue on rucaparib monotherapy as per investigator’s discretion.  
Patients discontinuing on rucaparib because of treatment-related toxicity may continue 
on ipatasertib monotherapy at the discretion of the investigator.  Ipatasertib and/or 
rucaparib treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures) with Medical Monitor approval.  The investigator and the Medical Monitor 
will determine the acceptable length of treatment interruption.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

Myelodysplastic syndrome 

Acute myeloid leukemia

Grade 3 diarrhea

Grade 3 hyperglycemia

Grade 3 rash

Grade 2 colitis/enterocolitis

Grade 2 pneumonitis
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, and 
Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.


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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 14 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 14 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 15):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event


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Table 15 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.2
Adverse Events that are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either an 
elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3baseline value in combination with total bilirubin 
2ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of the cancer should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Cancer 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 or PCWG3 criteria.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:
!
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:
!
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)
!
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)
!
Pregnancies (see Section 5.4.3 for details on reporting requirements)
!
Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.4 for 
details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:
!
New signs or symptoms or a change in the diagnosis
!
Significant new diagnostic test results
!
Change in causality based on new information
!
Change in the event's outcome, including recovery
!
Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D. (Primary)
Telephone No.:
Email:


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Medical Monitor:
, M.D. (Secondary) 
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D. (Tertiary)
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events that Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events that Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
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Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the final
dose of ipatasertib or within 6 months after the last dose of rucaparib.  A paper Clinical 
Trial Pregnancy Reporting Form should be completed and submitted to the Sponsor or 
its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
28 days after the final dose of ipatasertib or within 6 months after the last dose of 
rucaparib.  A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a 
male patient exposed to study drug.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been signed, 
the investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 


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and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). A therapeutic or elective abortion performed for reasons 
other than an underlying maternal or embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial Pregnancy 
Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 


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ipatasertib, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with ipatasertib, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.


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
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 28 days after the final
dose of study drug), all deaths, regardless of cause, should be reported through use of 
the Long-Term Survival Follow-Up eCRF.


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In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Ipatasertib Investigator's Brochure

Rucaparib Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary analysis will be based on patients data collected through study 
discontinuation or at the end of study.  All analyses will be conducted using the 
safety-evaluable population, defined as all patients who receive any amount of study 
treatment.
No formal hypothesis testing is planned.  The safety, tolerability, clinical activity, and 
pharmacokinetics of ipatasertib, and its metabolite G-037720, with rucaparib will be 
described and summarized.
Data will be described and summarized as warranted by sample size.  That is, listings 
may be used in lieu of tables in the event of small sample size.
Descriptive statistics will be used to summarize the safety and clinical activity of 
treatment regimens.  Continuous variables will be summarized using means, standard 


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deviation, median, and range; categorical variables will be summarized using count and 
percentage.
6.1
DETERMINATION OF SAMPLE SIZE
There is no formal hypothesis testing planned.  The determination of sample size for 
each part is described below.
For Part 1 (Dose-Escalation Phase), approximately 24 patients are planned to be 
enrolled based on the dose-escalation rules.
For Part 2 (Dose-Expansion Phase), approximately 30 patients with advanced prostate 
cancer who have had at least one line of prior therapy with second-generation 
AR-receptor targeted agents (e.g., abiraterone, enzalutamide, apalutamide) are planned 
to be enrolled. No formal statistical hypothesis testing is planned.  Instead, the analysis 
here is for hypothesis generation, and the emphasis is on estimations. To evaluate the 
primary endpoint of PSA response rate, the analyses will be based on patients enrolled 
in Part 2. Table 16 shows estimated PSA response rate and its 95% CI based on the 
Clopper-Pearson method given various observed numbers of responders among the 
30 patients. Thirty patients provide reasonably reliable estimates for hypothesis 
generation.
Table 16 Estimated PSA Response Rate and Its 95% CI for 30 Patients
Number of Responders
Response Rate (%)
95% CI (%)
6
20
7.71, 38.57
9
30
14.73, 49.40
12
40
22.66, 59.40
15
50
31.30, 68.70
18
60
40.60, 70.34
21
70
50.60, 85.27
24
80
61.43, 92.29
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for patient discontinuations from the study treatment and from 
the study will be listed and summarized.  Enrollment, study treatment administration, and 
major protocol deviations will be described, listed, or summarized and evaluated for their 
potential effects on the interpretation of study results.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics such as age, sex race/ethnicity, weight, type 
of malignancy, and baseline ECOG performance status will be summarized using means, 
standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.  Concomitant medications received during the 
treatment period will be summarized.
6.4
EFFICACY ANALYSES
Efficacy analyses will include all evaluable patients, defined as all patients who receive 
any amount of study treatment.
6.4.1
Primary Efficacy Endpoint for Patients with Prostate Cancer
For patients with prostate cancer, PSA response rate is defined as the proportion of 
patients achieving a PSA decline 50% from baseline.  Patients without a post-baseline 
PSA assessment will be considered non-responders.  The PSA response rate will be 
calculated, and the 95% CI will be estimated using the Clopper-Pearson method. 
6.4.2
Secondary Efficacy Endpoints for Patients with 
Prostate Cancer
For patients with prostate cancer, an objective response is defined as a CR or PR on 
two consecutive occasions 4 weeks apart, according to RECIST v1.1 and PCWG3 
criteria, in patients with measurable disease at baseline.  Patients without a 
post-baseline tumor assessment will be considered non-responders.  ORR is defined as 
the proportion of patients who have an objective response in patients with measurable 
disease at baseline.  ORR will be calculated, and the 95% CI will be estimated using the 
Clopper-Pearson method.
Among patients with an objective response (responders), DOR will be defined as the
time from first occurrence of a documented objective response until the time of
documented disease progression or death from any cause during the study, whichever
occurs first.  For patients who do not have documented disease progression or death 
during the study, DOR will be censored at the day of the last evaluable tumor 
assessment.
rPFS is defined as the time from study treatment initiation to the first occurrence of 
documented disease progression, as assessed by the investigator with use of the 
PCWG3 criteria (soft tissue by CT or MRI scans according to RECIST v1.1, and bone 
metastasis by bone scan according to the PCWG3 criteria) or death from any cause, 
whichever occurs first. For patients who do not have documented disease progression 
or death during the study, rPFS will be censored at the day of the last evaluable tumor 
assessment.


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OS will be defined as the time from study treatment initiation to the time of death due to 
any cause.  For patients who do not have death during the study, OS will be censored at 
the last known alive date.
Kaplan-Meier methodology will be used to estimate the median rPFS, DOR, and OS, 
and the Kaplan-Meier curves will be provided.  The Brookmeyer-Crowley method will be 
used to construct the 95% CI for each median.
6.4.3
Exploratory Efficacy Endpoints
Additional exploratory analyses will evaluate treatment effect in additional 
biomarker-defined segments (e.g., PTEN-loss) within prostate cancer in Part 2.
6.5
SAFETY ANALYSES
The safety analyses will include all patients who received at least one dose of any study
drug, and will be analyzed and summarized separately for the Part 1 and Part 2; data will 
not be combined across phases.
Adverse events, deaths, change in laboratory test results, change in vital signs, and
exposure to components of study treatment will be assessed to determine the safety of
treatment regimen.
For safety-evaluable patients, study drug administration data will be tabulated or listed
by arm, and any dose modifications will be flagged.  Descriptive statistics will be used to
summarize the total dose of ipatasertib and rucaparib received.
Verbatim descriptions of adverse events will be mapped to appropriate thesaurus terms.  
All adverse events occurring on or after treatment Day 1 will be summarized by the
mapped term, appropriate thesaurus levels, and NCI CTCAE v5.0 toxicity grade.  In 
addition, adverse events leading to treatment withdrawal or death, and serious adverse 
events will be listed with more detailed information, such as the day of onset of an 
adverse event, duration of adverse event, toxicity grade, and so on.
Relevant laboratory and vital signs (heart rate, blood pressure, and temperature) and
ECG data will be displayed by time post-dose, with NCI CTCAE Grade 3 and 4 values
identified where appropriate.  Additionally, changes in laboratory data will be
summarized by grade using the NCI CTCAE toxicity grade.  Selected vital signs and
selected laboratory data will be summarized by visit.
The extent of study drug exposure (dose and duration) will be examined to determine
the degree of treatment tolerability.  In addition to study treatment duration and total
dose received, any dose modification of study drugs will also be summarized.


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6.6
PHARMACOKINETIC ANALYSES
For Part 1, plasma samples for PK characterization of ipatasertib, its metabolite 
G-037720, and rucaparib will be collected on Day 1 of Cycle 1 for ipatasertib and 
G-037720, Day 15 of Cycle 1, and Days 1 and 15 of Cycle 2 (ipatasertib, G-037720, and 
rucaparib).  For ipatasertib, the sampling will allow for determination of the total 
exposure (area under the concentration–time curve from Time 0 to Time t [AUC0−t]) and 
the time to achieve maximum concentration (Tmax), and maximum concentration (Cmax) at 
steady state as a single agent (baseline) and in the presence of rucaparib.  For 
rucaparib, the sampling will allow for determination of predose trough concentrations.  
Any effect of rucaparib on ipatasertib, or its metabolite G-037720, will be evaluated by 
comparing the pharmacokinetics of ipatasertib in combination with rucaparib on Day 15 of
Cycle 1 to monotherapy pharmacokinetics with Day 1 of Cycle 1 after the single-agent run-in 
phase.  Mean and individual concentrationversus-time graphs will be plotted, and PK 
parameters will be tabulated and summary statistics reported for all analytes. Other PK 
parameters may be determined as data allow.  Potential correlations of relevant PK 
parameters with dose, safety or efficacy outcomes, and other covariates may be 
explored.
For Part 2, trough samples of ipatasertib, G-037720, and rucaparib will be collected on 
Day 15 of Cycle 1 and on Days 1 and 15 of Cycle 2 to confirm comparability to Part 1 
trough and/or historical data in a descriptive manner.
Any remaining PK samples after evaluation of ipatasertib, G-037720, and rucaparib may 
be used for exploratory evaluation of other analytes related to the administered drugs or 
biomarkers, enzymes, and transporters affecting their disposition or safety profile.
Additional PK analyses will be conducted as appropriate.
6.7
BIOMARKER ANALYSES
Exploratory biomarker analyses (in tumor tissues and plasma, whole blood, or serum) 
will be performed in an effort to understand the association of these markers with study 
drug response, including efficacy and/or adverse events.  Results will be presented in a 
separate report.
WGS data will be analyzed in the context of this study and may be explored in aggregate 
with data from other studies to increase researchers’ understanding of disease 
pathobiology and guide the development of new therapeutic approaches.
6.8
INTERIM ANALYSES
An interim analysis for safety (including DLTs) will be performed by the Sponsor prior to 
dose expansion (Part 2)
Given the hypothesis-generating nature of this study, the Sponsor may conduct an 
interim analysis of efficacy in Part 2.  The decision to conduct such an interim analysis 


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and its timing will be documented in the Sponsor’s study master file prior to the conduct 
of the interim analysis.  The Clinical Study Report will also document that such an 
interim analysis occurred.  The interim analysis, should it occur, will be performed and 
interpreted by members of Roche's study team and management.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 


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evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


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Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 


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to participate.  The final revised IRB/EC-approved Consent Forms must be provided to
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted clinical study reports 
and other summary reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored by F. Hoffmann-La Roche Ltd (Roche) and will be managed 
by Roche and a contract research organization (CRO).  The Sponsor will provide clinical 
operations oversight, data management, and medical monitoring.
Approximately 20 sites globally will participate to enroll approximately 54 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
The Study Medical Monitor and the Study Team (see Internal Safety Monitoring, 
Section 3.1.4) will monitor and evaluate patient safety throughout the study.


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9.5
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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2009;77(8):13481357.
Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib 
in patients with BRCA1 or BRCA2 mutations and advanced breast cancer:  a 
proof-of-concept trial. Lancet 2010;376(9737):23544.
Westin S, Litton J, Williams R, et al. Phase 1 expansion of olaparib (PARP inhibitor) and 
AZD5363 (AKT inhibitor) in recurrent ovarian, endometrial and triple negative 
breast cancer. Ann Oncol 2017;28 (suppl 5):12241
Yang SX, Polley E, Lipkowitz S. New insights on PI3K/AKT pathway alterations and 
clinical outcomes in breast cancer. Cancer Treat Rev 2016;45:8796.
Yoshimoto M, Cunha IW, Coudry RA, et al. FISH analysis of 107 prostate cancers 
shows that PTEN genomic deletion is associated with poor clinical outcome.  
Br J Cancer 2007;97(5):67885.
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme.  
Oncogene 2008;27(41):5497510.
Zafarana G, Ishkanian AS, Malloff CA, et al. Copy number alterations of c-MYC and 
PTEN are prognostic factors for relapse after prostate cancer radiotherapy.  
Cancer 2012;118(16):405362.


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
111/Protocol BO40933, Version 2
Appendix 1
Schedule of Activities
Assessment/Procedure
(Window)
Screening a
Ipatasertib 
single-agent 
PK Run-In 
(PART 1 only)
Cycle 1
Cycle 2
Cycle3
Cycles 4
Treatment
Discontinuation b
Post-Tx 
FU c
28 days of 
first dose
Day 
7
Day 
1
Day
1
Day 8
(2)
Day 15
d (2)
Day
1
Day
15
Day
1
Day
15 d
Day 1
Within 30 days 
of the Last Study 
Treatment
Every 
3 (1) 
Months
Informed consent(s)
x e
Demographic data (age, sex, 
and self-reported race/ethnicity)
x
Medical history and baseline 
conditions f
x
Archival FFPE tumor tissue
x g
Concomitant medications h
x
x
x
x
x
x
x
x
x
x
Adverse events i
x
x
x
x
x
x
x
x
x
x
x
Complete physical examination j
x a
x
Limited physical examination k
x
x
x
x
x
x
x
x
ECOG performance status
x a
x
x
x
x
x
Vital signs l
x
x
x
x
x
x
x
x
x
x
Weight and height (height at 
screening only)
x
x
x
x
x
x
Electrocardiogram m
x m
As clinically indicated
x m
PSA (prostate cancer only) n
x n
x
x
x
x
x
x
Serum testosterone (prostate 
cancer only) o
x
x
CA-125 (ovarian cancer only)
x
x
x
x
x


Appendix 1: Schedule of Activities
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
112/Protocol BO40933, Version 2
Assessment/Procedure
(Window)
Screening a
Ipatasertib 
single-agent 
PK Run-In 
(PART 1 only)
Cycle 1
Cycle 2
Cycle3
Cycles 4
Treatment
Discontinuation b
Post-Tx 
FU c
28 days of 
first dose
Day 
7
Day 
1
Day
1
Day 8
(2)
Day 15
d (2)
Day
1
Day
15
Day
1
Day
15 d
Day 1
Within 30 days 
of the Last Study 
Treatment
Every 
3 (1) 
Months
Hematology p
x
x q
x q
x q
x q
x q
x q
x q
x q
x
Fasting blood glucose r
x
x
x
x
x
x
x
x
x
x
x
Nonfasting blood glucose, serum 
(Part 1 only)
x s
x s
Chemistry panel t
x
x q
x q
x q
x q
x q
x q
x q
x q
x
Pregnancy test (females only) u
x
Urinalysis v
x
As clinically indicated
Coagulation:  aPTT, PT, and INR
x
As clinically indicated
Amylase and lipase
x
x
Day 1 of 
Cycles 4, 
6, 9, 12, 
and every 
3 cycles 
thereafter
x
Fasting lipid profile
x
x
x
Hemoglobin A1c
x
x
Tumor assessment of soft tissue 
per RECIST v1.1 w, x
x a
End of Cycles 2, 4, 6, 
and every 3 cycles
thereafter z
x
x
Tumor assessment:  bone scan y
x a
x
x
Ipatasertib administration z
Daily QD 
ipatasertib
Daily QD administration of ipatasertib
Rucaparib administration z
Daily BID administration of rucaparib
Drug accountability
x
x
x
x


Appendix 1: Schedule of Activities
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
113/Protocol BO40933, Version 2
Assessment/Procedure
(Window)
Screening a
Ipatasertib 
single-agent 
PK Run-In 
(PART 1 only)
Cycle 1
Cycle 2
Cycle3
Cycles 4
Treatment
Discontinuation b
Post-Tx 
FU c
28 days of 
first dose
Day 
7
Day 
1
Day
1
Day 8
(2)
Day 15
d (2)
Day
1
Day
15
Day
1
Day
15 d
Day 1
Within 30 days 
of the Last Study 
Treatment
Every 
3 (1) 
Months
Plasma PK sample aa
See Appendix 2
Blood sample for WGS control bb
See Appendix 3
Blood sample for 
pharmacogenomics bb
See Appendix 3
Plasma sample for somatic 
tumor mutations bb
See Appendix 3
Plasma sample for exploratory 
biomarkers bb
See Appendix 3
Blood sample for RBR (for DNA 
extraction; optional) cc
See Appendix 3
Optional tumor biopsy – dose 
escalation (Part 1) dd
See Appendix 3
Optional tumor biopsy – cohort 
expansion (Part 2) ee
See Appendix 3
Survival follow-up
x


Appendix 1: Schedule of Activities
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
114/Protocol BO40933, Version 2
CRcomplete response; CTcomputed tomography; Discont.Discontinuation; ECOG Eastern Cooperative Oncology Group; eCRF electronic 
Case Report Form; FFPEformalin-fixed, paraffin-embedded; FUFollow-up; IHC immunohistochemistry; IxRSinteractive voice- or Web-based 
response system; MRImagnetic resonance imaging; NGSnext-generation sequencing; PKpharmacokinetic; PCWG3Prostate Cancer 
Working Group 3; PRpartial response; PSAprostate-specific antigen; QDonce daily; RBRResearch Biosample Repository; RECIST 
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1; SD stable disease; Tx Treatment; WGSwhole genome sequencing.
Notes:  All visits should occur within 3 days of the scheduled visit, unless otherwise specified.  On treatment visit days, all assessments should be 
performed prior to dosing, unless otherwise specified.  Unplanned visits not specified by the protocol or unscheduled assessments (possibly 
including PK sample collection) may be performed as clinically indicated at discretion of the investigator; the associated data should be recorded on 
the relevant eCRF in support of an adverse event diagnosis or tumor assessments.
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Cycle 1, Day 1 may 
be used; such tests do not need to be repeated for screening.  Bone scans within 42 days prior to Cycle 1, Day 1 may be used.  If eligibility 
assessments were not completed within 28 days from the original date of the screening visit, the patient will need to be rescreened for eligibility 
(see Section 4.5.1 for details). 
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit within 30 (3) days after the last dose of 
study treatment.  The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit, 
provided that all tests required at the treatment discontinuation visit are performed.  Tumor assessments at the treatment discontinuation visit 
may be omitted if the most recent prior assessment was performed less than 28 days ago or the patient has already had confirmation of 
radiographic disease progression.
c After treatment discontinuation, patients with prostate cancer who discontinue study treatment in the absence of disease progression will return 
to the clinic for tumor assessment follow up visits approximately every 3 months from last tumor assessment (CT or MRI scan and bone scan) 
until radiographically assessed disease progression.  For all patients, unless the patient requests to be withdrawn from survival follow-up, the 
required information will be collected via telephone calls and/or clinic visits, or patients’ medical records, approximately every 3 months until 
death, loss to follow-up, or study termination by the Sponsor. 
d Day 15 clinical visit and assessments up to Cycle 3 only.  During subsequent cycles, site personnel may contact the patient by telephone to 
assess the occurrence of adverse events as described in footnote j.  The rationale for the telephone call is to allow proactive medical 
management of adverse events and to minimize delayed reporting by patient, owing to the monthly clinic visit schedule.
e Informed consent, including optional consent, must be documented before any study-specific screening procedure is performed and may be 
obtained more than 28 days before initiation of study treatment.
f
Medical history includes clinically significant diseases within the previous 5 years, surgeries, complete cancer history (including prior cancer 
therapies and procedures), complete cardiovascular history, reproductive status, and smoking history (see Section 4.5.2).


Appendix 1: Schedule of Activities
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
115/Protocol BO40933, Version 2
g A FFPE tumor tissue block or a minimum of 10 freshly cut, unstained, serial slides from patients will be submitted at screening.  Cytologic or 
fine-needle aspiration samples are not acceptable.  Tumor tissue from bone metastases is not acceptable.  If archival tissue is insufficient, a 
fresh tumor biopsy meeting the minimum requirement may be obtained with if the patient’s consent.  
h Concomitant medications include any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient from 14 days prior to prior to initiation of study treatment until 28 days after the last dose of study 
treatment.  
i
After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study 
treatment. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed by the investigator as stable and no further changes are expected, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered by the investigator to be related to study treatment or trial-
related procedures until a final outcome can be reported.
j
A complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the 
General Medical History and Baseline Conditions eCRF.  At study discontinuation visit, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
k Perform a limited, symptom-directed physical examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
l
Vital signs include respiratory rate, pulse (heart) rate, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits,
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
m ECG recordings will be obtained as part of the screening assessment, as clinically indicated during study treatment, and at the end of treatment 
visit.  
n If the progression disease will be based on PSA at screening, at least two PSA samples (obtained at least 1 week apart) will be assessed locally 
at screening for confirmation of eligibility (if no data are available prior to screening).  Central testing required for Day 1 of each cycle and at 
study treatment discontinuation.  Patients who discontinue study treatment prior to 12 weeks of treatment should have an assessment of PSA in 
post-treatment follow-up period that is at least 12 weeks following the start of study treatment if they have not yet started another systemic 
treatment.
o For patients with prostate cancer, serum testosterone samples will be assessed locally at screening for determination of eligibility and at study 
treatment discontinuation to confirm testosterone remains at castration level. 


Appendix 1: Schedule of Activities
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
116/Protocol BO40933, Version 2
p Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells).  
q Test may be performed 96 hours prior to dosing for each clinic visit during study treatment; screening assessments performed 96 hours prior 
to dosing on Day 1 of Cycle 1 do not have to be repeated on Day 1 of Cycle 1.  
r
For all clinic visits during study treatment, the glucose level of the patient must be performed 96 hours prior to dosing and must be reviewed 
prior to further ipatasertib administration and prior to discharge from the clinic.  Blood glucose may be obtained by a glucometer (fingerstick).  
For fasting blood glucose, patients should fast 8 hours prior to testing. 
s Nonfasting blood glucose samples are to be collected on PK collection days at the same timepoints listed for ipatasertib PK sample in 
Appendix 3.  Patients will be required to eat a meal approximately 30 minutes postdose on Day 1 of Cycle 1 and Day 15 of Cycle 1.  The exact 
date may be shifted by 7 days or more to match the PK collection per Appendix 3.
t
Chemistry panel includes sodium, potassium, chloride, magnesium, bicarbonate, BUN (or urea), creatinine, total protein, albumin, calcium, and 
liver function test panel (total and direct bilirubin, alkaline phosphatase, ALT, AST, and LDH. 
u Women of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of study drug.
v Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood).
w Tumor assessments should include the chest, abdomen, and pelvis (and other body regions if clinically indicated) at screening and at 
subsequent tumor assessments, even if there are no detectable lesions at baseline.  CT scans are the preferred imaging modality for tumor 
assessments.  MRI scans may be substituted for CT scans and the same imaging method used at screening should be used throughout the 
study.  Responses will be assessed according to RECIST v1.1. For patients with prostate cancer, CT or MRI assessments for soft tissue lesions 
should continue per Section 4.5.6 until radiographically assessed disease progression regardless of study treatment discontinuation.
x Tumor assessments should be performed 2 weeks of the scheduled cycles for the first 6 months and then every 12 weeks (or 3 cycles),
thereafter, and as clinically indicated.  At the investigator's discretion, imaging may be repeated at any time if progressive disease is suspected.  
The frequency of tumor assessments may be further reduced after 1 year with approval of the Medical Monitor.  Tumor assessments at the end 
of treatment visit are not required if radiographic disease progression per RECIST v1.1 or PCWG3 criteria (if applicable) has been documented 
previously or if the last tumor assessments were performed 4 weeks prior to the end of treatment visit.  If an initial CR or PR is noted, 
confirmatory scans should be performed 4 weeks later.  In the case of SD, follow-up measurements should have met the SD criteria at least 
once after study entry at a minimum interval of no less than 4 weeks.  For patients with prostate cancer, tumor assessments should continue per 
above schedule until radiographically assessed disease progression even if study treatment has been discontinued for other reasons.  For 
patients with breast and ovarian cancer, continuation of tumor assessments is preferred but not required.


Appendix 1: Schedule of Activities
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
117/Protocol BO40933, Version 2
y A technetium bone scan will be performed at screening (within 42 days before starting study treatment) to evaluate for the presence of bone 
metastases.  For patients with prostate cancer, bone scans must continue per Section 4.5.6 until radiographically assessed disease progression
regardless of study treatment discontinuation.  For patients with breast and ovarian cancer, a bone scan is needed for screening assessment.  
For patients with known or suspected bone metastases, follow up bone scans should be done at time of tumor assessments and at the study 
treatment discontinuation visit (unless followed by other imaging modalities).
z If dosing of study treatment is withheld for any reason, study day count should continue and the omitted dose will not be made up and will be 
reported on the eCRF as “not administered” for that day.  For patients enrolled in Part 1, rucaparib should be started in the evening of Day 1 of Cycle 1
following collection of all ipatasertib PK samples.  
aa See Appendix 2 for PK sample collection.
bb Samples will be collected only at sites with local regulatory authority approval.  See Appendix 3 for further details
cc The optional RBR blood sample (for DNA extraction) requires an additional informed consent and can be collected at any time during the course 
of the study.  See Appendix 3 for further details.
dd The optional predose tumor biopsy specimen will be obtained after eligibility criteria have been fulfilled and prior to Day 7 of Cycle 1.  A 
subsequent biopsy will be performed on either Day 1 or Day 1 of Cycle 1, prior to the administration of rucaparib.  An additional biopsy will be 
collected on Day 15 of Cycle 2.  See the laboratory manual for details. 
ee The optional predose tumor biopsy specimen will be obtained after eligibility criteria have been fulfilled and prior to Day 1 of Cycle 1.  An 
additional biopsy will be collected on Day 15 of Cycle 2.  See the laboratory manual for details.  


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
118/Protocol BO40933, Version 2
Appendix 2
Schedule of Pharmacokinetic Samples (Parts 1 and 2)
Table 1
Schedule of Pharmacokinetic Samples in Dose-Escalation Phase 
(Part 1)
Visit
Timepoint
Sample Type
Cycle 1, Day 7 a
Prior to first ipatasertib administration
Ipatasertib PK (Plasma)
Cycle 1, Day 1 b
1 hour (10 min) post-ipatasertib dose
Ipatasertib PK (Plasma)
2 hour (10 min) ipatasertib post-dose
Ipatasertib PK (Plasma)
3 hour (30 min) ipatasertib post-dose
Ipatasertib PK (Plasma)
5 hour (30 min) ipatasertib post dose
Ipatasertib PK (Plasma)
Cycle 1, Day 15 c
Prior to ipatasertib and rucaparib 
administration
Ipatasertib PK (Plasma)
Rucaparib PK (Plasma)
1 hour (10 min) post-ipatasertib dose
Ipatasertib PK (Plasma)
2 hour (10 min) post-ipatasertib dose
Ipatasertib PK (Plasma)
3 hour (30 min) post-ipatasertib dose
Ipatasertib PK (Plasma)
5 hour (30 min) post-ipatasertib dose
Ipatasertib PK (Plasma)
Cycle 2, Day 1 c
Prior to ipatasertib and rucaparib 
administration
Ipatasertib PK (Plasma)
Rucaparib PK (Plasma)
Cycle 2, Day 15 c
Prior to ipatasertib and rucaparib 
administration
Ipatasertib PK (Plasma)
Rucaparib PK (Plasma)
CPIcoproporphyrin I; CPIIIcoproporphyrin III; PKpharmacokinetic.
Note:  Ipatasertib PK samples will be collected for analysis of both ipatasertib and its metabolite 
G-037720.
a The Cycle 1, Day 7 assessment should be done prior to start of ipatasertib and rucaparib 
administration. The sample will be used for measurement of baseline CPI and CPIII levels prior to 
treatment initiation.
b PK sampling on Day 1 of Cycle 1 should be completed before initiation of rucaparib therapy.
c If a patient’s ipatasertib or rucaparib treatment has been interrupted for 1 day immediately 
before the Cycle 1, Day 15 and Cycle 2 visits, PK samples may be rescheduled to another 
day when both study treatments have been given for at least 5 consecutive days. Cycle 1,
Day 15 and Cycle 2 visit assessments during the treatment period should be performed 
within 7 days of the scheduled date.  Study assessments may be delayed or moved ahead 
of the window to accommodate holidays, vacations, and unforeseen delays.


Appendix 2: Schedule of Pharmacokinetic Samples (Parts 1 and 2)
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
119/Protocol BO40933, Version 2
Table 2
Schedule of Pharmacokinetic Samples in Dose-Expansion Phase 
(Part 2)
Visit
Timepoint
Sample Type
Cycle 1, Day 15
Prior to ipatasertib and 
rucaparib administration
Ipatasertib PK (Plasma)
Rucaparib PK (Plasma)
Cycle 2, Day 1 a 
Prior to ipatasertib and 
rucaparib administration
Ipatasertib PK (Plasma)
Rucaparib PK (Plasma)
Cycle 2, Day 15 a
Prior to ipatasertib and 
rucaparib administration
Ipatasertib PK (Plasma)
Rucaparib PK (Plasma)
PKpharmacokinetic.
Notes:  Except for Cycle 1, Day 1, all other study visits and assessments during the treatment 
period should be performed within 7 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.
Ipatasertib PK samples will be collected for analysis of both ipatasertib and its metabolite 
G-037720.
a If a patient’s ipatasertib or rucaparib treatment has been interrupted for 1 day immediately 
before the visit, PK samples may be rescheduled to another day when both study treatments 
have been given for at least 5 consecutive days.


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
120/Protocol BO40933, Version 2
Appendix 3
Schedule of Biomarker Samples (Parts 1 and 2)
Table 1
Schedule of Biomarker Samples in Dose-Escalation Phase 
(Part 1)
Visit
Timepoint
Sample Type 
Cycle 1, Day 7 
(Part 1)
Prior to first ipatasertib 
administration
Blood sample for WGS control
Blood sample for pharmacogenomics
Plasma sample for somatic tumor mutations
Plasma sample for exploratory biomarkers
Blood sample for RBR (for DNA extraction; 
optional)
Cycle 2, Day 1
Prior to ipatasertib and 
rucaparib administration
Plasma sample for somatic tumor mutations
Plasma sample for exploratory biomarkers
Treatment 
discontinuation
Plasma sample for somatic tumor mutations
Plasma sample for exploratory biomarkers
RBRResearch Biosample Repository; WGSwhole genome sequencing.
Table 2
Schedule of Biomarker Samples in Dose- Expansion Phase 
(Part 2)
Visit
Timepoint
Sample Type
Cycle 1, Day 1 
Prior to first ipatasertib 
administration
Blood sample for WGS control
Blood sample for pharmacogenomics
Plasma sample for somatic tumor mutations
Plasma sample for exploratory biomarkers
Blood sample for RBR (for DNA extraction; 
optional)
Cycle 2, Day 1
Prior to ipatasertib and 
rucaparib administration
Plasma sample for somatic tumor mutations
Plasma sample for exploratory biomarkers
Treatment 
discontinuation
Plasma sample for somatic tumor mutations
Plasma sample for exploratory biomarkers
RBRResearch Biosample Repository; WGSwhole genome sequencing.


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
121/Protocol BO40933, Version 2
Appendix 4
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead


 
Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd 
122/Protocol BO40933, Version 2 
Appendix 5  
PSA Progression Eligibility Criteria 
 
 
PSA=prostate-specific antigen. 
Eligibility based on prostate-specific antigen (PSA) changes.  The reference value (#1) is the last 
PSA measured before increases are documented, with subsequent values obtained a minimum 
of 1 week apart.  If the PSA at time point 3 (value #3A) is greater than that at point 2, then 
eligibility has been met.  If the PSA is not greater than point 2 (value #3B), but value #4 is, the 
patient is eligible assuming that other criteria are met, if values 3A or #4 are 1 ng/mL or higher. 
 
REFERENCES 
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: Recommendations from 
the PSA Working Group. J Clin Oncol 1999;17:3461−7. [Erratum: J Clin Oncol 
2000;18:2644, J Clin Oncol 2007;25:1154]. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. 
J Clin Oncol 2008;26:1128−59.   
 


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
123/Protocol BO40933, Version 2
Appendix 6
Criteria for Radiographic Progression per Prostate Cancer 
Working Group 3
Date 
Progression 
Detected 
(Visit) a
Criteria for Progression
Criteria for Confirmation 
of Progression 
(requirement and timing)
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan
Week 8
Bone lesions: Two or 
more new lesions 
compared to baseline
bone scan by PCWG3.
Timing: at least 6 weeks 
after progression 
identified or at Week 16 
visit.  c
Two or more new bone 
lesions on bone scan 
(compared to Week 8 
scan).
Soft tissue lesions: 
Progressive disease on 
CT or MRI scan by 
RECIST v1.1
b
No confirmatory scan 
required for soft tissue 
disease progression.
NA
Week 16 or later Bone lesions: Two or 
more new lesions on 
bone scan compared to 
Week 8 bone scan.
Timing: at least 6 weeks 
after progression 
identified; required for 
bone lesions observed 
on bone scan c
Persistent d or increased 
number of bone lesions 
on bone scan compared 
to prior scan.
Soft tissue lesions: 
Progressive disease on 
CT or MRI scan by 
RECIST v1.1.  b
No confirmatory scan 
required for soft tissue 
disease progression.
NA
CTcomputed tomography; MRImagnetic resonance imaging; NAnot applicable; 
PCWG3Prostate Cancer Working Group 3, RECIST v1.1Response Evaluation Criteria in 
Solid Tumors, Version 1.1.
Note:  Adapted from Scher et al. 2016.
a Progression detected by bone scan at an unscheduled visit will require a confirmatory scan at 
least 6 weeks later and should follow confirmation criteria outlined in the table for the next 
scheduled scan. Progression detected by bone scan at an unscheduled visit prior to Week 12 
will require a confirmatory scan at least 6 weeks later showing two or more new bone lesions 
on bone scan.
b For RECIST v1.1, see Appendix 8.  Up to five lesions (with a maximum of 2 lesions per organ) 
will be recorded as target lesions (e.g., lung, liver, adrenal, nodal).
c Confirmation must occur at the next available scan regardless of whether the patient will 
continue study treatment.
d For confirmation, at least two of the lesions first identified as new must be present at the next 
available scan.


Ipatasertib and Rucaparib—F. Hoffmann-La Roche Ltd
124/Protocol BO40933, Version 2
Appendix 7
Modified Gynecologic Cancer InterGroup (GCIG) Guidelines
GCIG GUIDELINES FOR RESPONSE USING CA-125 (ADAPTED FOR USE IN
THIS TRIAL)
Gynecologic Cancer InterGroup (GCIG) cancer antigen 125 (CA-125) definitions are 
available at http://gcig.igcs.org/CA-125.html. 
To be evaluable for response by CA-125 requires at least one pre-treatment 
sample 2upper limit of normal (ULN) and two post-treatment samples confirming a 
response.
A response to CA-125 has occurred if there is at least a 50% decrease as the result of 
the treatment.  The pre- or post-treatment samples must satisfy the following criteria:
1.
There must be at least one sample that is 2ULN prior to initiation of treatment.
2.
The second sample (post-treatment) must be 50% of the pre-treatment sample.
3.
The confirmatory third sample must be 21 days after the second sample and 110% 
of the second sample.
4.
Any intervening samples between samples 2 and 3 must be 110% of the previous 
sample unless considered to be increasing because of tumor lysis.
Patients are not evaluable by CA-125 if they have received mouse antibodies or if there 
has been medical or surgical interference with their peritoneum or pleura during the 
previous 28 days. 
REFERENCE:
Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in 
ovarian cancer clinical trials incorporating RECIST 1.1 and CA-125 agreed by the 
Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 
2011;21(2):41923.


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Appendix 8
Response Evaluation Criteria in Solid Tumors: 
Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 1 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
Measurable Tumor Lesions
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 

10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm
or pathological lymph nodes with 10 to 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
                                           
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


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Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:

Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component meets
the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if 
noncystic lesions are present in the same patient, these are preferred for selection 
as target lesions.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
Method of Assessment
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option.


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Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested.
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When 
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with intravenous (IV) contrast due to allergy or renal insufficiency, the decision as to 
whether a noncontrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement.
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.


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TUMOR RESPONSE EVALUATION
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above.
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or two 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
recorded as non-measurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
10 mm are considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 


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nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.

Complete response (CR):  disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to 10 mm.

Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters

Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.

Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study
Special Notes on the Assessment of Target Lesions
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
10 mm.


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Target Lesions That Become Too Small to Measure.  While in the study, all lesions 
(nodal and non-nodal) that are recorded at baseline should be recorded as actual 
measurements at each subsequent evaluation, even when very small (e.g., 2 mm).  
However, sometimes lesions or lymph nodes that are recorded as target lesions at 
baseline become so faint on the CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being too small to measure.  When 
this occurs, it is important that a value be recorded on the CRF as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well and BML should also be ticked.) 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.

CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level)
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.


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Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III studies when it is not a criterion of study entry to have measurable 
disease.  The same general concepts apply here as noted above; however, in this 
instance, there is no measurable disease assessment to factor into the interpretation of 
an increase in non-measurable disease burden.  Because worsening in non-target 
disease cannot be easily quantified (by definition:  if all lesions are truly non-measurable), 
a useful test that can be applied when assessing patients for unequivocal progression is 
to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required 
to declare progressive disease (PD) for measurable disease, that is, an increase in 
tumor burden representing an additional 73% increase in volume (which is equivalent to 
a 20% increase in diameter in a measurable lesion).  Examples include an increase in a 
pleural effusion from “trace” to “large” or an increase in lymphangitic disease from 
localized to widespread or may be described in protocols as “sufficient to require a 
change in therapy.”  If unequivocal progression is seen, the patient should be considered 
to have had overall PD at that point.  While it would be ideal to have objective criteria to 
apply to non-measurable disease, the very nature of that disease makes it impossible 
to do so; therefore, the increase must be substantial.


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New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify whether it represents truly new disease.  If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan.
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


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Table 1
Timepoint Response:  Patients with Target Lesions (With or 
Without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; 
PRpartial response; SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some studies; 
thus, assigning “stable disease” when no lesions can be measured is not advised.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen 
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and, during the study, only two lesions were assessed, but those gave 


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a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint.
Table 3
Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
CR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum duration for SD was 
met; otherwise, PD
PR
NE
SD, provided minimum duration for SD was 
met; otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
the minimum duration for SD was met.  However, sometimes CR may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had 
PR, not CR, at the first timepoint.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR.


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Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1, Table 2, and Table 3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion.