Clinical trial NCT02898207
Conditions: Metastatic High Grade Fallopian Tube Serous Adenocarcinoma Metastatic Malignant Solid Neoplasm Metastatic Primary Peritoneal Serous Adenocarcinoma Metastatic Triple-Negative Breast Carcinoma Platinum-Resistant Fallopian Tube Carcinoma Platinum-Resistant Ovarian Carcinoma Platinum-Resistant Primary Peritoneal Carcinoma Recurrent Breast Carcinoma Recurrent High Grade Fallopian Tube Serous Adenocarcinoma Recurrent High Grade Ovarian Serous Adenocarcinoma Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma Recurrent Triple-Negative Breast Carcinoma Refractory Fallopian Tube Serous Adenocarcinoma Refractory Ovarian Serous Adenocarcinoma Refractory Primary Peritoneal Serous Adenocarcinoma Refractory Triple-Negative Breast Carcinoma Unresectable High Grade Fallopian Tube Serous Adenocarcinoma Unresectable Malignant Solid Neoplasm Unresectable Primary Peritoneal Serous Adenocarcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-05-19; Completion date: 2022-01-14
Enrollment: 28 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase I trial studies the side effects and best dose of olaparib and onalespib when given together in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) or ovarian, fallopian tube, primary peritoneal, or triple-negative breast cancer that has come back (recurrent). Olaparib and onalespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To establish the maximum tolerated dose (MTDs) of olaparib and onalespib (AT13387) administered in combination in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To identify the dose-limiting toxicity (DLT) and other toxicities associated with olaparib and AT13387 administered in combination as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

II. To determine the recommended phase 2 doses (RP2D) of the combination of olaparib and AT13387.

III. To determine the plasma pharmacokinetics of olaparib and AT13387. IV. To document anti-tumor activity of the combination of olaparib and AT13387 as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression free survival (PFS). Although the clinical benefit of \[this/these\] drug(s) has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability.

OUTLINE: This is a dose-escalation study.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-7 (cycle 0). Beginning in cycle 1, patients receive olaparib PO BID on days 1-28 and onalespib intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 3 months for up to 2 years.

Arms: arm 1: Dose Level 0 (DL0): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200mg PO BID on days 1-28 and onalespib 20 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Dose Level 1 (DL1): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200mg PO BID on days 1-28 and onalespib 40 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Dose Level 2 (DL2): Patients received olaparib 300 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 300 mg PO BID on days 1-28 and onalespib 40 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Dose Level 3 (DL3): Patients received olaparib 300 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 300 mg PO BID on days 1-28 and onalespib 80 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity. arm 5: Dose Level 2a (DL2a): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200 mg PO BID on days 1-28 and onalespib 80 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity. arm 6: Dose Level 3a (DL3a): Patients received olaparib 200 mg PO BID on days 1-7 (cycle 0). Beginning in cycle 1, patients received olaparib 200 mg PO BID on days 1-28 and onalespib 120 mg/m\^2 IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Cycles repeated every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Olaparib intervention 2: Onalespib
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #:10031 
Version Date: February 10, 2020 
i 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment # 1 to 21 
 
NCI Protocol #: 10031 
 
Local Protocol #: 17-715 
 
NCI Version Date: February 10, 2020 
Protocol Date: February 10, 2020 
 
# 
Section 
Page 
Change 
1. 
Header; 
Title Page 
All; 2 
Protocol version date updated from December 13, 2019 to February 10, 2020. 
2. 
8.1.1 
Availability 
62 
Revision of the Protocol as Specified Below: 
Please add, “AT13387 clinical drug development program is completed.  The current 
clinical supply is expiring on May 31, 2020; thus, all patients must be off treatment 
by May 31, 2020.”  Please make this change in your next amendment request. 
PI Response: Statement added as outlined above 
3. 
5.5 
43 
Revision of the Protocol as Specified Below: 
Please indicate if patients will be allowed to continue olaparib alone if AT13387 is 
discontinued after May 31, 2020. It’s not clear if monotherapy is allowed. 
PI Response: Added “Patients may continue olaparib alone after May 31, 2020”. 
4. 
10 
71 
Revision of the Protocol as Specified Below: 
• 
Added “j. Patients who continue on olaparib monotherapy will have 
concomitant meds, physical exam, vital signs, CBC w/diff, platelets, serum 
chemistry, and adverse event evaluation on day 1 only of each cycle 
following AT13387 discontinuation”. 
5. 
ICF 
All 
Consent version updated from December 13, 2019 to February 10, 2020 
6. 
ICF 
2 
Revision of the ICD as Specified Below:  
Please indicate if patients will be allowed to continue olaparib alone if AT13387 is 
discontinued after May 31, 2020. It’s not clear if monotherapy is allowed. 
PI Response: Added “Patients who stop taking AT13387 (onalespib) may 
continue to take olaparib alone”. 


NCI Protocol #:10031 
Version Date: December 13, 2019 
 
1 
NCI Protocol #: 
10031 
Local Protocol #: 
17-715 
 
ClinicalTrials.gov Identifier:  TBD 
 
TITLE:  A Phase 1 Study of PARP inhibitor olaparib and HSP90 inhibitor AT13387 for 
treatment of advanced solid tumors with expansion in patients with recurrent epithelial ovarian, 
fallopian tube, peritoneal cancer or recurrent triple-negative breast cancer 
 
Corresponding Organization: LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
Principal Investigator: 
Panagiotis A. Konstantinopoulos MD, PhD 
Dana Farber Cancer Institute 
YC-1424, 450 Brookline Ave 
Boston, MA 02215 
617-632-5269 
617-632-3479 
Panagiotis_konstantinopoulos@dfci.harvard.edu 
 
Participating Organizations 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
 
 
Statistician: 
 
 
Research Project Manager: 
William T Barry, PhD 
Madeline Polak 
Center for Life Sciences Bldg, Room 11005 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
450 Brookline Ave.  
Boston, MA 02215 
Boston, MA 02215 
Phone: 617-632-5134 
Phone:  617-632-3743 
Fax: 617-632-2444 
Fax:  617-394-2662 
bbarry@jimmy.harvard.edu 
Madeline_Polak@dfci.harvard.edu 
 
 
Responsible Research Nurse: 
 
 
Christin Whalen, RN 
 
Dana Farber Cancer Institute 
 
450 Brookline Avenue 
 
Boston, MA 02215 
 
Phone:617-582-7738 
 
Fax:617-582-7921 
 
Pager: 617-632-3352 Pager #41948 
 
Christin_Whalen@dfci.harvard.edu 
 
 
 
 
 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
2 
NCI-Supplied Agent(s):  olaparib 
 
 
 
    NSC 747856 
                                           AT13387 (onalespib)     NSC 749712 
IND #:   
 
IND Sponsor: DCTD, NCI   
 
Protocol Type / Version # / Version Date: Amendment 18 / Version 21 / February 10, 2020 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
3 
 
 
PROTOCOL SYNOPSIS 
 
A Phase 1 Study of HSP90 Inhibitor AT13387 (NSC# 749712) in Combination with PARP 
Inhibitor Olaparib (NSC# 747856) for Treatment of Advanced Solid Tumors with 
Expansion in Patients with Recurrent Epithelial Ovarian, Fallopian Tube, or Peritoneal 
Cancer or Recurrent Triple-Negative Breast Cancer 
 
 
STUDY DRUGS: 
AT13387 (NSC# 749712) and Olaparib (NSC# 747856) 
 
PHASE:  
1 
 
INDICATION: 
Advanced Solid Tumors with Expansion in Patients with Recurrent  
Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer or Recurrent 
Triple-Negative Breast Cancer 
 
RATIONALE: 
Based on the results of our preclinical work, we hypothesize that the 
HSP90 inhibitor AT13387 will enhance the anticancer effects of the PARP 
inhibitor olaparib at tolerable doses in patients with advanced solid tumors 
 
 
TARGET POPULATION: 
Patients eligible for this study will have a solid tumor 
malignancy that is unresectable or metastatic and for which 
standard treatment is not available. 
 
NUMBER OF SUBJECTS: 
Phase 1 dose/regimen exploration: estimated 20 patients. 
 
Phase 1b expansion cohorts: estimated 20 patients. 
 
PRIMARY OBJETIVES: 
To establish the maximum tolerated dose (MTDs) of olaparib 
and AT13387 administered in combination in patients with 
advanced solid tumors. 
 
 
SECONDARY OBJECTIVES: 
To identify the dose-limiting toxicity (DLT) and 
other toxicities associated with olaparib and 
AT13387 administered in combination as assessed 
by CTCAE v5.0. 
 
To determine the recommended phase 2 doses 
(RP2D) of the combination of olaparib and 
AT13387. 
 
To document anti-tumor activity of the combination 
of olaparib and AT13387 as assessed by RECIST 
1.1 and progression free survival (PFS). 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
4 
 
To determine the plasma pharmacokinetics of 
olaparib and AT13387. 
 
 
EXPLORATORY OBJECTIVES: 
 
 
 
 
STUDY DESIGN 
 
This is a multi-center, Phase 1/1b clinical trial that will be conducted to define the MTD, RP2D 
and safety and tolerability of the combination of AT13887 and olaparib in patients with 
advanced solid tumor malignancies. The study will begin with an exploration of the dose and 
regimen of the combination of these 2 novel agents. As viable regimens are identified, an 
expansion cohort of patients with epithelial ovarian, fallopian or primary peritoneal or triple 
negative breast cancer (TNBC) patients will be enrolled with one of the schedules, for 
confirmation of safety, PK and PD. This cohort will include patients with BRCA-wildtype 
TNBC or patients with platinum resistant epithelial ovarian or fallopian or primary peritoneal 
cancers. A total of 40 patients is expected to be enrolled; approximately 20 in the exploration 
cohort and an additional 20 in the expansion cohort. 
 
In mouse xenograft models, continuous daily administration of olaparib yielded greater 
antitumor activity than intermittent administration at the same or at higher dose levels so it is 
recommended that olaparib is administered continuously. Therefore, in this trial we propose that 
olaparib will be dosed orally continuously twice daily. 
 
Regarding AT13387, the optimal schedule for HSP90 inhibition is unclear. However, our 
tolerability and efficacy studies with olaparib and AT13387 in ovarian PDX models, support 
twice weekly dosing of AT13387 (on Days 1 and 2 every week, i.e. 2 days on/5 days off). The 
twice weekly (Days 1 and 2) of AT13387 was also chosen based on previous experience by Dr 
Shapiro with another HSP90 inhibitor ganetespib (STA-9090)1. Therefore, the proposed regimen 
will be olaparib twice daily for 28 consecutive days and AT13387 on Days 1 and 2 every week, 
3 weeks of a 4 week (28 day) cycle (Days 1, 2, 8, 9, 15, 16). 
 
Cycle 0 is only 7 days and Cycle 1 begins 8 days after start of Cycle 0, i.e. immediately after 
Cycle 0 ends. During cycle 0, olaparib will be administered alone twice daily for 1 week (D1-7).  
Cycle 1 and beyond, olaparib will continue to be administered twice daily (days 1-28) and 
AT13387 will be administered for 2 consecutive days on 3 of a 4 week cycle. Given that our 
hypothesis is that AT13387 sensitizes to olaparib by inhibiting HR, by administering olaparib 
alone for cycle 0 only, we can test the hypothesis as a “proof of mechanism” for the combination 
of AT13387 and olaparib. Specifically, we expect that there will be induction of BRCA1 and 
RAD51 foci after administration of olaparib alone and reduced formation of these foci and 
downregulation of expression of HR pathway genes after the combination of AT13387 and 
olaparib.  
A standard 3+3 design will be utilized. Doses of olaparib will range from 50mg–300 mg twice 
daily; AT13387 doses will range from 20–160 mg/m2 (20-40-80-120-160) using a ping-pong  


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
5 
strategy as shown in the Table below. DLT events will be based on adverse events during cycles 
0 and 1, utilizing CTCAE v.5.0. 
 
There will be no stratification factors for the phase I of this study. We anticipate that between 2-3 
patients will be enrolled per month to this study. If the RP2D is at the highest dose level, we 
would expect a sample size of approximately 40 subjects. Therefore, recruitment for the current 
study will be done in approximately 12-18 months. The schedule will facilitate the assessment of 
olaparib PK (Cmax, Tmax AUC, t1/2) and PD in the absence and presence of AT13387. 
 
 
The following escalation scheme will be followed (one cycle is 28 days): 
DOSE LEVEL 
olaparib (tablets, oral, 
twice daily dosing 
continuous) 
AT13387 (IV 
two 
consecutive 
days weekly) 
-4 
50mg BID 
10mg/m2 
-3 
100mg BID 
10mg/m2 
-2* 
50mg BID 
20mg/m2 
-1**  
100mg BID 
20mg/m2 
0 (Starting Dose) 
200mg BID 
20mg/m2 
1 
200mg BID 
40mg/m2 
2*** 
300mg BID 
40mg/m2 
3*** 
300mg BID 
80mg/m2 
4 
300mg BID 
120mg/m2 
5 
300mg BID 
160mg/m2 
 
 
 
 
 
 
*If dose level -2 is tolerated, then escalation of AT13387 in combination with olaparib 50mg 
BID will be attempted i.e. 
-2a 
50mg BID 
40mg/m2 
-2b 
50mg BID 
80mg/m2 
-2c 
50mg BID 
120mg/m2 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
6 
-2d 
50mg BID 
160mg/m2 
 
 
**If dose level -1 is tolerated, then escalation of AT13387 in combination with olaparib 100mg 
BID will be attempted i.e. 
-1a 
100mg BID 
40mg/m2 
-1b 
100mg BID 
80mg/m2 
-1c 
100mg BID 
120mg/m2 
-1d 
100mg BID 
160mg/m2 
 
 
***If dose level 2 or dose level 3 is not tolerated, then escalation of AT13387 in combination 
with olaparib 200mg BID will be attempted i.e. 
2a 
200mg BID 
80mg/m2 
3a 
200mg BID 
120mg/m2 
4a 
200mg BID 
160mg/m2 
 
 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
7 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Diseases .........................................................................................................9 
2.2 
CTEP IND Agents .................................................................................................10 
2.3 
Rationale ................................................................................................................18 
2.4 
Correlative Studies Background ............................................................................21 
3. 
PATIENT SELECTION ....................................................................................................23 
3.1 
Eligibility Criteria ..................................................................................................23 
3.2 
Exclusion Criteria ..................................................................................................26 
3.3 
Inclusion of Women and Minorities ......................................................................26 
4. 
REGISTRATION PROCEDURES ...................................................................................27 
4.1 
Investigator and Research Associate Registration with CTEP ..............................27 
4.2 
Site Registration .....................................................................................................28 
4.3 
Patient Registration ................................................................................................30 
4.4 
General Guidelines .................................................................................................31 
5 
TREATMENT PLAN ........................................................................................................31 
5.1 
Agent Administration .............................................................................................31 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................37 
5.3 
Dose Expansion Cohorts ........................................................................................38 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................39 
5.5 
Duration of Therapy ...............................................................................................40 
5.6 
Duration of Follow Up ...........................................................................................41 
5.7 
Criteria for Removal from Study ...........................................................................41 
6 
DOSING DELAYS/DOSE MODIFICATIONS................................................................41 
6.1 
Anticipated Toxicities ............................................................................................42 
6.2 
General Toxicity Management, Dose Modifications / Delays ...............................42 
6.3 
Dose Modifications/Delays and Management for Specific Toxicities ..................43 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................48 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............48 
7.2 
Adverse Event Characteristics ...............................................................................54 
7.3 
Expedited Adverse Event Reporting ......................................................................55 
7.4 
Routine Adverse Event Reporting .........................................................................56 
7.5 
Secondary Malignancy ...........................................................................................57 
7.6 
Second Malignancy ................................................................................................57 


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8 
8 
PHARMACEUTICAL INFORMATION ..........................................................................57 
8.1 
CTEP IND Agent(s) ...............................................................................................57 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................62 
9.1 
Exploratory/Ancillary Correlative Studies ............................................................63 
9.2 
Clinical Pharmacology: ..........................................................................................63 
10 
STUDY CALENDAR .......................................................................................................66 
11 
MEASUREMENT OF EFFECT........................................................................................67 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................68 
11.2 
Antitumor Effect – Hematologic Tumors ..............................................................74 
11.3 
Other Response Parameters ...................................................................................74 
12 
Study Oversight and DATA REPORTING / REGULATORY REQUIREMENTS .........74 
12.1 
Study Oversight .....................................................................................................75 
12.2 
Data Reporting .......................................................................................................75 
12.3 
CTEP Multicenter Guidelines ................................................................................77 
12.4 
Collaborative Agreements Language .....................................................................77 
12.5 
Genomic Data Sharing Plan ...................................................................................79 
13 
STATISTICAL CONSIDERATIONS...............................................................................79 
13.1 
Study Design/Endpoints.........................................................................................79 
13.2 
Sample Size/Accrual Rate ......................................................................................80 
13.3 
Stratification Factors ..............................................................................................81 
13.4 
Interim Analysis .....................................................................................................81 
13.5 
Analysis of Secondary Endpoints ..........................................................................82 
13.6 
Reporting and Exclusions ......................................................................................82 
REFERENCES ..............................................................................................................................83 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................86 
APPENDIX B: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ........87 
APPENDIX C: KNOWN CYP3A4 INDUCERS AND INHIBITORS. ........................................91 
 
APPENDIX D: List of QT prolonging drugs to be used with caution ..........................................93 
 
APPENDIX E: List of Prohibited QT-Prolonging Drugs ..............................................................95 
 
APPENDIX F: PATIENT’S PILL DIARY: olaparib ....................................................................97 
APPENDIX G:  PHARMACOKINETIC SAMPLE COLLECTION AND HANDLING ...........98 
APPENDIX H: DIARRHEA MANAGEMENT .........................................................................100 
 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
9 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To establish the maximum tolerated dose (MTDs) of olaparib and AT13387 administered in 
combination in patients with advanced solid tumors. 
 
1.2 
Secondary Objectives 
 
To identify the dose-limiting toxicity (DLT) and other toxicities associated with olaparib and 
AT13387 administered in combination as assessed by CTCAE v5.0. 
 
To determine the recommended phase 2 doses (RP2D) of the combination of olaparib and 
AT13387. 
  
To determine the plasma pharmacokinetics of olaparib and AT13387. 
 
To document anti-tumor activity of the combination of olaparib and AT13387 as assessed by 
RECIST 1.1 and progression free survival (PFS). Although the clinical benefit of [this/these] 
drug(s) has not yet been established, the intent of offering this treatment is to provide a possible 
therapeutic benefit, and thus the patient will be carefully monitored for tumor response and 
symptom relief in addition to safety and tolerability. 
 
1.3 Exploratory Objectives 
 
 
 
2. BACKGROUND 
 
2.1 
Study Diseases 
 
2.1.1 Ovarian Cancer 
 
Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, with an estimated 
22,000 new cases and 15,000 deaths in the United States per year28.  Patients initially are 
diagnosed during exploratory laparotomy, during which time surgical staging is performed and 
gross disease is debulked.  Over 70% of patients present with advanced disease, with spread of 
disease to the upper abdomen (Stage III) or more widely metastatic disease such as malignant 
pleural effusions or liver/splenic intraparenchymal lesions (Stage IV).  Post-operative adjuvant 
chemotherapy is indicated for all patients with advanced disease, and options include 
intraperitoneal chemotherapy with cisplatin and paclitaxel or intravenous chemotherapy with 
carboplatin and paclitaxel.  In over 70% of cases, platinum and taxane-based combination 
therapy results in a clinical complete remission, typically defined as having no evidence of 
residual tumor, based on a normal serum CA-125 level, normal exam, and normal radiographic 
study such as a CT scan. 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
10 
 
Unfortunately, despite achieving initial remission, the majority of patients will develop a relapse 
of their cancer and eventually die of disease due to the persistence of chemoresistant and 
platinum-resistant cancer cells.  Despite aggressive surgical and chemotherapeutic approaches, 
the chance of achieving long-term disease-free survival for subjects with stage III and stage IV 
disease is only approximately 25% and <10%, respectively29.  Other less common Mullerian 
tumors such as primary peritoneal serous cancers and fallopian tube cancers have similar clinical 
courses and behavior.  Thus, it is these 3 types of gynecologic cancers into one entity for the 
purpose of treatment and clinical investigation.   Relapse in advanced ovarian cancer is generally 
incurable, and the goal of treatment changes to palliation.  The treatment of recurrent ovarian 
cancer with conventional cytotoxic agents is limited by the development of chemoresistance as 
well as intolerable side effects.  
 
 
2.1.2 Triple-Negative Breast Cancer 
 
There is an estimated 180,510 new cases of breast cancer diagnosed in the United States per 
year, and approximately 41,910 deaths attributed to this cancer30.  Up to 20% of breast cancers 
are negative for expression of all three receptors and constitute the subtype TNBC. 
 
Chemotherapy has been the mainstay of treatment for women with TNBC, but the current 
standard of care is inadequate.   Despite treatment with chemotherapy, TNBC is associated with 
poorer outcomes compared to other breast cancer subtypes. TNBC has an aggressive clinical 
course, marked by higher rates of visceral and central nervous system metastases and worse 
survival compared to hormone receptor-positive subtypes31. 
 
Approximately 70% of breast cancers in individuals carrying a germline BRCA1 mutation are 
TNBC; BRCA1-associated and sporadic TNBCs share many histopathologic features.  These 
cancers are frequently high grade, have frequent p53 mutations, and are typically basal-like by 
hierarchical clustering of transcriptional profiles with these cancers sharing a pattern of genomic 
instability characterized by allelic loss32-33. 
 
Drugs such as cisplatin have demonstrated activity in TNBC.   A recently published neoadjuvant 
cisplatin study in TNBC using 4 cycles of cisplatin at 75 mg/m2 every 21 days showed 
efficacy34.  These similarities have led to speculation that BRCA1-associated and at least a 
subset of sporadic TNBCs may share defects in a BRCA1-associated pathway as do HGSC (high 
grade serous cancer), hence the reason for both cancer subtypes to be included in this protocol 
with observed similarities between TNBC and HGSC both clinically as well as from a genetic 
standpoint35.   
 
2.2 
CTEP IND Agents 
 
2.2.1 PARP inhibitor olaparib 
 
Olaparib is a potent and well-tolerated oral inhibitor of polyadenosine 5’-diphosphoribose [poly-
(ADP-ribose)] polymerization (PARP)-1 and PARP2.  Olaparib is an active monotherapy in 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
11 
tumors with defective components of homologous recombination repair (HRR), which includes 
those with BRCA1/2 mutations. A first-in-man phase 1 dose escalation trial of single agent 
olaparib in a patient cohort enriched for patients with BRCA germline mutations indicated 
substantial PARP inhibition in surrogate tissues and anti-tumor activity in 40% of ovarian cancer 
patients with germline BRCA mutations, using combined RECIST and GCIG CA-125 criteria 2-4. 
 
Mechanism of Action 
Preclinically, olaparib displays antitumor activity against a variety of tumor cell lines and this 
sensitivity of the cells is believed to depend upon components of a defective HRR capability 
(Olaparib Investigator’s Brochure, 2013). As a major example of this selective activity, both 
BRCA1- and 2-deficient (-/-) tumors are sensitive to PARP inhibition. Early studies indicated 
that PARP inhibition in BRCA1/2 homozygous null cells, but not the isogenic BRCA 
heterozygous cells, led to cell death. BRCA1 and 2 are proteins necessary for proper function of 
HRR, the high fidelity repair system that addresses DNA double-strand breaks (DSBs). The 
backup repair system to HRR is base-excision repair (BER), which requires PARP function and 
primarily addresses single-strand breaks (SSBs). However, the system works both ways in that 
repair of SSBs in BER can lead to stalled replication forks that strain the system and cause 
double strand breaks, resulting in a situation that requires intact HRR and BRCA1 or BRCA2. 
Thus, HRR dysfunction sensitizes cells to PARP inhibition leading to further chromosomal 
instability, cell cycle arrest and apoptosis 2. This sensitivity is suggested to result in a large 
therapeutic window for PARP inhibition in mutation carriers. Pre-clinical studies support 
these findings showing that other BRCA mutant, but not wild-type, human cell lines are 
highly sensitive to olaparib5. 
 
Nonclinical Pharmacology and Efficacy 
Olaparib has demonstrated cellular activity in the low nM range with a cellular dose for 
50% inhibition (IC50) of 2 nM in HeLa cells (Olaparib Investigator’s Brochure, 2013). 
The effective concentration for inhibiting cellular PARP activity in cancer cells by >90% 
is approximately 30 nM to 100 nM olaparib in several tumor cell lines including ovarian 
A2780, breast MCF-7, and colorectal SW620. These concentrations lead to significant 
ablation of PARP activity (based on the inhibition of PAR formation), with maximal 
PARP-1 inhibition occurring at around 100 nM. Consistent with this, maximal 
potentiation of an appropriate DNA SSB-inducing chemotoxic agent (MMS) was also 
seen in vitro at 100 nM, which equates to 43.4 ng/mL. 
 
An analysis of the correlation of olaparib response with several standard-of-care (SOC) 
chemotherapies in a panel of breast cancer cell lines has demonstrated a strong 
correlation with both carboplatin (0.84, p=0.0006) and camptothecin (0.8, p=0.0018) 
(Olaparib Investigator’s Brochure, 2013). This is consistent with what is known about 
the types of DNA damage they induce (intra-strand and inter-strand cross-links for 
platinum and trapped topoisomerases-DNA adducts for camptothecins, both of which 
result in DNA DSB formation in replicating cells) and the DDR pathways that deal with 
them (primarily HRR in cells undergoing DNA replication). The same does not hold for 
a mechanistically unrelated chemotherapy, such as paclitaxel (-0.11) whose mechanism 
of action is unrelated to the induction of DNA damage. 
 


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The analysis of olaparib and platinum response was extended to additional tumor 
indications where platinum treatment is SOC and included ovarian, non-small cell lung 
cancer (NSCLC) and head and neck squamous cell carcinoma cell lines (Olaparib 
Investigator’s Brochure, 2013). Consistent with the breast cancer cell line data, the 
strong correlation between platinum response and olaparib response was observed. These 
in vitro data have been extended further into in vivo patient-derived tumor explant (PTX) 
models of both breast and NSCLC and again the correlation is seen between platinum 
sensitivity and olaparib sensitivity. 
 
In vitro combination studies demonstrate that olaparib is able to potentiate the 
cytotoxicity of DNA-damaging agents, including the monomethylating agent 
temozolomide (melanoma, glioblastoma, colorectal), topoisomerase-1 inhibitors such as 
camptothecin, irinotecan, and topotecan (ovarian, pancreatic, colorectal), and platinumbased 
agents such as cisplatin and carboplatin (breast) (Olaparib Investigator’s Brochure, 
2013). Studies with BRCA1-deficient orthotopically-transplanted in vivo mouse 
mammary tumor models showed that, in addition to single agent activity of olaparib, 
sequential treatment of mice with olaparib following a single dose of platinum agent 
increased the time to progression on treatment and extended OS. These data support the 
idea that olaparib can extend the antitumor effect of platinum agents when given as a 
maintenance treatment. 
 
Following single oral doses, absorption was rapid (maximum plasma concentration 
[Cmax] <2 hours in mice, rats and dogs) while bioavailability was <60% in male and 
female mice, <20% in male and female rats and ~79% in male dogs (Olaparib Investigator’s 
Brochure, 2013). Low oral bioavailability in rat may have been due to poor absorption or rapid 
first pass metabolism. Distribution of olaparib is in the gastrointestinal tract and in tissues 
associated with the metabolism and elimination of foreign compounds. Further investigations are 
still ongoing. Excretion is primarily via the feces and, to a lesser extent, the urine. 
Investigations in human in vitro systems indicated metabolism of olaparib was CYP mediated 
and that CYP3A4 and 3A5 were the dominant metabolic enzymes (Olaparib Investigator’s 
Brochure, 2013). Similar studies indicated flavin mono-oxygenase-3 was not able to metabolize 
olaparib. In in-vitro direct inhibition assays, olaparib (100 μM) had only limited effect against 
CYP3A (up to 46% inhibition) and less effect against other CYPs tested. In time dependent 
inhibition assays, olaparib had only very minor effects against CYP3A and no effect against 
other CYPs. Clinically significant direct inhibition of intestinal CYP3A is possible but 
significant effects against hepatic CYP3A are less likely. The CYP induction potential of 
olaparib was investigated in cultures of human hepatocytes. At the highest olaparib concentration 
(30 mcM), minor induction of CYP2B6 activity was observed (<40% positive control) and 
smaller effects on CYPs 2C9 and 2C19 activities were noted. These changes were unlikely to be 
of clinical significance. A small decrease in CYP3A activity was noted, which may suggest time 
dependent inhibition, however, this was not explored further. 
 
In studies using Madin-Darby Canine Kidney (MDCK) II cells transfected with multidrug 
resistance 1 (MDR1; Pgp), BCRP or MRP-2 drug efflux transporters, olaparib was shown to be a 
substrate of MDR1 but not BCRP or MRP-2 (Olaparib Investigator’s Brochure, 2013). In the 


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same systems, olaparib was an inhibitor of BCRP and MRP-2 but had little or no inhibitory 
effect on MDR1. 
 
In isolated human hepatocytes, olaparib was a substrate for organic anion transport 
proteins. In the same system, olaparib was shown to be an organic cation transporter 1 
(OCT1) inhibitor (IC50 11.9 μM) (Olaparib Investigator’s Brochure, 2013). In HEK-293 
cells transfected with OATP1B1, olaparib functioned as an inhibitor and IC50 values of 
20.3 mcM and 27.1 mcM were derived (substrate dependent). Using the criteria defined 
in the European Medicines Agency (EMA) guidelines on the investigations of drug 
interactions (EMA 2013), it is possible olaparib may precipitate an interaction via hepatic 
drug uptake transporters, particularly OCT1. 
 
SimCYP population PK simulations of the separate effect of co-administration of 
itraconazole and rifampicin (clinically relevant CYP3A inhibitor and inducer, 
respectively) on olaparib PK in humans, when administered at the recommended human 
dose, were performed (Olaparib Investigator’s Brochure, 2013). The itraconazole (200 
mg twice daily [BID] x 7 days) simulation indicated olaparib (400 mg bd x 7 days) steady 
state Cmax and area under the concentration-time curve (AUC) would increase by 2.8 and 
3.5 fold, respectively. The rifampicin simulation (600 mg x 6 days) indicated olaparib 
(400 mg BID x 6 days) steady state Cmax and AUC in the presence of rifampicin would be 
reduced to 33% and 29%, respectively, of the values in the absence of rifampicin. 
 
Nonclinical Toxicology 
Olaparib has been tested in dogs and rats (Olaparib Investigator’s Brochure, 2013). 
There were no noted effects on the cardiovascular or respiratory parameters of an 
anesthesized dog or any behavioral, autonomic, or motor effects in the rat. Toxicology 
studies indicate that the target organ of toxicity is the bone marrow. Ex vivo work has 
confirmed that olaparib is also active against human marrow. The cytotoxic effect 
becomes evident at a higher concentration than required to fully ablate PARP activity. 
28-day dog and rat studies demonstrate a reversible myelotoxic effect that is mild to 
moderate. Platelets are first affected, followed by white blood cells. In 26-week repeatdose 
studies in rats, doses were well-tolerated in male rats, with hematological effects 
and increased spleen weights observed at all dosages. In female rats, doses of 15 
mg/kg/day resulted in significant reduction in body weight. Hematological effects and 
increased spleen weights were again observed at all dosages. The difference between 
sexes was considered to be due to the fact that females had greater plasma exposure 
levels than males. In 26-week repeat-dose studies in dogs, olaparib was well-tolerated. 
Hematological changes were observed, characterized by pancytopenia. 
 
Clinical Pharmacology 
Olaparib is rapidly absorbed following capsule oral dosing in cancer patients (Olaparib 
Investigator’s Brochure, 2013). Mean volume of distribution was 40.3 L, mean plasma 
clearance was 4.55 L/h, and the estimated terminal half-life (t1/2) was between 5 and 12 
hours. Exposure increased proportionally with dose at doses up to 100 mg but increased 
in a less than proportional fashion at higher doses. On multiple dosing, there was no 
evidence of time dependency of the PK and no marked accumulation. There was no 


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evidence of ethnic difference in olaparib PK between Japanese and Caucasian patients. 
Recovery of administered radiolabelled olaparib dose was >94% in four patients and 
approximately 60% in a further two with the lower recoveries apparently due to slower 
fecal excretion of dosed material by these two patients. Drug-related material was 
eliminated in the urine (35-50%) and in the feces (12-60%) with 6-20% of the dosed 
material recovered in the urine as unchanged drug. Plasma concentrations of olaparib 
were similar to those of total radioactivity up to 6 or 8 hours after dosing but the profiles 
diverged thereafter indicating the presence of circulating metabolites. Metabolite 
identification in plasma and the excreta is ongoing. 
Studies of the relative single-dose bioavailability of capsule vs. tablet formulations 
showed that at the two lower tablet doses, the Cmax with the tablet formulation tended to 
be slightly higher and the AUC was similar (Olaparib Investigator’s Brochure, 2013). 
However, at the highest tablet dose (250 mg), the exposure delivered by the tablet 
formulation (both Cmax and AUC) was higher than that delivered by the 400 mg capsule. 
The tablet and the capsule formulations cannot therefore be considered to be 
bioequivalent. Further details regarding PK comparisons between the capsule and tablet 
formulations may be found in the 2013 Olaparib Investigator’s Brochure. 
 
Clinical Efficacy 
The first clinical study in man of olaparib (KU-36-92) was a dose-escalation study in 
patients with advanced solid tumors (Olaparib Investigator’s Brochure, 2013). 
Preliminary data demonstrated that olaparib is generally well-tolerated at doses up to and 
including the MTD of 400 mg BID in patients with various solid tumors. As of October 
2, 2013, approximately 2103 patients with ovarian, breast, pancreatic, melanoma, and 
other advanced solid tumors have received olaparib, either as monotherapy or in 
combination with other chemotherapy agents. AEs considered to be associated with 
olaparib included anemia (mild to moderate), neutropenia (mild to moderate), and 
thrombocytopenia (generally mild to moderate, sometimes severe), nausea and vomiting 
(mild to moderate), and fatigue (mild to moderate). 
Olaparib has also been studied in an expansion phase in BRCA-deficient ovarian cancer 
at a dose of 200 mg BID. Fifty patients were treated, including 48 with BRCA-deficient 
germline mutations and two patients of unknown status or significance. Twenty (40%) 
patients achieved complete response (CR) or partial response (PR) by RECIST and/or 
GCIG-CA125 criteria. An additional three patients experienced stable disease (SD) for 
more than four cycles 4. A multicenter phase 2 study enrolled two sequential cohorts of women 
with known germline BRCA2 or BRCA2 mutations and recurrent advanced ovarian cancer to 
receive olaparib continuously at a dose of 400 mg BID (Cohort 1) or 100 mg BID (Cohort 2) 6. 
Responses were observed in 33% (11 of 33) patients enrolled in the 400mg BID cohort and 13% 
(3 of 24) patients enrolled in the 100 mg BID cohort. A phase 2 study of olaparib in advanced 
serous ovarian cancer and triple-negative breast cancer included a cohort of 46 ovarian 
cancer patients who were known not to carry a germline BRCA mutation, in which an 
overall response rate (ORR) of 23.9% was observed 7. 
Additional studies of olaparib as monotherapy or in combination with a platinum reagent 
for treatment of metastatic BRCA-deficient ovarian cancer are ongoing. Results from a 
phase 2 trial investigating olaparib as maintenance therapy following platinum-based 
therapy for platinum-sensitive serous ovarian cancer demonstrated a significant 


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progression-free survival (PFS) benefit (8.4 vs. 4.8 months, P<0.001), with subgroup 
analyses demonstrating evidence of benefit regardless of BRCA status 8, 9. Additional phase 1 
and 2 trials in both BRCA-deficient and BRCA-competent ovarian cancer are currently ongoing. 
Olaparib was granted accelerated approved by the FDA in the United States as 
monotherapy in women with advanced ovarian cancer associated with germline BRCA 
mutation in the companion diagnostic test BRACAnalysis CDx and who have received at 
least 3 prior lines of therapy for ovarian cancer on December 19, 2014. 
 
2.2.2 HSP90 inhibitor AT13387 
 
Mechanism of Action: AT13387 (onalespib) is a synthetic non-ansamycin small molecule that 
acts as an inhibitor of heat shock protein 90 (HSP90). HSP90, which regulates the folding, 
stability and degradation of many oncogenic signaling proteins, is upregulated in a variety of 
tumor cells. HSP90 inhibitors are thought to affect multiple aberrant signaling pathways and may 
therefore be of clinical benefit in the treatment of a wide range of cancers. 
 
Pharmacodynamic Properties:  AT13387 (onalespib) exhibited high affinity for the ATP 
binding site at the N-terminal domain of HSP90, and was a potent inhibitor of the growth and 
survival of a variety of tumor cell lines. AT13387 (onalespib) caused degradation of multiple 
HSP90 client proteins, key regulators of cell proliferation and survival. In cancer xenograft 
models in nude or severe combined immunodeficiency (SCID) mice (tyrosine kinase inhibitor 
[TKI]-sensitive or -resistant non-small-cell lung cancer [NSCLC] driven by mutated epidermal 
growth factor receptor [EGFR] or translocated anaplastic lymphoma kinase [ALK]; 
vemurafenib-sensitive and -resistant B isoform of RAF kinase [BRAF] mutant melanoma), 
AT13387 (onalespib) inhibited tumor growth and was best tolerated weekly or twice weekly. In 
upfront combination with kinase inhibitors, AT13387 (onalespib) was able to delay the 
emergence of resistance in melanoma and NSCLC xenograft models. AT13387 (onalespib) 
caused prolonged knockdown of HSP90 client proteins in cells and tumors with a half-life of 38-
75 hours in tumor xenografts in mice, suggesting a potential for prolonged effect after a single 
dose. 
 
Pharmacokinetics (PK): After intravenous (IV) administration to mice, rats, and dogs and 
intraperitoneal (IP) administration to mice, AT13387 (onalespib) displayed a short plasma half-
life in mice and rats (1-3 hours) and a moderate half-life in dogs (11 hours) despite high plasma 
clearance. Volume of distribution was greater than total body water indicating distribution of 
AT13387 (onalespib) into tissues. PK studies demonstrated that AT13387 (onalespib) is highly 
distributed into xenograft tumors and is cleared slowly from tumors. The in vitro intrinsic 
clearance of AT13387 (onalespib) determined in isolated intact hepatocytes was high across all 
the species tested (mouse, rat, dog and human; scaled values ranged from 35 mL/min/kg in 
human to 184 mL/min/kg in rat). Binding of AT13387 (onalespib) to plasma proteins was 
moderate and comparable across all species tested, ranging from 77.2% in dog plasma to 90.1% 
in mouse plasma. Blood:plasma distribution in mouse, rat, dog and human whole blood ranged 
from 0.8, indicating approximately equal distribution between the plasma and cellular fraction, to 
5.0, showing that AT13387 (onalespib) favored partitioning into the red blood cells, depending 
on concentration and species. The potential for AT13387 (onalespib) to inhibit cytochromes 
P450 (CYP) 1A2, 3A4, 2D6, 2C9, and 2C19 was assessed, and results indicated a concentration 


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giving half-maximal inhibition (IC50) >10μM, suggesting a low potential for clinically 
significant drug-drug interactions mediated by these enzymes. AT13387 (onalespib) is a 
substrate for P-gp, a modest inhibitor of BCRP and P-gp, and strong inhibitor of MATE1 and 
MATE2-K. Glucuronidation, sulphation and N-oxidation appear to be routes of metabolism for 
AT13387 (onalespib) based on in vitro studies of cryopreserved hepatocytes as well as 
metabolites detected in samples in vivo. In a radiolabeled mass balance study in dogs, a mean 
maximum measured concentration (Cmax) of 793 ng-Eq/g occurred at the end of infusion. Area 
under the curve concentration-time curve from time 0 to the last data point (AUC0-t) values were 
5924 hr•ng-Eq/g and 7590 hr•ng-Eq/g for male and female dogs, respectively, with half life 
(t1/2) values of 21.3 and 20.5 hour, respectively. The majority (~83% in the male and ~72% in 
the female) of [14C] AT13387 (onalespib)-derived radioactivity was excreted via feces, with less 
found in urine (~15% in the male and ~22% in the female). 
 
Non clinical safety: No adverse central nervous system (CNS) effects were observed in the rat 
with AT13387 (onalespib) doses up to 200 mg/kg in males and 125 mg/kg in females, compared 
with control vehicle-treated animals. In a cardiovascular and respiratory (CV/R) safety study in 
Beagle dogs, a dose-related increase in heart rate was observed at 4 mg/kg and above, from 10 
minutes after the start of infusion, which peaked at the end of infusion and returned to control 
levels by approximately 5 hours after the end of infusion. The increased heart rate observed at 15 
mg/kg was associated with a concomitant decrease in blood pressure (systolic, diastolic and 
mean arterial). AT13387 (onalespib) had no significant effect on QT interval or QTc at any dose 
level tested.  
The toxicity profile of AT13387 (onalespib) was evaluated in rats and dogs. Infusion-site 
reactions were observed in both species, including local irritation/inflammation. While clinical 
pathology changes suggestive of adverse effects in the bone marrow, kidney, and liver were 
observed for both species, histopathologic changes were only seen in dogs and included testes, 
gallbladder, bone marrow (sternum), kidneys, and thymus. The overall effects observed in 
surviving rats and dogs were transient and reversible, with the exception of the testicular lesions 
observed in dogs at high doses, for which the recovery period of 14 days was not sufficient. 
In the definitive 1-cycle rat study, no unambiguous target organs of toxicity were identified and 
the no-observed-adverse-effect level (NOAEL) was estimated to be 50 mg/kg/dose given twice 
per week for 3 weeks (2QW×3). A dose severely toxic to 10% of rodents (STD10) could not be 
confidently determined in rats, although safety was established in this species. Dosing for 3 
cycles in rats using the 2QW×3 regimen (for 3 of 4 weeks per cycle) resulted in systemic 
inflammation secondary to local irritation at the infusion site, which led to mortalities beyond the 
first cycle and early termination of higher dose groups. A less aggressive, once-weekly (current 
clinical regimen for study AT13387-05) infusion study in rats is ongoing. In dogs dosed via a 
peripheral vein for 1 cycle, a clear dose-effect relationship was established for AT13387 
(onalespib). Histopathology in dogs revealed changes in the bone marrow, thymus, testes, 
gallbladder and kidney at 3, 10/7, and 12.5/10/7 mg/kg. The nominal highest non-severely toxic 
dose (HNSTD) was 3 mg/kg/dose given 2QW×3 over 1 or 3 cycles, and the NOAEL was 1 
mg/kg/dose on the same schedule for 1 cycle and 0.5 mg/kg over 3 cycles. 
 
Clinical Studies: 
 
AT13387 (onalespib) is administered by IV infusion over 1 hour. 


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Maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) for 28-day cycles: 
• 2QW×3 (Days 1, 4, 8, 11, 15, 18) regimen: 120 mg/m2/dose (monotherapy) 
• 2QW×3 (Days 1, 2, 8, 9, 15, 16) regimen: 160 mg/m2/dose (monotherapy) or 120 
mg/m2/dose (combination with abiraterone acetate + steroid) 
1QW×3 (Days 1, 8, 15) regimen: 260 mg/m2/dose (monotherapy) or 220 mg/m2/dose 
(combination with imatinib, crizotinib, or abiraterone acetate+ steroid) 
 
Number of subjects treated with AT13387 (onalespib) for the purpose of safety reporting in 
various clinical trials include 275 subjects: 
i) Six subjects died within 30 days of receiving treatment with AT13387 (onalespib) 
in Astex trials from causes not attributed to progression of disease. The causes of all 
deaths were considered to be not related to treatment. 
ii) For Astex-sponsored studies, the most common serious adverse events (SAEs) by 
System Organ Class (SOC; subjects counted once per SOC), regardless of 
relationship, through the cut-off date of 30 December 2014, were categorized under 
Respiratory, Thoracic, and Mediastinal Disorders (23/237; 10%); Gastrointestinal 
Disorders (17/237; 7%); and General Disorders and Administration Site Conditions 
(12/237; 5%). Individual event terms reported for >3 subjects were 8/237 (3.4%) for 
dyspnea (6 resolved, 1 decreased in severity, and 1 not resolved); 6/237 (2.5%) for 
diarrhea (5 resolved and 1 not resolved); 5/237 (2.1%) each for dehydration (4 
resolved and 1 resolved with sequelae) and pulmonary embolism (4 resolved and 1 
not resolved); and 4/237 (1.7%) each for back pain (all resolved), muscular weakness 
(1 resolved, 1 decreased in severity, and 2 not resolved), and pneumonia (2 resolved 
and 2 fatal). For Studies AT13387-01, -02, -04, and -05, the most common individual 
events (occurring in ≥25.0% of subjects) were diarrhea (70.5%), fatigue (51.5%), 
nausea (48.9%), decreased appetite (35.4%), and vomiting (32.9%). Most AEs were 
reported as Grade 1 or 2. The most common related AEs (occurring in ≥25.0% of 
subjects) across all studies were diarrhea (65.0%), nausea (41.8%), and fatigue 
(40.9%). Most related AEs were reported as Grade 1 or 2. Related Grade 3 or 4 AEs 
reported for ≥2.0% subjects were diarrhea (10.5%), fatigue (3.8%), and anemia 
(3.4%). 
 
The PK of AT13387 (onalespib) showed dose-dependent increase in AUC0-t and Cmax from 10 
to 310 mg/m2/dose with relatively low inter-individual variability. Elimination half-life (t1/2 el) 
was dose-independent with mean cohort values ranging from 6.6 to 11.5 hours. Maximum t1/2 
observed was 14 hours. There was no notable accumulation or reduction in exposures between 
Day 1 and Day 18 (twice weekly) or Day 1 and Day 15 (once weekly) of Cycle 1. The AT13387 
(onalespib) PK profile and exposures were similar across several studies, whether as a single 
agent (AT13387-01) or in combination with imatinib (AT13387-02), abiraterone acetate 
(AT13387-04), or crizotinib (AT13387-05), at comparable dose levels, indicating no potential 
for interactions affecting AT13387 (onalespib) PK by these agents. Plasma increases in HSP70 
were detected at all dose levels in Study AT13387-01. HSP70 induction is a pharmacodynamic 
marker of target engagement, but has not been demonstrated to be predictive of clinical response. 
 


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Dedicated drug-drug interaction studies have not been conducted. However, olanespib PK does 
not appear to be affected when coadministered with imatinib (AT13387-02), abiraterone acetate 
(AT13387-04), or crizotinib (AT13387-05).  Olanespib did not affect the PK of crizotinib. 
 
In terms of efficacy, in Study AT13387-01 (monotherapy), the best response to treatment was 1 
partial response (PR) in a subject with GIST and stable disease persisting for ≥6 months in 4 
subjects (2 with GIST, 1 with adenoid cystic carcinoma of the right parotid, 1 with metastatic 
uveal melanoma). In Study AT13387-02 (coadministration with imatinib) in GIST subjects, 
disease control at 4 months occurred in 5 (19.2%) subjects. In ongoing Study AT13387-05 
(coadministration with crizotinib) in NSCLC subjects, 4 PRs have been reported during the dose-
escalation part of the study (Part A). 
 
Overall, risks and common AEs in clinical studies include: 
• Gastrointestinal toxicities (diarrhea, nausea, abdominal pain, vomiting, dry mouth, 
constipation), which are mostly Grade 1 to 2 and manageable with medications. 
• Local infusion-related irritation occurring during the infusion or systemic infusion 
reactions occurring during the infusion or shortly afterwards. Systemic reactions are 
reversible and often characterized by flushing, itching, rigors, chills, nausea, 
tachycardia/ bradycardia, alterations in blood pressure, and dizziness. Incidence 
increases at higher doses. 
• Visual impairment including peripheral flashes (photopsia), blurred or double 
vision, floaters, color distortion and dimness, difficulties with light/dark 
accommodation, tunnel vision or other field defects, halos, apparent movement of 
stationary objects, and complex disturbances. Symptoms are generally Grade 1, 
intermittent, reversible, and transient, lasting a few seconds to a few minutes and 
occurring on 1-3 days/cycle. 
• Other common toxicities include fatigue, decreased appetite, dizziness, anemia, 
headache, muscle spasms, insomnia, chills, dehydration, and hyperhidrosis. 
• Renal AEs were reported in combination with imatinib. 
• Electrocardographic (ECG) analysis of AT13387 (onalespib) as monotherapy could 
not exclude a small effect on cardiac repolarization (QTcF duration), <10 ms, which 
is not likely to be clinically relevant. Dose-related changes in heart rate and in QTc 
were reported in combination with imatinib. 
 
2.3 
Rationale 
 
PARP-inhibitors as anticancer agents: PARP-inhibitors (PARPis) have demonstrated single 
agent activity in homologous recombination (HR)-deficient tumors 2-4, 6, 10, 11.  Of these drugs, 
olaparib has been the most widely studied thus far, associated with an objective response rate 
(ORR) of 28%-33% and a median duration of response of 28-41 weeks in BRCA1 or 2-mutated, 
recurrent epithelial ovarian cancer. PARPis have also demonstrated activity in BRCA1-mutated 
triple negative breast cancers 7, 12. In addition, an association between response to olaparib and 
platinum sensitivity has been observed, and in BRCA1/2-mutated epithelial ovarian cancer the 
olaparib clinical benefit response decreases from 69.2% in platinum-sensitive disease, to 45.8% 
in platinum-resistant disease, to 23.1% in platinum-refractory disease 4.  Olaparib has also 
demonstrated objective response rate (ORR) in 24% of non-BRCA1/2-mutated ovarian cancer; 


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(50% among platinum sensitive but only 4% among platinum resistant non-BRCA1/2 ovarian 
cancers)7. This activity is thought to be related to the presence of defective homologous 
recombination (HR) in these tumors which may occur in the absence of germline BRCA1/2 
mutations. For example in ovarian cancer, defective HR may result from genetic and epigenetic 
alterations involving members of the HR DNA-repair pathway, i.e. somatic BRCA1/2 mutations, 
hypermethylation of BRCA1 or RAD51C, amplification or mutation of EMSY, focal deletion or 
mutation of PTEN, mutation of ATM or ATR, and mutation of Fanconi anemia genes 13.  
Tumors that exhibit defective HR via mechanisms that are unrelated to germline BRCA1 or 
BRCA2 mutations are commonly referred to as having a ‘BRCAness’ phenotype 14, 15.  Although 
several potential biomarkers of BRCAness and defective HR have been developed 16-19, there is 
currently no clinically available biomarker of HR-deficient cancers that accurately predicts 
defective HR and responsiveness to platinum and PARP inhibitors, and this is an area of high 
priority for ovarian and breast cancer research. 
 
PARPis in HR proficient tumors: The promise of PARP inhibitors in the management of 
ovarian and breast cancers is tempered by the fact that HR-proficient cancers do not respond well 
to these agents, suggesting that approximately 50% of ovarian cancer patients (i.e. those without 
HR alterations) do not benefit from this novel class of drugs.  Combination of PARPis with 
agents that inhibit HR may represent an effective strategy to sensitize HR proficient tumors to 
PARPis and thus potentially expand use of these agents beyond patients with HR deficient 
EOCs. Strategies designed to selectively disrupt HR in cancer cells and sensitize them to PARP 
inhibition, thereby extending the use of this class of agents to HR-proficient cancers, include 
PI3K-pathway inhibition 20, 21 and CDK inhibition 22, both of which have been translated to 
clinical trials.  
 
Rationale for combination of HSP90 and PARPis:  Multiple components of the HR pathway 
are HSP90 clients, including BRCA1, BRCA2 and RAD51, suggesting that HSP90 inhibition 
may similarly sensitize cancer cells to PARP inhibition. We have previously shown that 
exposure of HR-proficient breast cancer cell lines to HSP90 inhibitor (HSP90i) 17-AAG(17-
allylamino-17-demethoxygeldanamycin) downregulated HR, ATM and Fanconi Anemia 
pathways 23. In HR-proficient epithelial ovarian cancer (EOC) cells, 17-AAG suppressed HR as 
assessed using the RAD51 foci formation assay and this was further confirmed using the Direct 
Repeat-GFP reporter assay. Furthermore, 17-AAG downregulated BRCA1 and/or RAD51 
protein levels, and induced significantly more γH2AX activation in combination with olaparib 
compared to olaparib alone23.  Of note, sublethal concentrations of 17-AAG sensitized HR-
proficient EOC lines to olaparib and carboplatin thereby provide the preclinical rationale for 
using a combination of PARP inhibitors/HSP90 inhibitors in HR-proficient EOC. Similar 
experiments have also been conducted in non small cell lung cancer (NSCLC) cells, showing 
that HSP90 inhibition depletes BRCA2, BRCA1 and RAD51 from HR-proficient NCI-H1299 
cells and sensitizes them to PARP inhibition thus providing the proof of principle that HSP90 
inhibitor mediated sensitization to PARP inhibition can occur in additional solid tumor models.  
 
In addition, we have recently published on a novel mechanism of PARP inhibitor resistance 24.  
MDA-MB-436 triple-negative breast cancer cells harboring a BRCA1 BRCT domain mutation 
were rendered rucaparib-resistant via exposure to graded concentrations over time.  Resistance 
was associated with HSP90-mediated stabilization of the mutant protein, without evidence for 


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BRCA1 reversion mutation.  Because the BRCT domain mutant protein cannot engage CtIP, 
there was a concomitant 53BP1 mutation in resistant clones, which lowered 53BP1 levels and 
permitted BRCA1-independent end resection.  However, the mutant protein remains capable of 
binding to PALB2 and BRCA2 and is critical for efficient RAD51 loading, mediating restoration 
of HR and ultimate resistance.  Importantly, resistance was reversed with the application of an 
HSP90 inhibitor, so that PARP inhibitor sensitivity was restored24. 
 
We have also performed additional in vitro and in vivo experiments to demonstrate the 
cytotoxicity of the combination of an HSP90 inhibitor with a PARP-inhibitor.  
a. In vitro: We have now assessed the combination of the PARP-inhibitor talazoparib 
(BMN673) and the HSP90-inhibitor AT13387 in 4 HR proficient ovarian cancer cell lines 
(OVCAR4, OVCAR5, SKOV3 and CAOV3) using colony formation assays. In all cases, 
addition of sublethal concentrations of AT13387 enhanced the cytotoxicity of talazoparib 
(BMN673). 
b. In vivo: We have performed tolerability and efficacy studies of PARP-inhibitor olaparib and 
the HSP90-inhibitor AT13387 in ovarian PDX models. 
We initially performed tolerability studies and as shown in Figure 1, doses of olaparib up to 
100mg/kg po daily x 3 weeks and AT13387 up to 45mg/kg po for 2 days (D1,D2) on / 5 days off 
x 3 weeks (i.e. Days 1, 2, 8, 9, 15, 16) were well tolerated without weight loss in the mice. 
 
 
 
Figure 1. Tolerability of olaparib and AT13387 combination in ovarian PDX models. 
 
Efficacy studies were subsequently performed. Olaparib was dosed at 100mg/kg po daily x 4 
weeks, AT13387 was administered at 45mg/kg po for 2 days (D1,D2) on / 5 days off x 4 weeks 
(i.e. Days 1, 2, 8, 9, 15, 16, 22, 23). As shown in Figure 2, the combination of AT13387 and 
olaparib induced inhibition of tumor growth in several ovarian PDX models as opposed to 


NCI Protocol #:10031 
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21 
vehicle control, olaparib alone and AT13387 alone. 
 
 
 
Figure 2. AT13387+olaparib vs olaparib alone vs AT13387 alone vs vehicle in ovarian PDX 
models. 
 
Of note, all models except for DF83 were derived from patients with platinum resistant tumors. 
Strikingly, the DF101 model was derived from a patient with BRCA1-mutation and platinum and 
PARPi resistant disease, which has been resistant to combinations of olaparib and the PI3K 
inhibitors BKM120 or BYL719. Finally, we noted that 2 of the models harbored CDKN2A loss 
and 1 CCNE1 amplification. Amplification of CCNE1 is one of the most common focal copy 
number change events in serous ovarian cancer, occurring at a frequency of 20%; these tumors 
are enriched for platinum resistance and are associated with inferior outcome. Furthermore, in 
the TCGA dataset, expression of CDKN2A, which is a negative regulator of cyclins and cyclin-
dependent kinases, is very low or not expressed in approximately 1/3 of ovarian cancer cases.  
 
Based on these tolerability and efficacy studies with olaparib and AT13387 in ovarian PDX 
models, we will proceed with twice weekly dosing of AT13387 (on Days 1 and 2 every week, 
i.e. 2 days on/5 days off).  
 
2.4 
Correlative Studies Background 
 
 
Clinical Pharmacology: 
 


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22 
The pharmacokinetic study has been designed to assess the effect of olanespib on the steady state 
pharmacokinetics of olaparib and if the pharmacokinetics of olanespib is affected by the 
concurrent administration of olaparib.  Pharmacokinetic sampling will be performed in all 
patients enrolled in the dose escalation and expansion cohorts to provide data that may be 
informative for dose escalation decisions and correlation analysis with clinical and 
pharmacodynamic data.  Pharmacokinetic sampling will be performed to define the plasma 
concentration-time profile of olaparib over the dosing interval for the day 7 dose when given 
alone in cycle 0.  Pharmacokinetic samples will also be collected over a 24 h interval on days 1 
and 15 of cycle 1 to define the plasma profiles for olaparib and olanespib.   
 
The sampling schedule has been devised to accommodate treatment on an outpatient basis.  
Patients will be instructed to take the two daily doses of olaparib at the same time every day during 
the pharmacokinetic study.  The morning dose of olaparib should be taken at a time that will allow 
the patient to arrive at the clinical to obtain pharmacokinetic samples before dosing and to remain 
for an additional 8 hours.  The second daily dose of olaparib should be taken approximately 12 
hours after the morning dose.  It is very important that the patient is aware that the morning dose 
of olaparib must not be taken before arriving at the clinic on cycle 0 day 7, cycle 1 day 1, and 
cycle 1 day 15.  The olanespib i.v. infusion should be started at the same time that the patient 
takes the olaparib dose on days 1 and 15 of cycle 1.  The first set of blood samples (3 mL) on 
cycle 0 day 7 will be obtained at the indicated times according to the PK Sample Collection 
Time Points table below.  The second and third sets of blood samples (6 mL) on cycle 1 day 1 
and cycle 1 day 15 will be obtained at the same time points as indicated by the PK Sample 
Collection Time Points table below, with one additional sample collected 30 min after 
completing the 1 h IV infusion of olanespib.  Procedures for PK sample collection, processing, 
storage, and shipment is provided in Appendix G. 
 
PK Sampling Schedule 
Visit 
Collection Time 
Sample No. 
Cycle 0 Day 1 
Pre-dose (0-5 min prior to first 
olaparib dose) 
PK-00 
Cycle 0 Day 7 
Pre-dose (0-5 min prior to morning 
olaparib dose) 
PK-01 
Cycle 0 Day 7 
0.5 h ± 5 min post-dose 
PK-02 
Cycle 0 Day 7 
1.0 h ± 5 min post-dose 
PK-03 
Cycle 0 Day 7 
1.5 h ± 5 min post-dose 
PK-04 
Cycle 0 Day 7 
2.0 h ± 5 min post-dose 
PK-05 
Cycle 0 Day 7 
3.0 h ± 5 min post-dose 
PK-06 
Cycle 0 Day 7 
4.0 h ± 10 min post-dose 
PK-07 
Cycle 0 Day 7 
6.0 h ± 10 min post-dose 
PK-08 
Cycle 0 Day 7 
8.0 h ± 10 min post-dose 
PK-09 
Cycle 1 Day 1 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-10 
Cycle 1 Day 1 
0.5 h ± 5 min post-dose 
PK-11 
Cycle 1 Day 1 
1.0 h ± 5 min post-dose 
PK-12 
Cycle 1 Day 1 
1.5 h ± 5 min post-dose 
PK-13 
Cycle 1 Day 1 
2.0 h ± 5 min post-dose 
PK-14 


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23 
Cycle 1 Day 1 
3.0 h ± 5 min post-dose 
PK-15 
Cycle 1 Day 1 
4.0 h ± 10 min post-dose 
PK-16 
Cycle 1 Day 1 
6.0 h ± 10 min post-dose 
PK-17 
Cycle 1 Day 1 
8.0 h ± 10 min post-dose 
PK-18 
Cycle 1 Day 2 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-19 
Cycle 1 Day 15 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-20 
Cycle 1 Day 15 
0.5 h ± 5 min post-dose 
PK-21 
Cycle 1 Day 15 
1.0 h ± 5 min post-dose 
PK-22 
Cycle 1 Day 15 
1.5 h ± 5 min post-dose 
PK-23 
Cycle 1 Day 15 
2.0 h ± 5 min post-dose 
PK-24 
Cycle 1 Day 15 
3.0 h ± 5 min post-dose 
PK-25 
Cycle 1 Day 15 
4.0 h ± 10 min post-dose 
PK-26 
Cycle 1 Day 15 
6.0 h ± 10 min post-dose 
PK-27 
Cycle 1 Day 15 
8.0 h ± 10 min post-dose 
PK-28 
Cycle 1 Day 16 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-29 
 
Analytical methods for the determination of olaparib and olanespib by high performance liquid 
chromatography with tandem mass spectrometric detection have been developed and validated as 
recommended by the FDA Guidance for Industry:  Bioanalytical Method Validation, May 2001 
(http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf).  Individual patient plasma 
concentration-time curves will be analyzed by noncompartmental methods using routines 
supplied in the WinNonlin Professional software package (Pharsight Corp., Cary, NC).  
Pharmacokinetic parameters and variables will be calculated according to standard equations.  
Mean values of pharmacokinetic parameters will be statistically compared using the two-tailed t-
test of the log-transformed data.   
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 


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24 
3.1.1 For the dose escalation cohort:   
i) Patients must have histologically or cytologically confirmed malignancy that is 
metastatic or unresectable and for which standard curative or palliative measures do not 
exist or are no longer effective. 
ii)  Patients may have received any number of prior therapies. 
3.1.2 For the dose expansion cohort: 
i) Participants must have histologically or cytologically confirmed diagnosis of either: 
a) ovarian, fallopian tube, or primary peritoneal cancer of high grade serous 
histology which has recurred despite standard therapy. Up to 3 prior lines in the 
platinum resistant setting (i.e. up to 3 lines after patients have become platinum 
resistant); patients may have received unlimited lines while platinum sensitive. 
b) triple-negative breast cancer (TNBC) which has recurred despite standard therapy. 
Recurrent TNBC needs to have metastatic disease and patients with an in breast 
recurrence are not eligible. Up to 4 prior lines in the recurrent setting for patients 
with triple-negative breast cancer are allowed.  
ii) Patients with ovarian, fallopian tube or primary peritoneal cancer must have platinum 
resistant disease defined as progression within 6 months after last platinum 
regimen. Platinum refractory disease is allowed. 
iii)  Patients with triple-negative breast cancer may not be BRCA1/2 germline mutation 
carriers  
3.1.3 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of olaparib in combination with AT13387 in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials. 
3.1.4 There must be availability of a formalin-fixed, paraffin-embedded tumor specimen. 
3.1.5 ECOG performance status 0 or 1 (Karnofsky >60%, see Appendix A). 
3.1.6 Life expectancy of greater than 12 weeks. 
3.1.7 Patients must have normal organ and marrow function as defined below: 
− 
leukocytes 
≥3,000/mcL 
− 
hemoglobin 
≥10 g/dL with no blood transfusion in the past 28 days 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤ 3 × institutional upper limit of normal 
− 
creatinine 
≤ the institutional upper limit of normal 
OR 
− 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
− 
QTcF ≤450 ms 
− 
Any clinically significant electrolyte imbalance, particularly hypokalemia and 
hypomagnesemia, should be corrected before treatment. 
− 
Pre-Study evaluation must include an ophthalmologic exam by an opthalmologist 
(not optometrist) and should minimally include visual acuity testing, slit lamp 
examination, and fundoscopic examination. Follow up eye-exams will only be 
performed if subjects develop/report any visual impairment.  Visual impairment may 
include peripheral flashes (photopsia), blurred or double vision, floaters, color 
distortion and dimness, difficulties with light/dark accommodation, tunnel vision or 


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25 
other field defects, halos, apparent movement of stationary objects, and complex 
disturbances. Follow up eye-exams will minimally include visual acuity testing, slit 
lamp examination, and fundoscopic examination; additional testing will be based on 
symptoms, what is observed and ophthalmologist recommendations. 
3.1.8 For the expansion cohort only: measurable disease by RECIST v1.1 with at least one 
measurable target lesion.  
3.1.9 The effects of olaparib in combination with AT13387on the developing human fetus are 
unknown.  For this reason and because olaparib and AT13387 are anti-neoplastic small 
molecule inhibitors, which are agents that are potentially teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 3 months after the last dose of study drugs. Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating in 
this study, she should inform her treating physician immediately.  Men treated or enrolled 
on this protocol must also agree to use adequate contraception prior to the study, for the 
duration of study participation, and 4 months after completion of olaparib and/or 
AT13387 administration. 
3.1.10 Patients must be able to swallow tablets and have no significant impairment in 
gastrointestinal absorption.  
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
 
 
 
 
 


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26 
3.2 
Exclusion Criteria 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier. 
3.2.2 All acute, clinically significant treatment-related toxicity from prior therapy, except for 
alopecia, must have resolved to Grade ≤1. 
3.2.3 Patients who are receiving any other investigational agents. 
3.2.4 Patients with known active or history of brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to olaparib and AT13387 used in study. 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
3.2.7 Pregnant women are excluded from this study because olaparib and AT13387 are agents 
with the potential for teratogenic or abortifacient effects.  Because there is an unknown 
but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with AT13387 or olaparib, breastfeeding should be discontinued if the mother is 
treated with olaparib or AT13387.  
3.2.8 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with olaparib or AT13387.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
3.2.9 Known history of QT/QTc prolongation or Torsades de Pointes (TdP). Patients who are 
currently receiving treatment with medication with a known risk to prolong the QT 
interval or inducing Torsades de Pointes and the treatment cannot either be discontinued 
or switched to a different medication prior to starting study drugs. 
3.2.10 Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible (see Appendix C).  The 
study team should check a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of. As part of the enrollment/informed consent procedures, the 
patient will be counseled on the risk of interactions with other agents, and what to do if 
new medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product.  
3.2.11 Participants with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML.  
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 


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27 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.   
 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Members of all races and ethnic groups are eligible for this trial. For the expansion cohort, only 
women develop ovarian cancer, but men with recurrent triple negative breast cancer will be 
eligible for this study. Please refer to Planned Enrollment Report table in Section 13.2.  
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site 
staff requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the 
table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 


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28 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list 
all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
For questions, please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10031 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 


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29 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand and then select LAO-MA036 
and protocol 10031. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, load to RSS as described above.) 
 
4.2.2 Requirements For 10031 Site Registration: 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
• You can verify your site registration status on the members’ section of the CTSU 
website. Go to https://www.ctsu.org and log in using your CTEP IAM username 
and password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration tab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 


NCI Protocol #:10031 
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30 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
Once a slot reservation request has been made, the following source documentation 
should be emailed to the Lead Institution Project Manager or designee for confirmation 
of eligibility. 
 
• Copy of required laboratory tests: 
• CBC with differential 
• Serum chemistries (sodium, potassium, chloride, CO2, BUN, creatinine, 
glucose, albumin, calcium, phosphorus, ALP, AST (SGOT), ALT 
(SGPT), total bilirubin, total protein) 
• Coagulation (PT or INR with PTT) 
• Signed informed consent form 
• HIPAA authorization form (if separate from the informed consent document) 
• EKG 
• MUGA or ECHO 
• CT scan or MRI (with documentation of measurable disease per RESIST 1.1) 
• Pathology report 
• Documentation that archival tissue is available 
• Screening or most recent clinic visit note (including documentation of oncologic 
history, past medical history, concomitant medications, and vitals) 
• Clinic note from eye exam 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
 


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4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type.  
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7802 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days. Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5 
TREATMENT PLAN 
 
5.1 Agent Administration 
 
Screening tests including tumor measurements must be done and deemed acceptable per 
Section 3 and completed ≤ 4 weeks prior to start of protocol therapy. Treatment will be 
administered on an outpatient basis.  Reported adverse events and potential risks are described in 
Section 7.  Appropriate dose modifications are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered with the 


NCI Protocol #:10031 
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32 
intent to treat the patient's malignancy. 
 
Dose Escalation 
A standard 3+3 design will be utilized, escalating if 0/3 or 1/6 participants have a DLT during 
Cycles 0 and 1  of therapy.  Cycle 0 is only 7 days and Cycle 1 begins 8 days after start of Cycle 
0, i.e. immediately after Cycle 0 ends. 
If ≥ 2 DLT’s are encountered on a dose level, that dose level will be considered the DLT dose, 
and the next dose level lower will be considered the MTD. Dose-limiting toxicity (DLT) will be 
based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 and 
refers to toxicities experienced during the first 1 cycle of treatment.  Based on our tolerability 
and efficacy studies with olaparib and AT13387 in ovarian PDX models, AT13387 will be 
administered for 2 consecutive days every week for 3 weeks of a 4 week (28 day) cycle (Days 1, 
2, 8, 9, 15, 16). The RP2D of AT13387 administered IV for 2 consecutive days every week for 3 
weeks of a 4 week (28 day) cycle (Days 1, 2, 8, 9, 15, 16) is 160 mg/m2/dose.  
Doses of olaparib will range from 50mg–300 mg twice daily; AT13387 doses will range from 
20–160 mg/m2 (20-40-80-120-160) using a ping-pong strategy as shown in the Table below.  
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
The following escalation scheme will be followed (one cycle consists of 28 days): 
DOSE LEVEL 
olaparib (tablets, oral, 
twice daily dosing 
continuous) 
AT13387 (IV two 
consecutive days 
weekly) 


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33 
-4 
50mg BID 
10mg/m2 
-3 
100mg BID 
10mg/m2 
-2* 
50mg BID 
20mg/m2 
-1**  
100mg BID 
20mg/m2 
0 (Starting Dose) 
200mg BID 
20mg/m2 
1 
200mg BID 
40mg/m2 
2*** 
300mg BID 
40mg/m2 
3*** 
300mg BID 
80mg/m2 
4 
300mg BID 
120mg/m2 
5 
300mg BID 
160mg/m2 
 
*If dose level -2 is tolerated, then escalation of AT13387 (40mg/m2, 80mg/m2, 120mg/m2 and 
160mg/m2) in combination with olaparib 50mg BID will be attempted i.e. 
-2a 
50mg BID 
40mg/m2 
-2b 
50mg BID 
80mg/m2 
-2c 
50mg BID 
120mg/m2 
-2d 
50mg BID 
160mg/m2 
 
**If dose level -1 is tolerated, then escalation of AT13387 (40mg/m2, 80mg/m2, 120mg/m2 and 
160mg/m2) in combination with olaparib 100mg BID will be attempted i.e. 
 
-1a 
100mg BID 
40mg/m2 
-1b 
100mg BID 
80mg/m2 
-1c 
100mg BID 
120mg/m2 
-1d 
100mg BID 
160mg/m2 
 
***If dose level 2 or dose level 3 is not tolerated, then escalation of AT13387 (80mg/m2, 
120mg/m2 and 160mg/m2) in combination with olaparib 200mg BID will be attempted i.e. 
2a 
200mg BID 
80mg/m2 
3a 
200mg BID 
120mg/m2 
4a 
200mg BID 
160mg/m2 
 


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In mouse xenograft models, continuous daily administration of olaparib yielded greater 
antitumor activity than intermittent administration at the same or at higher dose levels so it is 
recommended that olaparib is administered continuously.  
 
The twice weekly (Days 1 and 2) of AT13387 was also chosen based on previous experience by 
Dr. Shapiro with another HSP90 inhibitor ganetespib (STA-9090)1 . Therefore, the proposed 
regimen will be olaparib twice daily and AT13387 on Days 1 and 2 every week, cycle (Days 1, 
2, 8, 9, 15, 16) of a 28 day cycle. 
 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
olaparib 
See dose level table 
above 
Oral 
Days 1-28 
twice daily, 12 
hours apart 
 
28 days  
(4 weeks) 
 
 
 
AT13387 
See dose level table 
above 
1-hour IV 
infusion 
Days 1, 2, 8, 9, 
15,16 
 
During cycle 0, olaparib will be administered alone twice daily at the same times each day,12 
hours apart, for 1 week (D1-7).  Cycle 1 and beyond, olaparib will continue to be administered 
twice daily and AT13387 will be administered for 2 consecutive days every week for 3 weeks of 
a 4 week cycle, i.e. on Days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. On days that olaparib and 
AT13387 are administered on the same day, during cycle 1, AT13387 should be started at the 
same time that the patient takes olaparib. For all other cycles, olaparib can be administered at any 
time during the AT13387 infusion. Given that our hypothesis is that AT13387 sensitizes to 
olaparib by inhibiting HR, by administering olaparib alone for cycle 0 only (7 days), we can test 
this hypothesis as a “proof of mechanism” for the combination of AT13387 and olaparib. 
Specifically, we expect that there will be induction of BRCA1 and RAD51 foci after 
administration of olaparib alone and reduced formation of these foci and downregulation of 
expression of HR pathway genes after the combination of AT13387 and olaparib. To reiterate, 
olaparib will be administered alone in cycle 0 (7 days); in all subsequent cycles, olaparib will be 
administered daily and AT13387 will be administered QDx2 for QWx3 (Days 1, 2, 8, 9, 15, 16) 
of a 28 day cycle.  
 
COMPLIANCE: The patient will be requested to maintain a medication diary of each dose of 
medication.  A copy of the medication diary is in Appendix F. It will be returned to clinic staff at 
the end of each cycle. 
 
The dose will depend on which combination and dose level the participant is on. Participants will 
be reassessed for tumor response every 2 cycles (8 weeks from Cycle 1 Day 1), +/- 1 week. 
During the DLT dosing period (Cycles 0 and 1), if dosing needs to be interrupted for toxicities, 
both drugs should be stopped and reinstituted simultaneously when appropriate according to 
Section 6. During cycles 2 and beyond, if a toxicity can be ascribed to a specific study drug, then 
that drug may be stopped while the non-offending drug can be maintained (see Section 6). 
Patients will have up to 28 days to resolve a toxicity to at least grade 1; if the toxicity does not 
decrease to grade 1 or less, the patient will be removed from the study. Furthermore, DLT 


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definition also includes toxicities that do not resolve to at least grade 1 within 28 days to allow 
patients to start Cycle 2. In other words, if patients are unable to start Cycle 2 because the 
toxicities have not resolved to at least grade 1 after 28 days, then this is also a DLT. 
During the first 2 cycles of therapy, participants will be seen weekly for blood count and 
chemistry/liver/renal panels in addition to clinical status (which includes performance status, 
history/physical, medication reconciliation, vital signs). The DLT assessment period will be 
during the first 5 weeks of therapy (i.e., cycle 0 and 1). PK samples will be collected during 
cycle 1 as per section 2.3. During cycle 1, patients will be called by someone on the research 
team on Monday through Friday to confirm they are dosing study medications correctly. If the 
patient is being seen in clinic on one of these week days and confirmation of dosing was 
obtained during the clinic visit then a phone call is not necessary. 
 
Intrapatient Dose Escalation 
Intrapatient dose escalation in this trial will be allows given that AT13387 and olaparib have 
non-overlapping toxicities and that both drugs are not associated with any cumulative toxicities. 
Intrapatient dose escalation may occur as long as patients are tolerating their current drug dose 
levels, the next higher dose is deemed safe via the 3+3 design, and dose escalation is agreed 
upon with the treating physician and principal investigator. This dose escalation will not count 
towards the next cohort of 3+3 in the formal escalation of the trial. Patients must be treated on 
their initial dose level for at least 2 cycles before their dose can be escalated. Patients who have 
their dose escalated will follow the same rules for dose delays and modifications as described in 
section 6.0.  Since DLT refers to toxicities experienced during cycle 0 and the first cycle of 
treatment, and intrapatient dose escalation is allowed after patients have been treated on their 
initial dose level for at least 2 cycles, toxicities after intrapatient dose escalation are not 
considered DLTs. There is no maximum number of times a patient can be dose escalated, as long 
as they have acceptable toxicities for 2 cycles on a specific dose level and are receiving benefit 
from the study drugs.  
 
5.1.1 Pre-Treatment Criteria 
 
Screening Visit 
Participants must meet criteria at screening as outlined in Section 3.0. 
 
Cycle 0: Day 1 
Participants must continue to meet all eligibility criteria as outlined in protocol section 3.0 and 
the table below.  
 
Cycle 1: Day 8, 15, and 22 
Participants must meet the laboratory and performance status criteria listed in the table below. If 
dosing needs to be interrupted for toxicities, both drugs should be stopped and reinstituted when 
appropriate according to Sections 5 and 6. 
 
Cycle 2 and Beyond: Day 1 
Participants must meet the laboratory and performance status criteria listed in the table below. 
All toxicities experienced during the preceding cycle must have returned to grade 1 or less with 
the exception of specific laboratory parameters as listed in the table below. If dosing needs to be 


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interrupted for toxicities, the offending drug(s) should be stopped and reinstituted when 
appropriate according to Section 6. If one study drug is being taken the study clock does not 
stop, and the offending drug will be marked as held at the start of the next cycle. The study clock 
will not stop for drug(s) held and restarted within a cycle. If on day one both drugs are held, the 
next cycle will not start until one or both of the drugs are restarted. 
 
TABLE: Pre-treatment Criteria 
 
Cycle 0: D1 
Cycle 1: D 8, 15 and 22 
Cycle 2 and Beyond: Day 1* 
ANC 
≥1,500/mcL 
≥1,000/mcL 
≥1,000/mcL 
Platelets 
≥100,000/mcL 
≥75,000/mcL 
≥75,000/mcL 
HgB 
≥10g/dl 
≥8g/dl 
≥8g/dl 
WBC 
≥3,000/mcL 
N/A 
N/A 
Tot Bili 
WNL 
≤1.5 x ULN 
≤1.5 x ULN 
SGPT 
≤ 3 x ULN 
≤ 3 x ULN 
≤ 3 x ULN 
SGOT 
≤ 3 x ULN 
≤ 3 x ULN 
≤ 3 x ULN 
Creatinine 
≤ institutional 
ULN** 
≤1.5 x ULN 
≤1.5 x ULN 
Magnesium WNL 
≤ Grade 1 
≤ Grade 1 
Potassium 
WNL 
≤ Grade 1 
≤ Grade 1 
ECOG 
0 or 1 
0 or 1 
0 or 1 
 
*For cycle 2 and beyond, hold only offending drug if pre-treatment criteria are not met 
** or creatinine clearance ≥60mL/min/1.73m2 if creatinine above normal 
 
At All Times During the Study 
Participants must meet the following criteria at all times during the study to continue 
dosing: 
• No evidence of life-threatening medical problems. 
• No evidence of an impending bowel obstruction. 
• Patient must be able and willing to swallow capsules. 
 
5.1.2 olaparib  
Administration 
Olaparib at the appropriate dose level will be given orally continuously twice daily. Tablets are 
taken by mouth and can be taken with a light meal/snack if needed to reduce stomach irritation. 
The correct number of tablets comprising the appropriate dose should be taken at the same times 
each day with approximately 240 mL of water. The olaparib tablets should be swallowed whole 
and not chewed, crushed, dissolved, or divided.  
 


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A 28-day supply (+/-4 day window to allow for holidays and vacations) of Olaparib will be 
dispensed at the start of each cycle. Participants will be provided with a pill diary (Appendix F), 
instructed in its use, and asked to bring it with them to each appointment.  
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only 
be replaced if all of the intact tablets can be seen and counted. Should any participant 
enrolled on the study miss a scheduled dose, the participant will be allowed to take the 
scheduled dose up to a maximum of 2 hours after that scheduled dose time. If greater 
than 2 hours after the scheduled dose time, the missed dose should not be taken, and the 
participant should take their allotted dose at the next scheduled time. 
 
Dosing: Please refer to section 5.1. 
 
5.1.3 AT13387 (Olanespib) 
 
Administration 
 
In this trial, AT13387 will be administered in the following dosing schedule: 
One hour IV infusion (+/- 10 minutes) on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (twice-
weekly for 3 weeks of a 4 week cycle); refer to section 5.1 for dose schedule. Dosing of 
AT13387 will be based on the weight obtained on days 1, 8 and 15 of each cycle, and this weight 
can be used for dosing on the following day, that is, days 2, 9 and 16, respectively.. AT13387 
dose rounding will be done as per institutional guidelines.  
 
Treatment with AT13387 (onalespib) may be associated with local infusion-related irritation, as 
well as systemic infusion reactions, which occur either during the infusion or shortly afterwards 
(same day).  
 
Infuse over 1 hour (+/- 10 minutes) through a central line or a well-defined peripheral vein.  If using 
a peripheral line, be sure to aspirate venous blood prior to starting the infusion.  Check the infusion 
site every 15 minutes and change the site of infusion should evidence if swelling or discoloration is 
observed.  
 
If patient experiences pain at the infusion site, slow the infusion rate (i.e. > 1-hour duration) and/or 
infuse D5W or 0.9% NS through a “Y” connector.  The additional volume of D5W or 0.9% NS 
dilutes AT13387 concentration at the local site of the infusion and alleviates the irritation. 
Premedication with dexamethasone, antihistamine and 5HT3 antagonists can also be given. 
 
5.2 Definition of Dose-Limiting Toxicity 
 
Dose-limiting toxicity (DLT) is based on the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.0.  
 
Definition of DLT: Dose limiting toxicity (DLT) refers to both non-hematologic and 
hematologic toxicities experienced during cycle 0 and the first cycle (i.e. first 4 weeks) of 
treatment.  


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A DLT will be defined as any of the following, numbers 1-5, occurring during Cycles 0 and 1: 
 
1. Non-Hematologic Toxicity 
Any Grade 3 or 4 event, excluding: 
• Grade 3 Fatigue 
• Grade 3 nausea and/or vomiting controlled with supportive measures within 24 hours 
• Grade 3 constipation controlled with supportive measures within 24 hours 
• Grade 3 diarrhea controlled with supportive measures within 24 hours 
• Grade 3 hypophosphatemia 
• Grade 3 hyponatremia 
• Grade 3 hypomagnesemia 
• Grade 3 rash that resolves to grade 2 or grade 1 within < 5 days 
 
2. Hematologic Toxicity 
• Grade 4 neutropenia of > 7 day’s duration 
• Febrile neutropenia (a disorder characterized by an ANC < 1000/mm3 and a single 
temperature of > 38.3 °C (101 °F) or a sustained temperature of > 38 °C (100.4 
°F) for more than one hour. 
• Grade 4 thrombocytopenia or bleeding associated with grade 3 thrombocytopenia. 
• Requirement for repeated blood transfusion within 4-6 weeks 
• All other Grade 4 hematologic toxicities 
 
3. Any study treatment related death. 
 
4. Any Grade 3 or grade 4 toxicity considered, in the opinion of the investigator, to be 
dose-limiting. 
 
5. Inability to take 75% or more of the planned dose for olaparib and 4 out of 6 doses for 
AT13387 in Cycle 1 due to treatment-related AEs.  
If patients cannot take 75% or more of the planned olaparib or who receive fewer than 4 doses of 
AT13387, for reasons other than toxicity or DLT, these patients will not be evaluable for DLT 
assessment and will be replaced. 
 
If a participant experiences a DLT, a PK sample should not be drawn. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
The study team will review data and the progress of the study on a monthly bases including 
during the expansion cohort 
 
5.3 Dose Expansion Cohorts 
 
Once the RP2D is reached, an additional 20 patients with either TNBC or ovarian cancer will be 
treated at this dose.  Monitoring of all safety and toxicity data is done by the Principal 
Investigator and the Corresponding Organization on a real-time basis as data are entered into 


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Medidata Rave using the Web Reporting Module. All participating sites are expected to notify 
the Principal Investigator when a DLT has occurred.   
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
 
Please see section 8 for potential drug interactions. 
 
Patient should receive general concomitant and supportive care medications based on best 
medical practice. Neupogen and other bone marrow-supportive agents, including erythropoiesis 
stimulating agents, are not allowed during treatment. The use of any natural/herbal products or 
other “folk remedies” is not allowed on study. All medications must be recorded in the case 
report form and be reviewed by the treating physician at each visit. 
 
Because there is a potential for interaction of olaparib and/or AT13387 with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies.  The Principal Investigator should be alerted if 
the patient is taking any agent known to affect or with the potential for drug interactions. 
 
Participants on chronic medications that can be given concomitantly with protocol drugs should 
be maintained on the same dose and dose schedule throughout the study period, as medically 
feasible. The investigator should instruct the participant to notify the study site about any new 
medications he/she takes after the start of the study drug. All supportive measures consistent 
with optimal patient care will be given throughout the study. Bisphosphonates, vitamin D and 
calcium supplementation, topical medications, antiemetics, anti-diarrheal medications, 
anticoagulants and anti-infective agents may be used at the discretion of the treating physician. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted with the following exceptions: 
• Other investigational therapies must not be used while the participant is on the study. 
• Myeloid growth factors are not permitted during any cycle of therapy. 
• Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) other 
than the study treatments must not be given to participants while he/she is on the study. If 
such agents are required for a participant then the participant must be removed from this 
study. 
 
The study team should check a frequently-updated medical reference for a list of drugs to avoid 
or minimize use of.  APPENDIX B – AT13387 PATIENT DRUG INFORMATION handout and 
wallet card should be provided to patients. 
 
Medications that could alter the QTc interval 
 
Participants must also not take medications that could alter the QTc interval which are listed in 
Appendices C and D. Medications listed in Appendix C can be used but with caution. Please note 
that some anti-emetics have a known risk for Torsades de Pointes (TdP) and are prohibited.  
If a participant, after study enrollment, requires the concomitant use of any QT prolonging 
medication with a possible or conditional risk for torsade de pointes then the investigators, at 


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their discretion, may co-administer such medications. Participants receiving such medications 
must be monitored. Refer to Appendix C for a list of QT prolonging medications to be used with 
caution. Please refer also to Appendix D for a list of prohibited QT prolonging medication. 
 
5.5 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
Due to the expiration date of the terminal lot of AT13387 (Onalespib), all participants must 
discontinue AT13387 treatment before May 31, 2020.  Patients may continue olaparib alone after 
May 31, 2020. 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 


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5.6 Duration of Follow Up 
 
Final Visit 
The final visit will occur at the time the participant discontinues study medication. 
Following the Final Visit, participants will be followed for disease progression (if reason 
for treatment discontinuation is other than progression) and survival. Follow-up will be 
reported in 3 month intervals for up to two years after removal from study treatment or 
until death, whichever occurs first. Participants removed from study treatment for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. 
 
Follow Up 
Participants will be followed for disease progression (if reason off treatment is other than 
progression) and survival. Follow-up will be reported in 3 month intervals for up to two 
years after removal from study treatment or until death, whichever occurs first. 
Participants removed from study treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
5.7 Criteria for Removal from Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Completion of all study requirements 
 
The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form (CRF). Alternative care options will be discussed with the participant. 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) until March 31, 2018. CTCAE version 5.0 will be used for toxicity 
assessments beginning April 1, 2018. The CTCAE is identified and located on the CTEP website 
at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. If possible, 
symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
All adverse events experienced by participants will be collected from the time of the first 


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42 
dose of study treatment, through the study and until the final study visit. Participants continuing 
to experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
6.1 Anticipated Toxicities 
 
A list of the adverse events and potential risks associated with the agents administered in 
this study appears below and will determine whether dose delays and modifications will be made 
or whether the event requires expedited reporting in addition to routine reporting. Please refer to 
section 7 for specifics. 
 
6.2 General Toxicity Management, Dose Modifications / Delays 
 
The management of general adverse events not otherwise specified will be as per the table in 
section 6.2.1; for specific toxicities of diarrhea, QTc prolongation, nausea and hematological 
toxicities, please see section 6.3. 
 
Investigators will make the determination of whether a toxicity is related either to olaparib or 
AT13387. If dose reductions are necessary, the agent that will be dose reduced will be the one 
that has toxicities attributed to it. If both drugs are causing drug-related toxicities, both agents 
will be dose reduced one dose level (i.e. immediately lower dose on dose escalation Table, 
Section 5.1). 
 
6.2.1 General Dose Modifications and Management of olaparib and 
AT13387 toxicities 
 
For toxicities that have their own management algorithm as listed in 6.2, please see that specific 
section below. 
 
In this phase 1 study, doses of olaparib and AT13387 will be administered at the same dose level 
throughout a cycle if no toxicities that require a dose reduction occur. 
 
If any individual participant develops a DLT, the study drugs should be held. If the toxicity is not 
resolved within 28 days, the participants will be removed from the study. Participants who 
experience a DLT that resolves to baseline or Grade 1 and whose therapy has been held for less 
than or equal to 28 days may resume therapy at the next lowest dose of drug(s), if necessary. 
 
 
Observation 
Action 
AE resolves within 48 hours with 
supportive care 
Maintain dose level 
Any non-hematologic or 
hematologic AE at least possibly 
related to olaparib or AT13387 
that meets DLT definition 
Hold treatment (both study drugs in Cycle 1, and 
offending drug in cycle 2 and beyond) for up to 28 days 
until toxicity resolves to ≤ grade 1. Treatment will be 
restarted at the next lowest dose levels of drug(s) causing 
the toxicity (section 5.1, dose escalation table). The 


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overall PI of the study should be informed of all dose 
modifications. 
Other grade 2 or 3 non-
hematologic toxicities that last ≤ 7 
days, and at least possibly related 
to either olaparib or AT13387 
Hold treatment (both study drugs in Cycle 1, and 
offending drug in cycle 2 and beyond) for up to 7 days 
until toxicity resolves to ≤ grade 1. Resume at the same 
dose level. 
Other grade 2 or 3 non-
hematologic toxicities that are 
persistent (lasting greater than 7 
days despite maximal supportive 
measures) and/or intolerable and at 
least possibly related to either 
olaparib or AT13387. 
 
and 
 
for grade 3 or 4 events that are 
unlikely/unrelated to either 
AT13387 or olaparib 
Hold treatment (both study drugs in Cycle 1, and 
offending drug in cycle 2 and beyond) for up to 28 days 
until toxicity resolves to ≤ grade 1. Treatment will be 
restarted at the next lowest dose levels of drug(s) causing 
the toxicity (section 5.1, dose escalation table). The 
overall PI of the study should be informed of all dose 
modifications. 
 
6.3 Dose Modifications/Delays and Management for Specific Toxicities 
 
6.3.1 Diarrhea 
 
Management of Diarrhea 
Toxicity Grade 
Action 
Grade 1 
Consider loperamide (4 mg at first onset, followed by 2 mg q 2–4 hours 
until free of diarrhea for 12 hours. The total maximum daily dose of 
loperamide should not exceed 8 tablets (16 mg). Maintain dose level. 
Grade 2 
Loperamide (4 mg at first onset, followed by 2 mg q 2–4 hours until free of 
diarrhea for 12 hours. The total maximum daily dose of loperamide should 
not exceed 8 tablets (16 mg). Omit dose until resolved to ≤ grade 1, then 
restart the same dose. 
Grade 3 and 
Grade 4 
Loperamide as above. Omit dose until resolved to Grade ≤ 1, then reduce 
AT13387 by 1 dose level. 
 
Diarrhea has been reported within the ongoing studies of AT13387. In order to effectively 
manage diarrhea and mitigate the escalation in severity or duration of diarrhea, patient education 
as well as proper management of diarrhea is mandatory. 
The following section outlines the recommended algorithm for management and treatment of 
AT13387-induced diarrhea. 
 
Patient history of diarrhea 
At screening, the patient’s history of diarrhea should be reviewed and the patient should be 
appropriately informed of potential study drug-induced diarrhea and its management: 


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• Review previous medical history of diarrhea within the last 12 months; laxative use, 
colon surgery, abdominal and pelvic irradiation, nocturnal diarrhea, pain, ulcerative 
colitis and other diarrhea-inducing diseases/conditions; 
• Stop all diarrheogenic agents at screening if possible, otherwise exclude from trial; 
• Instruct patients regarding risk of developing diarrhea; 
• Perform baseline clinical/laboratory studies according to the trial protocol (e.g. one could 
rule out carrier state of Salmonella spp., Clostridium difficile, Campylobacter spp., 
Giardia, Entamoeba, Cryptosporidium which can lead to opportunistic infections in 
immunosuppressed patients) 
• Explain the frequency of diarrhea and its relationship to NCI CTCAE grading 
 
First report of diarrhea 
• Obtain history of onset and duration of diarrhea 
• Description of number of stools and stool composition (e.g. watery, blood, mucus in 
stool) 
• Assess patient for fever, abdominal pain, cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, dehydration) 
• Obtain medication profile (i.e., to identify any diarrheogenic agents) and dietary profile 
(i.e., to identify diarrhea-enhancing foods) 
Proactively look for occurrence of diarrhea. If no problems occur, instruct the patient to call 
when a problem does arise. 
 
Management of diarrhea 
General recommendations: 
• Stop all lactose-containing products, alcohol 
• Stop laxatives, bulk fiber (e.g. Metamucil®) and stool softeners (e.g. docusate sodium, 
Colace®) 
• Stop high-osmolar food supplements such as Ensure Plus® and Jevity Plus® (with fiber) 
• Drink 8 to 10 large glasses of clear liquids per day (e.g. water, Pedialyte®, Gatorade®, 
broth) 
• Eat frequent small meals (e.g. bananas, rice, apple sauce, toast) 
It is recommended that patients are provided with loperamide tablets at the start of each cycle. 
Patients should be instructed on the use of loperamide at Cycle 1 in order to manage signs or 
symptoms of diarrhea at home. Patients should be instructed to start oral loperamide (initial 
administration of 4 mg, then 2 mg every 4 hrs (maximum of 16 mg/day) at the first sign of loose 
stool or symptoms of abdominal pain. These instructions should be provided at each cycle and 
the site should ensure that the patient understands the instruction. At the beginning of each cycle, 
each patient should be specifically questioned regarding any experience of diarrhea or diarrhea 
related symptoms. If symptoms were experienced, then the site should question the patient 
regarding the actions taken for these symptoms. 
Intensive management of diarrhea must be instituted at the first sign of abdominal cramping, 
loose stools or overt diarrhea. Note that all concomitant therapies used for treatment of diarrhea 
must be recorded on the Concomitant Medications/Non-drug Therapies eCRF. Loperamide is the 
first-line treatment of diarrhea (any Grade) in this recommended algorithm. Persistent symptoms 
may require the administration of high dose loperamide followed by treatment with second-line 
agents such as opium tincture and octreotide acetate, based on severity and duration of diarrhea 


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and related signs/symptoms. Another first-line treatment for diarrhea is diphenoxylate 
hydrochloride/atropine sulfate. This medication may be used in place of loperamide however it is 
important to note that loperamide and diphenoxylate hydrochloride/atropine sulfate must not be 
used in conjunction with one another due to the risk of developing paralytic ileus. Upon 
treatment with any antidiarrheal agents, the patient’s response to treatment should be observed 
and appropriately documented in the source document and eCRF. 
 
Treatment of diarrhea CTCAE grade 1 or 2 
Diarrhea CTCAE grade 1 or 2 will be treated with standard loperamide (initial at first 
administration 4 mg, then 2 mg every 4 hrs (maximum of 16 mg/day) or after each unformed 
stool). 
 
12-24 hrs later: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide after 12 hrs diarrhea-free interval 
Diarrhea unresolved 
Persisting diarrhea CTCAE grade 1 or 2 will be treated with addition of opium tincture or 
dihydrocodeine tartrate tablets/injections with monitoring of patients condition to rule out 
dehydration, sepsis, ileus) medical check and selected workup if patient does not need 
hospitalization (see section Diarrhea workup and additional test in the particular trial 
protocol). Observe patient for response to antidiarrheal treatment. 
Persisting diarrhea CTCAE grade 3 or 4 may be treated with hospitalization, high dose 
loperamide (initial 4 mg, then 2 mg every 2 hrs) and addition of opium tincture (DTO) or 
dihydrocodeine tartrate tablets/injections, start of IV fluids and antibiotics as needed with 
monitoring of patient’s condition (to rule out dehydration, sepsis, ileus) medical check and 
workup (perform appropriate additional testing). Observe patient for response. 
 
After 12-24 hrs: 
Diarrhea resolved 
• Continue instructions for dietary modification 
• Gradually add solid foods to diet 
• Discontinue loperamide and/or other treatment after 12 hrs diarrhea-free interval 
Diarrhea unresolved 
• If diarrhea still persisting (CTCAE grades 1 and 2), after 2x 24 hrs with high dose 
loperamide and opiates then admit to hospital and employ measures as for CTCAE grade 
3 and 4 until diarrhea resolved. 
• If diarrhea still persisting and progressed to CTCAE grades 3 and 4, employ measures 
described below. 
 
Treatment of diarrhea CTCAE grade 3 or 4 
Severe diarrhea CTCAE grade 3 or 4 may be treated with hospitalization, high dose 
loperamide (initial 4 mg, then 2 mg every 2 hrs and addition of opium tincture or 
dihydrocodeine tartrate tablets/injections, start of IV fluids and antibiotics as needed with 
monitoring of patients condition (to rule out dehydration, sepsis, ileus) medical check and 


NCI Protocol #:10031 
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46 
workup (see section Diarrhea workup and additional test in the particular trial protocol). 
Observe patient for response. 
 
After 12-24 hrs: 
• If diarrhea persisting administer s.c. Sandostatin/octreotide (100-500 mcg tid) 
• Continue IV fluids and antibiotics as needed 
• If diarrhea CTCAE grade 3 or 4 still persists patients should receive opium tincture or 
dihydrocodeine tartrate injections s.c. or i.m. 
• If diarrhea CTCAE grade 3 or 4 is still persisting s.c. Sandostatin/octreotide (500-1000 
mcg TID) should be administered. 
• To control and/or resolve diarrhea, next cycle of treatment should be delayed by 1 or 2 
weeks. Treatment should be continued only when diarrhea resolved. 
 
Diarrhea workup 
Perform appropriate tests: 
Spot stool analysis 
• Collect stool separating it from urine (special containers, analysis immediately, 
exceptionally freeze samples) 
• Blood 
• Fecal leukocytes (Wright's staining and microscopy) or 
• Clostridium difficile toxin 
• Fecal cultures including Salmonella spp., Campylobacter spp., Giardia, Entamoeba, 
Cryptosporidium (which can lead to opportunistic infections in immunosuppressed 
patients), plus Shigella and pathogenic E. coli - enterotoxigenic, enterohemorrhagic etc., 
possibly Aeromonas, Pleisiomonas (if suspected exposure to contaminated water) 
 
Endoscopic examinations 
Endoscopic examinations may be considered only if absolutely necessary. The bowel is likely 
to be fragile with evidence of colitis and thus great care and caution must be exercised in 
undertaking these invasive procedures. 
• Gastroscopy to obtain jejunal fluid - re. bacterial overgrowth for cultures and biopsy of 
proximal jejunum to assess extent of inflammatory jejunitis 
• Sigmoidoscopy - reassessment of colitis 
 
6.3.2 QTc prolongation 
 
Management of QTc prolongation: 
At the screening visit a 12-lead electrocardiogram (ECG), and an echocardiogram or MUGA 
(ECHO/MUGA) will be performed to assess eligibility. A 12 lead ECG will be done in triplicate 
at 2-5 minute intervals as part of screening, cycle 1, day 15, cycle 2, day 15 and day 1 of each 
following cycle. 
 
Management of QTc Prolongation 
Observation 
Action 
QTcF > 500 ms 
First Occurrence:  


NCI Protocol #:10031 
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47 
(> grade 3) or > 
60 ms change 
from baseline on 
at least two 
separate ECGs 
Omit AT13387.  
Perform a repeat ECG within one hour of the first QTc of >500ms or >60 
ms from baseline: if QTcF remains >500ms or >60 ms from baseline, 
repeat ECG as clinically indicated, but at least once a day until QTcF 
returns to <480ms.  
Seek cardiologist input; address electrolytes, calcium and magnesium 
abnormalities; concomitant medication must be reviewed.  
Once QTcF prolongation has resolved, AT13387 may be restarted at one 
lower dose level.  
Second Occurrence:  
Permanently discontinue AT13387 
 
6.3.3 Nausea (olaparib and AT13387) 
 
Nausea 
Management/Next Dose for 
olaparib 
Management/Next Dose for 
AT13387 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Hold until ≤ Grade 1.  Resume at 
same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Hold* until < Grade 2.  Resume at 
one dose level lower, if 
indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
6.3.4 Hematologic Toxicities 
 
Management of Hematologic Toxicities 
 
If: 
any study treatment is interrupted/delayed because of one or more of the following: 
1) ≥ 2 week interruption/delay in study treatment due to CTC grade >2 neutropenia 
2) ≥ 2 week interruption/delay in study treatment due to CTC grade >2 
thrombocytopenia 
3) ≥ 2 week interruption/delay in study treatment due to CTC grade >2 anemia and 
or development of blood transfusion dependence 
Note: Myeloid growth factors are not permitted during any cycle of therapy. 
 
Then: 
Weekly blood counts should be performed during the study treatment interruption/delay. 
If the levels have still not recovered to CTC Grade ≤1 after 4 weeks of dose interruption, 
the participant should be referred to a hematologist for further investigations. Bone marrow 
analysis or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice. 


NCI Protocol #:10031 
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48 
 
For any participants with an episode of grade 3 anemia, the olaparib dose should be reduced to 
the next lowest dose of drug. If grade 3 anemia persists despite one dose reduction, the dose of 
olaparib can be reduced by another dose. A maximum of 2 dose reductions can be made. 
Participants should be transfused as per institutional policies. For participants who receive 
multiple blood transfusions because of anemia that is related to olaparib use, the treating 
investigator can dose reduce olaparib in consultation with the Principal Investigator. 
 
Dose Modification and Management of Hematologic Adverse Events 
Absolute neutrophil count ≥ 
1000/mcL (1.0 x 109/L)  
AND  
Platelets ≥ 75,000/mcL  
AND  
Hemoglobin ≥ 8g/dL 
Maintain dose level 
Absolute neutrophil count < 
1000/mcL (1.0 x 109/L) 
OR  
Platelets < 75,000/mcL  
OR  
Hemoglobin < 8g/dL 
Hold treatment for up to 28 days until absolute 
neutrophil count ≥ 1000/mcL, platelets ≥ 75,000/mcL, 
and hemoglobin ≥ 8 g/dL. Treatment will be 
restarted at one dose level lower for the drug(s) 
causing the toxicity, if the participant has experienced 
a DLT in cycle 1, or for participants in 
cycle 2 and beyond. 
 
Treatment may be restarted at the same dose level for 
participants still in the DLT period and have not 
experienced a DLT, after discussion with the PI. 
 
Patients whose counts have not recovered to absolute 
neutrophil count ≥ 1000/mcL, platelets ≥ 75,000/mcL, 
and hemoglobin ≥ 8 g/dL after 28 days should be 
removed from study. 
 
The overall PI of the study should be informed 
regarding all dose modifications. 
 
 
 
7 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 


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49 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
7.1.1 CAEPRs for olaparib and AT13387 
 
7.1.1.1 CAEPR for olaparib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for further clarification. 
Frequency is provided based on 2073 patients. Below is the CAEPR for Olaparib (AZD2281). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in 
the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
Version 2.4, April 24, 20191 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 2073] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 


NCI Protocol #:10031 
Version Date: February 10, 2020 
 
50 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 2073] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Leukemia secondary to oncology 
chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
 
NOTE: New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other contributing factors/potential 
alternative explanations for the development of the new primary malignancy in all cases, including documented 
BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy including carboplatin, taxanes, 
anthracyclines and other alkylating and DNA damaging agents. Most are not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATION SOC. 


NCI Protocol #:10031 
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51 
 
Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that olaparib (AZD2281) caused the adverse event: 
 
CARDIAC DISORDERS - Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; Flatulence; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intestinal perforation); Ileus; Jejunal 
perforation; Mucositis oral; Pancreatitis; Periodontal disease; Rectal hemorrhage; Small intestinal obstruction; 
Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Gastrointestinal anastomotic 
leak; Injury, poisoning and procedural complications - Other (vena cava injury); Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; GGT increased; Hemoglobin increased; Lipase increased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; 
Generalized muscle weakness; Muscle cramp; Muscle weakness lower limb; Myalgia; Neck pain; Pain in extremity; 
Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (decreased 
glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.1.1.2 CAEPR for AT13387 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
AT13387 (Onalespib, NSC 749712) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 


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52 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 119 patients. Below is the CAEPR for AT13387 (Onalespib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.1, December 28, 20181 
 
 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 5.0 Term) 
[n= 119] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Vision decreased 
 
 Vision decreased (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Flatulence 
 
 Flatulence (Gr 2) 
 
Gastrointestinal hemorrhage2 
 
  
 
Hemorrhoids 
 
 
 Hemorrhoids (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever3 
 
 Fever3 (Gr 2) 
Injection site reaction4 
 
 
 Injection site reaction4 (Gr 2) 
 
Malaise 
 
 Malaise (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
 Infection5 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction3 
 
 Infusion related reaction3 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
CPK increased 
 
 CPK increased (Gr 2) 
 
Electrocardiogram QT corrected 
interval prolonged 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  


NCI Protocol #:10031 
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53 
 
 Adverse Events with Possible  
 Relationship to AT13387 (Onalespib) 
 (CTCAE 5.0 Term) 
[n= 119] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
 Hyponatremia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Hiccups 
 
 Hiccups (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hyperhidrosis3 
 
 Hyperhidrosis3 (Gr 2) 
 
Rash acneiform 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Flushing 
 
 Flushing (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Infusion-related reactions may include, tachycardia/bradycardia, hypotension/hypertension, flushing, chills, fever, 
hyperhidrosis, itching, rigors, and abdominal cramps. 
 
4Injection site reaction may include injection site irritation, injection site pain, injection site inflammation or redness, 
or erythema. 
 
5Infection may include all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Adverse events reported on AT13387 (Onalespib) trials, but for which there is insufficient evidence to suggest 


NCI Protocol #:10031 
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54 
that there was a reasonable possibility that AT13387 (Onalespib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Cardiac disorders - Other (atrioventricular block NOS); Left ventricular systolic 
dysfunction; Palpitations 
EYE DISORDERS - Dry eye; Eye disorders - Other (color distortion); Eye disorders - Other (diplopia); Eye 
disorders - Other (halos); Eye disorders - Other (loss of visual acuity during changes in ambient light levels); Eye 
disorders - Other (tunnel vision); Eye disorders - Other (visual color darkening); Eye disorders - Other (visual 
disturbances); Eye pain; Flashing lights; Floaters; Keratitis; Night blindness; Papilledema; Photophobia; 
Retinopathy 
GASTROINTESTINAL DISORDERS - Colitis; Mucositis oral; Oral dysesthesia; Oral pain; Salivary duct 
inflammation 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills3; Flu like symptoms 
HEPATOBILIARY DISORDERS - Hepatic hemorrhage 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Creatinine 
increased; Ejection fraction decreased; Neutrophil count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypoalbuminemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Generalized 
muscle weakness 
NERVOUS SYSTEM DISORDERS - Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Palmar-plantar erythrodysesthesia syndrome; Pruritus; 
Skin hyperpigmentation 
VASCULAR DISORDERS - Hypertension3 
 
 
Note: AT13387 (Onalespib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 


NCI Protocol #:10031 
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55 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
 
 
7.3 Expedited Adverse Event Reporting 
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.2). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.1 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.2 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
under the system organ class (SOC) “General disorders and administration site 
conditions.” Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
 


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56 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 


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57 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8 PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 CTEP IND Agent(s)  
 
8.1.1 CTEP IND AT13387 (NSC 749712)  
 
Chemical Name:    (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3- 
dihydro-isoindol-2-yl]-methanone, L-lactic acid salt 
 
Other Name: 
AT13387AU, onalespib 
 


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58 
Classification:   
   Heat shock protein 90 (HSP90) inhibitor 
 
Molecular Formula:   C24H31N3O3.C3H6O3  
 
M.W.:  499.61 
 
Mode of Action:  AT13387 is a synthetic non-ansamycin small molecule that inhibits heat shock 
protein 90 (HSP90.  HSP90 seems to affect multiple aberrant signaling pathways and therefore 
may be of clinical benefit in several cancer treatments.  
  
How Supplied:  AT13387 is supplied by Astex Pharmaceuticals Inc. and distributed by CTEP, 
NCI as a 265 mg free base equivalent (L-lactic acid salt) vial, containing white to off-white 
lyophilized powder.  The agent is formulated in pH 5.0 (red cap). 
 
Preparation:  Reconstitute the 265 mg lyophilized powder with 10 mL of Sterile Water for 
Injection (SWFI) resulting in 25.7 mg/mL concentration (10.3 mL total volume).  A sticky mass 
will be formed. Vigorously shake the vial. Agitate until the contents are fully dissolved (about 5 
minutes).  Leave the diluted vial at ambient temperature for 15-30 minutes to allow any foam to 
dissipate. If not used immediately, store the reconstituted vial(s) at 20 to 80 C not to exceed 8 
hours. 
Withdraw the calculated dose of AT13387 and further dilute it in 250 mL of D5W or 0.9% NS. 
The Prepared IV solution is compatible in PVC or non-PVC infusion bags.   
 
Store the prepared IV solution refrigerated at 20 to 80 C not to exceed 8 hours if not used 
immediately.  When removed from the refrigerator, allows the prepared IV solution to sit at room 
temperature between 15 to 30 minutes before administering to patients. The prepared IV solution 
must be used within 24 hours -i.e., from the time the drug vial is diluted to the time the IV 
administration is complete.  Protection from light during the infusion period is not required. 
 
Storage:     Store the intact vials at 150 to 25ºC (59 to 77ºF).  Protect from light. 
 
If a storage temperature excursion is identified, promptly return AT13387 to 150 to 25ºC (59 to 
77ºF) and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:     Shelf life surveillance of the intact vials is ongoing.    
 
Route of Administration:     Intravenous 
 
Method of Administration:  Infuse over 1 hour through a central line or a well-defined peripheral 
vein (Note: an in-line filter is NOT required).  If use a peripheral line, be sure to aspirate venous 
blood prior to starting the infusion.  Check the infusion site every 15 minutes. Change infusion site 
should evidence of swelling or discoloration is observed.   
 
Potential Drug Interactions:   AT13387 is a substrate of UGT with a relatively low affinity for 
UGT isoforms. In vitro data demonstrate that AT13387 is a weak inhibitor of UGT1A1, UGT1A3 
and UGT1A9.   AT13387 is also a weak inhibitor of CYP1A2, -3A4, -2D6, -2C9 and -2C19.  


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59 
AT13387 appears to metabolize via the glucuronidation, sulphation and N-oxidation. 
 
Pre-clinical studies suggest that AT13387 is a substrate of P-gp, the efflux ratios was above 2 
(ranging from 3.4 to 4.6); a moderate inhibitor of BCRP (35.9% +/- 2%, p=0.0001) and P-gp 
(31.3% +/- 1.2%, p= 0.0009), and a strong inhibitor of MATE1 (94.6% +/- 0.2%, p=0.0001) and 
MATE2-K (91.2% +/- 1.2%, p= 0.0002). 
 
Patient Care Implications:  There are no genotoxicity, carcinogenicity, developmental and 
reproductive studies conducted with AT13387.  Women of childbearing potential should not 
become pregnant or breastfeed and men should not father a child during the study.  All subjects 
must use acceptable contraceptive measures during the treatment of AT13387 and 3 months after 
the last dose of the investigational drug. 
Systemic infusion reactions (e.g., vomiting, itching skin, or swelling), slow the infusion and/or 
administer NS or D5W through a “Y” connector in parallel to AT13387 IV infusion.  Pre-
medication (e.g., dexamethasone, H-1 and H-2 antagonist) may be given before subsequent 
infusions and/or administer additional volume of 500 mL over 1 hour if medically appropriate. 
Avoid extravasation. For local irritation, apply cold compress or topical pain medication.  
 
Availability 
 
AT13387 is an investigational agent supplied to investigators by the Division of Cancer Treatment 
and Diagnosis (DCTD), NCI. AT13387 is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
AT13387 clinical drug development program is completed.  The current clinical supply is 
expiring on May 31, 2020; thus, all patients must be off treatment by May 31, 2020. 
 
8.1.2 CTEP IND olaparib (NSC 747856) 
 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula:  C24H23FN4O3 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient 
in the homologous recombination DNA repair pathway (example, BRCA mutants), 
inhibition of PARP by olaparib causes accumulation of DNA double-strand breaks and 


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60 
genomic instability. Olaparib may also enhance the effects of DNA damage caused by 
ionizing radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, film-
coated tablets in 25 mg, 100 mg and 150 mg strengths.  
 
• 25 mg tablets are 6 mm round-shaped 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each bottle contains 32 tablets with desiccant.  
 
Tablet core components include active drug substance, copovidone, colloidal silicon 
dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl 
methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, 
iron oxide yellow and iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F). Sites are not permitted to re-package 
tablets. Once the bottle is opened, olaparib tablets must be used within 3 months of the 
opening date; unused tablets should be discarded. Instruct patients not to open a bottle 
until they are ready to use it. 
 
Stability:  Shelf-life studies are ongoing. 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to 
room temperature and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Route and Method of Administration:  Tablets are taken by mouth and can be taken with a light 
meal/snack if needed to reduce stomach irritation. 
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 
strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document 
or study investigator prior to making any dose adjustments related to potential drug-drug 
interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib.   
 


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61 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those with 
narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 
caution when given concomitantly with olaparib. 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects embryofetal 
survival and development. Therefore, women of child-bearing potential and their partners 
should agree to use two (2) highly effective forms of contraception throughout study 
participation and for at least one (1) month after the last dose of olaparib.  Male study 
participants should avoid fathering a child or donating sperm during the study and for three 
(3) months after the last dose of olaparib. The study investigator should discuss the most 
appropriate forms of highly effective contraceptive methods for each patient.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and 
dizziness, patients should be advised to use caution while driving or using machinery. 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where the 
patient is to be treated.  PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained).  The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA Form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure 
Form (FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead investigator at that institution. 
 
A starter supply is not allowed.  A confirmation of patient enrollment is needed in 
the “Comments” field in OAOP for the initial drug shipment. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 


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62 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   
 
8.1.3.2 
Agent Inventory Records  
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol.  
 
8.1.3.3 
Investigator Brochure Availability 
 
The current versions of the IBs for PMB-supplied agents will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account status 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
coordinator via email. 
 
8.1.3.4 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
 
 
9 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Based on the results of our preclinical work, we hypothesize that the HSP90 inhibitor AT13387 
will enhance the anticancer effects of the PARPi olaparib at tolerable doses in patients with 
advanced solid tumors.   
 
During cycle 0, olaparib will be administered alone once daily for 1 week (D1-7).  Then in cycle 
1 and afterwards, olaparib will continue to be administered twice daily and AT13387 will be 


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63 
administered for 2 consecutive days every week for 3 weeks of a 4 week cycle, i.e. on Days 1, 2, 
8, 9, 15 and 16 of a 28 day cycle. Given that our hypothesis is that AT13387 sensitizes to 
olaparib by inhibiting HR, by administering olaparib alone for cycle 0 only, we can test this 
hypothesis as a “proof of mechanism” for the combination of AT13387 and olaparib. 
Specifically, we expect that there will be induction of BRCA1 and RAD51 foci after 
administration of olaparib alone and reduced formation of these foci and downregulation of 
expression of HR pathway genes after the combination of AT13387 and olaparib.  
 
Three biopsies, one pretreatment, one after olaparib alone and one after one of the combinations 
of olaparib/AT13387 will be voluntary, but encouraged in the expansion and dose escalation 
cohorts.  
 
9.1 Exploratory/Ancillary Correlative Studies 
 
 
 
9.1.1  Collection, Shipping and Sites performing exploratory assays. 
 
As a part of the eligibility criteria, only patients with available archival FFPE tissue (either one 
paraffin embedded tissue block OR 10 5-micron unstained slides from the block on regular [non-
plus] slides and 1 H&E slide) will be accrued onto this study. This archival FFPE tissue 
specimen will be analyzed with the aforementioned assays (section 9.1). 
 
On study biopsies collection: FFPE core biopsies (neutral buffered formalin) will be collected 
per institutional guidelines. 
 
FFPE block or 10 unstained slides and on-study biopsies will be batch shipped to Dr. Panagiotis 
Konstantinopoulos (address below):  
Jennifer Curtis 
Dana-Farber Cancer Institute  
450 Brookline Ave, Dana 116  
Boston, MA 02215  
Phone: 617-582-7183  
Email: jennifer_curtis@dfci.harvard.edu 
 
 
9.2 Clinical Pharmacology: 
 
The pharmacokinetic study has been designed to assess the effect of olanespib on the steady state 
pharmacokinetics of olaparib and if the pharmacokinetics of olanespib is affected by the 
concurrent administration of olaparib.  Pharmacokinetic sampling will be performed in all 
patients enrolled in the dose escalation and expansion cohorts to provide data that may be 
informative for dose escalation decisions and correlation analysis with clinical and 
pharmacodynamic data.  Pharmacokinetic sampling will be performed to define the plasma 
concentration-time profile of olaparib over the dosing interval for the day 7 dose when given 
alone in cycle 0.  Pharmacokinetic samples will also be collected over a 24 h interval on days 1 


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64 
and 15 of cycle 1 to define the plasma profiles for olaparib and olanespib.   
 
The sampling schedule has been devised to accommodate treatment on an outpatient basis.  
Patients will be instructed to take the two daily doses of olaparib at the same time every day during 
the pharmacokinetic study.  The morning dose of olaparib should be taken at a time that will allow 
the patient to arrive at the clinical to obtain pharmacokinetic samples before dosing and to remain 
for an additional 8 hours.  The second daily dose of olaparib should be taken approximately 12 
hours after the morning dose.  It is very important that the patient is aware that the morning dose 
of olaparib must not be taken before arriving at the clinic on cycle 0 day 7, cycle 1 day 1, and 
cycle 1 day 15.  The olanespib i.v. infusion should be started at the same time that the patient 
takes the olaparib dose on days 1 and 15 of cycle 1.  The first set of blood samples (3 mL) on 
cycle 0 day 7 will be obtained at the indicated times according to the PK Sample Collection 
Time Points table below.  The second and third sets of blood samples (6 mL) on cycle 1 day 1 
and cycle 1 day 15 will be obtained at the same time points as indicated by the PK Sample 
Collection Time Points table below, with one additional sample collected 30 min after 
completing the 1 h IV infusion of olanespib.  Procedures for PK sample collection, processing, 
storage, and shipment is provided in Appendix G. 
 
 
 
PK Sampling Schedule 
Visit 
Collection Time 
Sample No. 
Cycle 0 Day 1 
Pre-dose (0-5 min prior to first 
olaparib dose) 
PK-00 
Cycle 0 Day 7 
Pre-dose (0-5 min prior to morning 
olaparib dose) 
PK-01 
Cycle 0 Day 7 
0.5 h ± 5 min post-dose 
PK-02 
Cycle 0 Day 7 
1.0 h ± 5 min post-dose 
PK-03 
Cycle 0 Day 7 
1.5 h ± 5 min post-dose 
PK-04 
Cycle 0 Day 7 
2.0 h ± 5 min post-dose 
PK-05 
Cycle 0 Day 7 
3.0 h ± 5 min post-dose 
PK-06 
Cycle 0 Day 7 
4.0 h ± 10 min post-dose 
PK-07 
Cycle 0 Day 7 
6.0 h ± 10 min post-dose 
PK-08 
Cycle 0 Day 7 
8.0 h ± 10 min post-dose 
PK-09 
Cycle 1 Day 1 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-10 
Cycle 1 Day 1 
0.5 h ± 5 min post-dose 
PK-11 
Cycle 1 Day 1 
1.0 h ± 5 min post-dose 
PK-12 
Cycle 1 Day 1 
1.5 h ± 5 min post-dose 
PK-13 
Cycle 1 Day 1 
2.0 h ± 5 min post-dose 
PK-14 
Cycle 1 Day 1 
3.0 h ± 5 min post-dose 
PK-15 
Cycle 1 Day 1 
4.0 h ± 10 min post-dose 
PK-16 
Cycle 1 Day 1 
6.0 h ± 10 min post-dose 
PK-17 
Cycle 1 Day 1 
8.0 h ± 10 min post-dose 
PK-18 
Cycle 1 Day 2 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-19 


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65 
Cycle 1 Day 15 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-20 
Cycle 1 Day 15 
0.5 h ± 5 min post-dose 
PK-21 
Cycle 1 Day 15 
1.0 h ± 5 min post-dose 
PK-22 
Cycle 1 Day 15 
1.5 h ± 5 min post-dose 
PK-23 
Cycle 1 Day 15 
2.0 h ± 5 min post-dose 
PK-24 
Cycle 1 Day 15 
3.0 h ± 5 min post-dose 
PK-25 
Cycle 1 Day 15 
4.0 h ± 10 min post-dose 
PK-26 
Cycle 1 Day 15 
6.0 h ± 10 min post-dose 
PK-27 
Cycle 1 Day 15 
8.0 h ± 10 min post-dose 
PK-28 
Cycle 1 Day 16 
Pre-dose (0-5 min prior to study 
medication dosing) 
PK-29 


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66 
 
10 STUDY CALENDAR 
 
In pre-study/screen the baseline eye exam, physical examination, medical history, concomitant 
medications recorded, ECOG PS, complete blood count with differential and platelets, and 
clinical chemistry should be done ≤14 days prior to initiation of treatment. However, if these 
initial examinations are obtained within 3 days prior to the initiation of treatment they do not 
have to be repeated. Scans to document evaluable disease (i.e., tumor measurement) should be 
performed ≤ 28 days prior to initiation of treatment and should be performed as close to the start 
of treatment as possible. 
 
Assessments must be performed prior to administration of any study agent.  
 
No treatment window will be allowed for Cycle 0 and Cycle 1, however, Cycle 1 day 1 
assessments can be done on day 7 of Cycle 0. A +/- 3 day window will be allowed for Cycle 2 
Day 1 and subsequent treatment cycles Day 1. If Day 1 is adjusted, days 8 and 15 will be re-
adjusted accordingly, A +/- 1 day window will be allowed for Day 8 and 15 of Cycle 2 and 
subsequent treatment cycles.   
 
 
Screen/ 
Baseline 
Cycle 0 
(1 week) 
Cycle 1 
(4 Week Duration) 
Cycle 2 
and subsequent cycles 
(4 Week Duration)j 
Off 
Treatmenth 
Follow-
up i 
Pre- 
Study/Screen 
Day 1 
Day 1 
Day 8 
Day 15 
Day 
22 
Day 1 
(+/- 3 
days) 
Day 8 
(+/- 1 
day) 
 
Day 
15(+/- 1 
day) 
 
AT13387 
 
 
Days 
1,2 
Days 8,9 
Days 
15,16 
 
Day 1,2 
Day 8,9 
Day 15, 
16 
 
 
olaparib 
 
Days 1-7 
Days 1-28 
Days 1-28 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Archival FFPE sample 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Vital signs a 
X 
X 
Days1,
2 
Days 8,9 
Days 
15,16 
X 
Day 1, 2 
Day 8, 9 
Day 15, 
16 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Performance status 
X 
 
X 
 
 
 
X 
 
 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation c 
(PT,PTT,INR) 
X 
 
 
 
 
 
 
 
 
 
 
ECG (as indicated) d 
X 
 
 
 
X 
 
 
 
Xd 
 
 
Adverse event 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 


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67 
evaluation 
Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Eye Exam e 
X 
If ocular toxicity has occurred.  
 
B-HCG 
X 
X 
X 
 
 
 
X 
 
 
 
 
CT or MRI (chest, 
abdomen, pelvis) and 
Tumor Assessments 
(RECIST 1.1) f 
X 
CT scan and tumor assessment should be performed before cycle 3 and every 2 cycles 
(± 7 days) thereafter.  
X 
 
Optional Tumor 
Biopsies g 
X 
X (Day 5 
or 6 or 7) 
 
 
X (+/- 5 
days) 
 
 
 
 
 
 
PK  
 
X 
X 
 
X 
 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
 
a. 
Vital signs will include resting heart rate, blood pressure, temperature and weight, and at the screening visit will include 
height. After Screening, height will not be measured. Vital signs and weight will be obtained prior to chemotherapy 
administration. Dosing of AT13387 will be based on the weight obtained on days 1, 8 and 15 of each cycle, and this weight 
can be used for dosing on the following day, that is, days 2, 9 and 16, respectively.  
b. 
Clinical chemistry will include measurements of glucose, BUN, creatinine, sodium, magnesium, potassium, chloride, 
calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, and albumin. 
c. 
Coagulation studies will be performed at baseline only (PT or INR with PTT); they will be repeated beginning of every 
cycle if patient on coumadin. 
d. 
ECGs will be performed in triplicate at 2-5 minute intervals. All ECGs after Cycle 2 will be performed on Day 1 of the 
cycle.  
e. 
More frequent eye exams can be performed as clinically indicated. Pre-Study evaluation must include an ophthalmologic 
exam by an opthalmologist (not optometrist) and should minimally include visual acuity testing, slit lamp examination, and 
fundoscopic examination. Follow up eye-exams will only be performed if subjects develop/report any visual impairment.  
Visual impairment may include peripheral flashes (photopsia), blurred or double vision, floaters, color distortion and 
dimness, difficulties with light/dark accommodation, tunnel vision or other field defects, halos, apparent movement of 
stationary objects, and complex disturbances. Follow up eye-exams will minimally include visual acuity testing, slit lamp 
examination, and fundoscopic examination; additional testing will be based on symptoms, what is observed and 
ophthalmologist recommendations.  
f. 
CT scans of the chest and abdomen and pelvis are required at baseline and every 2 cycles (± 7 days). The same method of 
assessment and the same technique must be used to characterize each identified and reported lesion at baseline and during 
subsequent imaging procedures. Patients continuing study treatment for a minimum of 1 year may have the tumor imaging 
assessments expanded to every 4 cycles (12 weeks [±7 days]). Patients with unacceptable toxicity should be discontinued 
from the study; patients with SD or response to therapy will continue treatment. Patients without evidence of undue toxicity 
may continue treatment with study drugs until disease progression occurs as long as they are achieving clinical benefit and 
desire to continue therapy. Patients with progressive disease per RECIST 1.1 will be discontinued from the study. 
g. 
Refer to section 9.1 for details.  
h. 
The End of Study Treatment Visit will be performed at the 30 day follow-up visit. Reassessments for toxicity, disease 
progression, and survival will be performed 30 days from last treatment dose. 
i. 
Please see section 5.6 for specifics on Follow-up. 
j. 
Patients who continue on olaparib monotherapy will have concomitant meds, physical exam, vital signs, CBC w/diff, 
platelets, serum chemistry, and adverse event evaluation on day 1 only of each cycle following AT13387 discontinuation.  
 
 
11 MEASUREMENT OF EFFECT 
 
Although the clinical benefit of Olaparib and AT13387 have not yet been established, the intent 
of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor response and symptom relief in addition to safety and tolerability.  
Patients with measurable disease will be assessed by standard criteria.  For the purposes of this 
study, patients should be re-evaluated every 8 or 9 weeks. In addition to a baseline scan, 


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confirmatory scans will also be obtained every 8 or 9 weeks following initial documentation of 
an objective response. 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 weeks (not less than 4) 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with olaparib and/or AT13387. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 


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69 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 


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71 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 


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may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 


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73 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    A confirmation scan will be required for CR and PR responses. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  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 the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


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74 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
 
For patients enrolled at DF/HCC sites, tumor metrics central imaging will serve as the 
reading for all radiographic imaging for this study. For patients enrolled at non-DF/HCC 
sites, assessment of response will be performed by the investigators in each site 
participating in the study. 
  
11.2 
Antitumor Effect – Hematologic Tumors 
 
Not Applicable. 
 
11.3 
Other Response Parameters 
 
Not Applicable.  
 
 
12 STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 


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75 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Read-Only, CRA, Lab Admin, SLA or Site Investigator) 
on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold 
the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 


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76 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-
based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  and 
CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS will 
utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) 


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77 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
12.3 
CTEP Multicenter Guidelines 
 
Not Applicable. 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 


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78 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 


NCI Protocol #:10031 
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79 
proprietary information. 
 
12.5 
 Genomic Data Sharing Plan 
 
Not applicable 
 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 
 Study Design/Endpoints 
 
The phase I component of this study will employ a 3+3 design, escalating if 0/3 or 1/6 
participants have a DLT during Cycles 0 and 1, at the discretion of the Principal Investigator.   
 
The planned dose escalation and dose levels of olaparib and AT13387 for this study are outlined 
in Section 5.1. Additional dose levels or schedules may be tested based on ongoing phase I 
results and/or preclinical testing. 
 
Safety: 
Dose limiting toxicity (DLT) refers to toxicities experienced during cycles 0 and 1 of 
treatment. A DLT will be defined using the criteria in Section 5.2. 
Probabilities of escalation in a 3+3 design are tabulated below for a series of assumed true 
toxicity rates (based on a binomial distribution): 
 
True 
Toxicity 
Rate 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.65 
0.7 
0.8 
0.9 
Probability 
of 
Escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.053 
0.032 
0.009 
0.001 
    
At least 6 patients will be treated at MTD, and no more than 1 patient should experience a DLT 
at the MTD level.  Based on the exact binomial distribution, we would be unlikely to escalate the 
dose level (the probability is 0.053) if the true toxicity was 65% or greater. 
 
To evaluate the properties of the 3+3 (x+y) escalation/de-escalation design, a simulation study 
was performed. In the simulation study, each dose-level was considered to be the ‘true MTD’, 
defined using a two-parameter logistic model for the dose-toxicity relationship of each agent. 
Using an intercept of 0.183 and slope of 1 on the log2-scale for each agent, the probability of a 
DLT at the true MTD of the combination would be the common assumption of 33.3% and odds 
would double with a doubling of either agent.  
 
Dose 
level 
Olaparib 
dose 
AT13387 
dose 
Probability or reaching 
True 
MTB 
No 
MTB 
Below 
Above 
* 
-4 
50 
10 
0.459 
0.408 
n/a 
0.133 


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80 
-3 
100 
10 
0.475 
0.099 
0.29 
0.136 
-2 
50 
20 
0.439 
0.098 
0.343 
0.12 
-1 
100 
20 
0.477 
0 
0.418 
0.105 
0 
200 
20 
0.487 
0 
0.441 
0.072 
1 
200 
40 
0.296 
0 
0.587 
0.117 
2 
300 
40 
0.329 
0 
0.611 
0.06 
3 
300 
80 
0.313 
0 
0.564 
0.123 
4 
300 
120 
0.2 
0 
0.664 
0.136 
5 
300 
160 
0.203 
0 
0.797 
n/a 
2a 
200 
80 
0.187 
0 
0.538 
0.275 
2b 
200 
120 
0.116 
0 
0.557 
0.327 
2c 
200 
160 
0.11 
0 
0.656 
0.234 
-1a 
100 
40 
0.35 
0 
0.536 
0.114 
-1b 
100 
80 
0.199 
0 
0.598 
0.203 
-1c 
100 
120 
0.141 
0 
0.634 
0.225 
-1d 
100 
160 
0.169 
0 
0.727 
0.104 
-2a 
50 
40 
0.342 
0.042 
0.479 
0.137 
-2b 
50 
80 
0.224 
0.039 
0.546 
0.191 
-2c 
50 
120 
0.139 
0.03 
0.65 
0.181 
-2d 
50 
160 
0.15 
0.029 
0.72 
0.101 
 
* In the simulation study, dose levels are defined as being above the MTD if the probability of a 
DLT under the bivariable logistic model is greater than 33.3%.  
 
13.2 
 Sample Size/Accrual Rate 
 
Depending on the number of dose levels, it is anticipated that between 15 and 30 patients will be 
enrolled to the dose escalation portion of this study and an additional 20 patients with either 
TNBC or ovarian cancer will be enrolled in the dose expansion cohort. With 20 patients treated 
at the MTD, the probability of observing at least one serious toxicity event is 0.88 if the true 
toxicity rate is 10% and 0.64 if the true toxicity rate is as low as 5%. With 20 participants, the 
maximum width to a binomial exact 90% confidence interval is 0.456. 
 
We anticipate that between 2-3 patients will be enrolled per month to this study. If the RP2D is 
at the highest dose level, we would expect a sample size of approximately 40 subjects. Therefore, 
recruitment for the current study will be done in approximately 12-18 months.  
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 


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81 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
2 
0 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
3 
1 
1 
0 
5 
White 
28 
3 
2 
0 
33 
More Than One Race 
0 
0 
0 
0 
0 
Total 
33 
4 
3 
0 
40 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-
0001/0002 
 
13.3 
 Stratification Factors 
 
There will be no stratification factors for this study.  One expanded MTD cohort of epithelial 
ovarian, fallopian or primary peritoneal or triple negative breast cancer (TNBC) patients will be 
enrolled with one of the schedules, for confirmation of safety, PK and PD. A total of 20 patients 
will be enrolled in this expansion cohort.  
 
13.4 
Interim Analysis 
 
For the dose expansion cohort, a continuous monitoring plan will be conducted following the 
method of Ivanova, et al36 with Pocock-style boundaries for early stopping. Required input 
parameters are the proportion which represents a maximum-tolerated level of toxicity, θ,  and the 
probability of early stopping , φ, if θ is true toxicity rate.  
 
We specified θ = 0.333 according to the MTD corresponding to the 3+3 design, and allow for a φ 
= 0.2 chance of early stopping. Boundaries are listed in the table below. If the number of subjects 
with toxicity reaches the specified limits, accrual of additional patients to this study will stop 
until satisfactory changes to the RP2D have been made to ensure subject safety 
 
Number 
Enrolled 
1-2 
3 
4-5 
6-8 
9-10 
11-12 
13-15 
16-17 
18-20 


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82 
Number with an 
Adverse Event 
- 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
The probabilities of stopping the trial early are presented below for a range of true adverse event 
rates: 
True rate 
Probability of  
stopping early 
0.333 
0.19 
0.4 
0.37 
0.5 
0.69 
0.6 
0.91 
0.7 
0.99 
0.8 
>0.99 
 
13.5 
Analysis of Secondary Endpoints 
 
 
13.6 
 Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.6.2 Evaluation of response 
 
All participants included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible. Each participant 
should be assigned one of the following categories: 
1) complete response, 
2) partial response, 
3) stable disease, 
4) progressive disease, 
5) early death from malignant disease, 
6) early death from toxicity, 
7) early death because of other cause, or 
9) unknown (not assessable, insufficient data). 
By arbitrary convention, category 9 usually designates the "unknown" status of any type 
of data in a clinical database. 
All of the participants who met the eligibility criteria and who receive at least one dose of 
study drug will be included in the main analysis of the response rate. 
 
 


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83 
 
REFERENCES 
 
 
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Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor 
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Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-
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Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-
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Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with 
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10. 
Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic 
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Liu JF, Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: current 
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Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib 
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TCGA. Integrated genomic analyses of ovarian carcinoma. Nature. Jun 30 
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14. 
Tan DS, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a 
case-control study describing the clinical features and outcome of patients with epithelial 
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15. 
Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev 
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16. 
Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Gene expression profile of 


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BRCAness that correlates with responsiveness to chemotherapy and with outcome in 
patients with epithelial ovarian cancer. J Clin Oncol. Aug 1 2010;28(22):3555-3561. 
17. 
Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity 
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Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective 
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19. 
Watkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of 
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Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K inhibition impairs BRCA1/2 
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Johnson N, Li YC, Walton ZE, et al. Compromised CDK1 activity sensitizes BRCA-
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23. 
Choi YE, Battelli C, Watson J, et al. Sublethal concentrations of 17-AAG suppress 
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Johnson N, Johnson SF, Yao W, et al. Stabilization of mutant BRCA1 protein confers 
PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. Oct 15 
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Bedin M, Catelli MG, Cabanie L, Gaben AM, Mester J. Indirect participation of Hsp90 in 
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26. 
Bedin M, Gaben AM, Saucier C, Mester J. Geldanamycin, an inhibitor of the chaperone 
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Cannistra SA. Cancer of the ovary. N Engl J Med. Dec 9 2004;351(24):2519-2529. 
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Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 
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29. 
McGuire, W.P., W.J. Hoskins, M.F. Brady, et al.  (1996)  Cyclophosphamide and 
cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV 
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DeSantis C, Siegel R, Bandi P et al.  Breast cancer statistics 2011.  CA Cancer Journal 
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Hudis CA, Giani L.  Triple-negative breast cancer: an unmet medical need.  Oncologist 
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Verhoog LC, Brekelmans CT, Seynaeve C et al.  Survival and tumor characteristics of 
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Perou CM, Sorlie T, Eisen MB et al.  Molecular portraits of human breast tumors.  Nature 
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Silver DP, Richardson AL, Eklund AC et al.  Efficacy of neoadjuvant cisplatin in triple 
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35.  
Wang ZC, Birkbak NJ, Culhane A, Drapkin RI, Fatima A, Tian R, Schwede M, Alsop K, 
Daniels KE, Piao H, Liu J, Etemadmoghadam D, Miron A, Salvesen HB, Mitchell G, 
Defazio A, Quackenbush J, Berkowitz RS, Iglehart JD, Bowtell DD, Matulonis UA.  
Profiles of genomic instability in high-grade serous ovarian cancer predict treatment 
outcome.   Clin Cancer Res.18(20):5806-5815, 2012 
36. 
Ivanova, A., B.F. Qaqish, and M.J. Schell, Continuous toxicity monitoring in phase II 
trials in oncology. Biometrics, 2005. 61(2): p. 540-5. 
 
 


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86 
 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


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87 
 
APPENDIX B: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, olaparib (AZD2281).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Olaparib interacts with certain specific enzymes in the liver and certain transport proteins that 
help move drugs in and out of cells. 
 
• The enzymes in question are CYP 3A4/5, 1A2, 2B6, 2C9, 2C19 and UGT1A1. Olaparib is 
cleared by CYP3A4/5 and is affected by strong and moderate inhibitors and inducers of 
CYP3A4/5. Olaparib inhibits CYP3A4 and UGT1A1enzymes and may increase levels of 
other drugs that are cleared by these enzymes. Olaparib induces CYP 1A2, 2B6 and 3A4 
enzymes and has the possibility of inducing CYP 2C9, 2C19 enzymes that may result in 
decreased levels of other drugs that are cleared by these enzymes.   
• The transport proteins in question are P-glycoprotein (P-gp), organic anion-transporting 
polypeptides (OATP1B1 and OAT3), organic cation transporters (OCT1 and OCT2), 
multi-drug and toxin extrusion proteins (MATE1 and MATE2K) and breast cancer 
resistance protein (BCRP). Olaparib requires P-gp to move in and out of cells and 
concomitant administration of strong P-gp inhibitors and inducers should be avoided. 
Olaparib inhibits P-gp, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K 
transporters and has the possibility of inducing P-gp and that may affect the transport of 
other drugs that depend on these proteins to move in and out of cells. Use caution when 
taking substrates of these transporters, such as statins. 
 
 
 
 
 
 
 
 
  
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Olaparib may interact with many drugs which can cause side effects. Because of this, it is very 
important to tell your study doctors about all of your medicines before you enroll on this clinical 
trial.  It is also very important to tell them if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), 
or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles 
or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  


NCI Protocol #:10031 
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88 
 
These are the things that you (the patient) and your prescribers need to know: 
 
Olaparib must be used very carefully with other medicines that need certain liver enzymes and 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP3A4/5 
and P-gp.” Olaparib inhibits enzymes “CYP3A4, UGT1A1, P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP.” Olaparib possibly induces “CYP 1A2, 2B6, 3A4, 2C9, 
2C19 and P-gp.” These characteristics may change how other medicine works in your body. 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
• Avoid ingesting grapefruit, grapefruit juice and Seville oranges while taking olaparib. 
• You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
• Your study doctor’s name is __________________________________________                
  
   and he or she can be contacted at _____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
olaparib (AZD2281).  This clinical trial is sponsored by the NCI.  
Olaparib interacts with drugs that are processed by your liver, or use 
certain transport proteins in your body.  Because of this, it is very 
important to: 
 Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 Olaparib interacts with liver enzymes, CYP3A4/5, 1A2, 2B6, 2C9, 
2C19, UGT1A1, and transport proteins, P-gp, OATP1B1, OCT1, 
OCT2, OAT3, MATE1, MATE2K and BCRP.    
 
 Olaparib must be used very carefully with other medicines that 
interact with these enzymes and proteins.  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered ““strong or moderate 
inducers/inhibitors of CYP3A4/5 and P-gp.” Olaparib inhibits 
“CYP 3A4, UGT1A1 and transport proteins P-gp, OATP1B1, 
OCT1, OCT2, OAT3, MATE1, MATE2K and BCRP and induces 
CYP 1A2, 2B6, 3A4, 2C9, 2C19 and transport protein P-gp.” It 
may change how other medicine works in your body. 
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


NCI Protocol #:10031 
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89 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, AT13387 (onalespib).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that your prescriber needs to know: 
  
Pre-clinical data show that AT13387 (onalespib) interacts with certain specific enzymes in the 
liver and certain transport proteins that help move drugs in and out of cells.  
 
The enzymes in question are UGT1A1, UGT1A3, UGT1A9 and CYP 1A2, 3A4, 2D6, 2C9, and 
2C19.   
 
• AT13387 (onalespib) is metabolized by UGT1A1 and UGT1A3 and may be affected by 
other drugs that inhibit or induce these enzymes.   
• AT13387 (onalespib) is a “weak” inhibitor of UGT1A1, UGT1A3, UGT1A9 and CYP 
1A2, 3A4, 2D6, 2C9, and 2C19 and may affect the metabolism of other drugs. 
• The proteins in questions are P-gp, BCRP, MATE-1, and MATE2-K.  AT13387 
(onalespib) is a P-gp substrate and may be affected by other drugs that inhibit/induce      
P-gp.  AT13387 is a “moderate inhibitor” of BCRP and P-gp, and a “strong inhibitor” of 
MATE1 and MATE2-K and may affect transport of other drugs in and out of cells.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
AT13387 (onalespib) may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  
 
These are the things that you (the patient) and your prescribers need to know:  
AT13387 (onalespib) must be used very carefully with other medicines that need certain liver 
enzymes or transport proteins to be effective or to be cleared from your body. Before you enroll 
onto the clinical trial, your study doctor will work with your regular health care providers to 
review any medicines and herbal supplements that are considered “strong/moderate 
inhibitor/inducer or substrate of UGT1A1, UGT1A3, BCRP, P-gp, MATE1 and MATE2-K, 


NCI Protocol #:10031 
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90 
CYP1A2, -3A4, -2D6, -2C9, and -2C19.”  
•  Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
•  Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.   
• Your study doctor’s name is: _____________________________________ and he or she 
can be contacted at _____________________________________.                                                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug AT13387 
(onalespib).  This clinical trial is sponsored by the NCI.  AT13387  
interacts with drugs that are processed by your liver, or use certain transport 
proteins in your body.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistant, nurse 
practitioners, pharmacists) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 AT13387 (onalespib) interacts with drugs that are processed via 
UGT1A1, UGT1A3.  It may also interact with transport proteins (P-gp, BCRP,  
 
MATE1, and MATE2K) and liver enzymes (CYP 1A2, -3A4, -2D6, -
2C9, and -2C19); thus, it must be used very carefully with other 
medicines that interact with these enzymes and proteins.  
 Before you enroll onto the clinical trial, your study doctor will work 
with your regular health care providers to review any medicines that 
are considered ““strong or moderate inducers/inhibitors” of these 
enzymes and protein transporters.  
 Before prescribing new medicines, your regular health care providers 
should go to a frequently-updated medical reference for a list of 
drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ and 
can be contacted at _________________________________.  


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APPENDIX C: KNOWN CYP3A4 INDUCERS AND INHIBITORS.   
 
INVESTIGATORS SHOULD ALSO REFERENCE THE FOLLOWING WEBSITES FOR 
UPDATED INFORMATION REGARDING CYP3A4 INTERACTIONS: 
 
CYP3A4 Inducers (prohibited) 
Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine  
Dexamethasone1  
Efavirenz   
Fosphenytoin1 
Glucocorticoids2 (see note) 
Modafinil2  
Nafcillin1  
Nevirapine  
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifapentine1 
St. John’s wort2 
Troglitazone3 
Note:  Topical steroids are permitted.  Please contact overall PI if systemic steroids are clinically 
indicated while on trial. 
1 Cited in Cytochrome P450 Enzymes:  Substrates, Inhibitors, and Inducers.  In:  Lacy CF, Armstrong LL, Goldman MP, Lance 
LL, eds.  Drug Information Handbook 20th ed.  Hudson, OH; LexiComp Inc. 2011-2012: 1810-1818 
2 Cited in Flockhart DA.  Drug Interactions:  Cytochrome P450 Drug Interaction Table.  Indiana University School of Medicine 
(2007).  http://medicine.iupui.edu/clinpharm/ddis/table.asp.  Accessed Nov 2011. 
3 Weak inhibitor per Lacy et al.  May be used with caution. 
 Note:  Drugs without a superscript are cited in both the Lacy and Flockhart references. 
 
CYP3A4 Inhibitors 
Strong Inhibitors 
(prohibited) 
Moderate Inhibitors 
(prohibited) 
  Weak Inhibitors 
(use with caution, avoid if possible) 
Amprenavir1 
Atazanavir1 
Clarithromycin 
Conivaptan1 
Delavirdine1 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconazole 
Ketoconazole 
Miconazole1 
Nefazodone 
Nelfinavir 
Nicardipine1 
Posaconazole1 
Propofol1 
Quinidine1 
Ritonavir 
Saquinavir2 
Telithromycin 
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimazole1 
Cyclosporine1 
Desipramine1 
Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Haloperidol1 
Lidocaine1 
Metronidazole1 
Norfloxacin1 
Sertraline1 
Tetracycline1 
Verapamil 
Voriconazole1 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star fruit2 
Troleandomycin2 
1 Cited in Cytochrome P450 Enzymes:  Substrates, Inhibitors, and Inducers.  In:  Lacy CF, Armstrong LL, Goldman MP, Lance 
LL, eds.  Drug Information Handbook 20th ed.  Hudson, OH; LexiComp Inc. 2011-2012: 1810-1818 
2 Cited in Flockhart DA.  Drug Interactions:  Cytochrome P450 Drug Interaction Table.  Indiana University School of Medicine 
(2007).  http://medicine.iupui.edu/clinpharm/ddis/table.asp.  Accessed Nov 2011. 


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 Note:  Drugs without a superscript are cited in both the Lacy and Flockhart references. 


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APPENDIX D: List of QT prolonging drugs to be used with caution 
This table does not contain an exhaustive list of drugs with QT-prolongation.  The drug list is 
frequently updated and the following website should be checked for the most current information as 
needed: https://www.crediblemeds.org/index.php. 
 
List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 
Alfuzosin 
possible risk for Torsades de Pointes 
 
Amantadine 
possible risk for Torsades de Pointes 
 
Amitriptyline 
conditional risk for Torsades de Pointes 
 
Azithromycin 
possible risk for Torsades de Pointes 
 
Chloral hydrate 
possible risk for Torsades de Pointes 
 
Citalopram 
conditional risk for Torsades de Pointes 
 
Clomipramine 
conditional risk for Torsades de Pointes 
 
Clozapine 
possible risk for Torsades de Pointes 
 
Desipramine 
conditional risk for Torsades de Pointes 
 
Diphenhydramine 
conditional risk for Torsades de Pointes 
 
Dolasetron 
possible risk for Torsades de Pointes 
 
Doxepin 
conditional risk for Torsades de Pointes 
 
Dronedarone 
possible risk for Torsades de Pointes 
 
Felbamate 
possible risk for Torsades de Pointes 
 
Flecainide 
possible risk for Torsades de Pointes 
 
Fluoxetine 
conditional risk for Torsades de Pointes 
 
Foscarnet 
possible risk for Torsades de Pointes 
 
Fosphenytoin 
possible risk for Torsades de Pointes 
 
Galantamine 
conditional risk for Torsades de Pointes 
 
Gatifloxacin 
possible risk for Torsades de Pointes 
 
Gemifloxacin 
possible risk for Torsades de Pointes 
 
Granisetron 
possible risk for Torsades de Pointes 
 
Imipramine 
conditional risk for Torsades de Pointes 
 
Indapamide 
possible risk for Torsades de Pointes 
 
Isradipine 
possible risk for Torsades de Pointes 
 
Levofloxacin 
possible risk for Torsades de Pointes 
 
Lithium 
possible risk for Torsades de Pointes 
 
Mexiletine 
conditional risk for Torsades de Pointes 
 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
 


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List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 
Moxifloxacin 
possible risk for Torsades de Pointes 
 
Nicardipine 
possible risk for Torsades de Pointes 
 
Nortriptyline 
conditional risk for Torsades de Pointes 
 
Octreotide 
possible risk for Torsades de Pointes 
 
Ofloxacin 
possible risk for Torsades de Pointes 
 
Ondansetron 
possible risk for Torsades de Pointes 
 
Oxytocin 
possible risk for Torsades de Pointes 
 
Paliperidone 
possible risk for Torsades de Pointes 
 
Paroxetine 
conditional risk for Torsades de Pointes 
 
Perflutren lipid 
microspheres 
possible risk for Torsades de Pointes 
 
Protriptyline 
conditional risk for Torsades de Pointes 
 
Ranolazine 
possible risk for Torsades de Pointes 
 
Risperidone 
possible risk for Torsades de Pointes 
 
Roxithromycin* 
possible risk for Torsades de Pointes 
*not available in the 
United States 
Sertindole 
possible risk for Torsades de Pointes 
 
Sertraline 
conditional risk for Torsades de Pointes 
 
Solifenacin 
conditional risk for Torsades de Pointes 
 
Tizanidine 
possible risk for Torsades de Pointes 
 
Trazodone 
conditional risk for Torsades de Pointes 
 
Trimethoprim-Sulfa 
conditional risk for Torsades de Pointes 
 
Trimipramine 
conditional risk for Torsades de Pointes 
 
Venlafaxine 
possible risk for Torsades de Pointes 
 
Ziprasidone 
possible risk for Torsades de Pointes 
 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E: List of Prohibited QT-Prolonging Drugs  
 
All QT-prolonging drugs listed in Appendix E are prohibited for all participants from screening  
through permanent discontinuation of study treatment.  This Appendix lists drugs with a known 
risk for Torsades de Pointes (TdP) as well as sensitive CYP3A substrates (with narrow TI) with a 
possible or conditional risk for TdP. 
This table does not contain an exhaustive list of drugs with QT-prolongation.  The drug list is 
frequently updated and the following website should be checked for the most current information as 
needed: https://www.crediblemeds.org/index.php. 
 
List of Prohibited QT-Prolonging Drugs 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females>Males,TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, QT 
prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 


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List of Prohibited QT-Prolonging Drugs 
Drug 
QT risk(*) 
Comment 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 sibstrate 
with narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a 
potent inhibitor of the respective enzyme. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F: PATIENT’S PILL DIARY: olaparib  
Today’s Date ________________________________  
 
Cycle #_______________ 
Patient Name_______________________________  Patient Study ID ___________________ 
(initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. 
You will take ___ (number) ____ mg (dosage) tablet(s)twice a day 12 hours apart.. 
2. 
Complete one form for each cycle (28 days). Record the date, the number of tablets you took, and when you took them.   
3. 
Tablets cannot be chewed, dissolved or crushed. 
4. 
Tablets are taken by mouth and can be taken with a light meal/snack if needed to reduce stomach irritation. 
5. 
If you vomit a dose, please record in the diary. Replace the dose ONLY if you can see all of the intact tablets.  If you forget to take 
your dose and it is 2 hours past your scheduled dose, then record in your diary and do NOT make up the missed dose.  
6. 
Please bring your pill bottle (including empty bottles) and this form to your physician when you go for your next appointment. 
 
Day 
 
Date 
# of tablets and when taken: olaparib 
 
Day 
 
Date 
# of tablets and when taken: olaparib 
25mg 
100mg 
150mg 
Time 
AM 
Time 
PM 
25mg 
100mg 
150mg 
Time 
AM 
Time 
PM 
1 
 
 
 
 
 
 
15 
 
 
 
 
 
 
2 
 
 
 
 
 
 
16 
 
 
 
 
 
 
3 
 
 
 
 
 
 
17 
 
 
 
 
 
 
4 
 
 
 
 
 
 
18 
 
 
 
 
 
 
5 
 
 
 
 
 
 
19 
 
 
 
 
 
 
6 
 
 
 
 
 
 
20 
 
 
 
 
 
 
7 
 
 
 
 
 
 
21 
 
 
 
 
 
 
8 
 
 
 
 
 
 
22 
 
 
 
 
 
 
9 
 
 
 
 
 
 
23 
 
 
 
 
 
 
10 
 
 
 
 
 
 
24 
 
 
 
 
 
 
11 
 
 
 
 
 
 
25 
 
 
 
 
 
 
12 
 
 
 
 
 
 
26 
 
 
 
 
 
 
13 
 
 
 
 
 
 
27 
 
 
 
 
 
 
14 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient’s Signature: ________________________________________  Date: _________________________ 
Physician’s Office will complete this section: 
1.Date patient started protocol treatment________________   Date patient was removed from study _____________________ 
 
2.Patient’s planned daily dose________________________    Total number of tablets taken this month ____________________ 
 
Physician/Nurse/Data Manager’s Signature __________________________________________________________________ 
 
_________________________________________________________________ 
 


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APPENDIX G:  PHARMACOKINETIC SAMPLE COLLECTION AND HANDLING 
 
1. 
Do not collect pharmacokinetic blood samples from the catheter used to infuse olanespib, 
including the port of a multi-lumen catheter that was not used for infusing the drug.   
2. 
When using a peripheral catheter for sampling, use a syringe to clear the catheter of the 
lock solution approximately 1 min before the specified sample time and withdraw about 
0.5 mL of blood into the syringe for disposal.   
3. 
Collect samples in a 3.0 mL (cycle 0) or 6.0 mL (cycle 1) plastic purple stoppered 
Vacutainer tube with spray dried K2EDTA. 
4. 
Immediately after filling the tube, gently invert the collection tube 5-times to thoroughly 
mix the blood with the anticoagulant and place the tube on wet ice until centrifuged.  
5. 
Centrifuge at 1,500 x g for 10 min at 4°C within 30 min after collection.   
6. 
Use a disposable pipette to transfer the plasma, removed without disturbing the blood 
cells, equally into two (2) 2.0 mL self-standing polypropylene cryogenic storage vials 
with external threads for Aliquot A and Aliquot B.   
7. 
Affix a computer printed label with the following information onto the tube:  CTEP 
Protocol No., Subject Study No., Sample No., Aliquot #.  Orient the label crosswise 
toward the upper part of the tube being careful not to overlap the vial cap.  Wrap the label 
with polyester protective label tape (Fisher Scientific, cat. no. 11-867B) to prevent the 
label from detaching from the vial when stored frozen.   
8. 
Immediately place the cryovials in crushed dry ice until transferred to an ultralow 
temperature freezer (≤-70°C) for storage until shipment.  
9. 
Ship the complete set of "Aliquot A" samples for each patient after the last sample has 
been collected.  Ship the Aliquot B samples separately after verifying receipt of the 
Aliquot A samples.  Do not send the Aliquot A and Aliquot B samples for the same 
patient in the same package.   
10. 
Place the sample tubes for each patient in a separate zip lock plastic bag and seal the bag.   
11. 
Put at least three inches of crushed dry ice in a seamless styrofoam container.   
12. 
Place the plastic bag(s) containing the samples in the box, on top of the crushed dry ice, 
and cover with an additional three inches or more of dry ice.   
13. 
Seal the styrofoam container within a tight-fitting cardboard shipping box.   
14. 
Send the samples on Monday to Wednesday by overnight courier for delivery by 10:00 
a.m. on the following day.  Never ship samples on a Thursday or Friday.   
15. 
Recipient address: 
Dr. Jeffrey G. Supko 


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99 
 
Massachusetts General Hospital 
 
55 Fruit St., GRJ 1025 
 
Boston, MA 02114 
 
Tel: 617-724-1970 
16. 
Notification of the shipment and the courier tracking no. must be 
made by sending and e-mail to the following:  (1) MGHCCPOSPL@partners.org; and (2) 
jsupko@partners.org.  Attached a scanned copy of the Pharmacokinetic Time Record for 
all samples in the shipment to the email.   


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APPENDIX H: DIARRHEA MANAGEMENT 
Diarrhea is a common problem experienced by many patients and is a risk with olaparib as well 
as AT13387.  If it is not controlled quickly, it can lead to dehydration. 
 
WHEN TO CALL YOUR DOCTOR TO REPORT DIARRHEA 
• 
Fever 100.5° or higher with diarrhea. 
• 
If you are experiencing diarrhea for the first time after starting therapy.  Based on questions 
answered during that phone call, we will advise starting Imodium AD if it seems the symptoms 
are related to the treatment. 
• 
If you still have diarrhea 24 hours after starting Imodium AD (your doctor may advise 
additional medications or want to evaluate you in person if there is a concern that you are 
becoming dehydrated). 
OVER THE COUNTER MEDICATION MANAGEMENT OF DIARRHEA: 
• 
For diarrhea that occurs more than 2 episodes a day, use Imodium AD. We recommend that 
you have Imodium AD on hand at home before starting therapy. 
o 1st episode of diarrhea: Take 2 caplets (4mg) 
o During the day: Take 1 caplet (2mg) after each episode of diarrhea 
o During the night: Take 2 caplets (4mg) at bedtime if you are still having diarrhea 
DRINK PLENTY OF FLUIDS 
• 
Drink 8 to 10 large glasses of liquids a day to replace those lost by diarrhea. Drink small 
quantities at a time slowly. 
• 
AVOID caffeinated, very hot, or very cold fluids 
Examples of fluids: 
o Water (should only be part of the 8 to 10 glasses a day) 
o Jello 
 
o Gatorade  
o  Clear soup or broth  
EAT SMALL MEALS OFTEN 
• 
A good choice of foods for diarrhea is the BRAT diet: 
o B- bananas 
o R- rice 
o A- apple sauce 
o T- toast 
• 
When these foods are being well tolerated, then you can add other bland low fiber foods 
such as: 
o Chicken- white meat without the skin, steamed rice, crackers, white bread, pasta 
noodles without sauce, and canned or cooked fruits without skins 
o Foods high in potassium: bananas, apricots without skin, peach nectar, potatoes 
without skin, broccoli, halibut, mushrooms, asparagus, non-fat milk 
• 
Foods that can make diarrhea and cramping worse: 
o Fatty, fried, greasy, or spicy foods can cause more problems and discomfort 
o High-fiber foods: bran, whole grain cereals, dried fruit, fruit skins, popcorn, nuts and 
vegetables 
o Foods that cause gas: Beer, beans, cabbage, carbonated drink