A Phase I Study of AZD8186 in Combination With Docetaxel in Patients With PTEN Mutated or PIK3CB Mutated Advanced Solid Tumors, Potentially Amenable to Docetaxel
Phase: PHASE1
Conditions: Advanced Breast Carcinoma, Advanced Malignant Solid Neoplasm, Advanced Prostate Carcinoma, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Castration-Resistant Prostate Carcinoma, Metastatic Breast Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Prostate Carcinoma, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage IV Breast Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Triple-Negative Breast Carcinoma, Unresectable Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

NCI Protocol #:10131 
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i 
 
SUMMARY OF CHANGES- Protocol 
 
 
# 
Section 
Comments 
1. 
N/A 
Formatting and editorial changes made throughout the protocol (e.g., page numbers). 
2. 
Title Page Protocol version date revised to reflect current changes.  
3. 
Schema 
5.1 
Sections revised to notify that AZD8186 60 mg. tablets will expire and treatment needs to 
be completed by April 30, 2022. 
4. 
Schema  
5.3 
5.4  
Sections revised to notify that Part 2 and Part 3 will no longer open after Part 1 is 
completed.  
5. 
6 
Section revised to indicate that patients cannot be dose reduced to dose level -1. Doses 
should be reduced by 60 mg.  
6. 
8.1.1 
Section revised on how AZD8186 is supplied.  
7.  
Table 7 
Contact information updated in regards to AZD8186 PK collection/notification.  

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NCI Protocol #: 10131 
 
Local Protocol #: 18-237 
 
ClinicalTrials.gov Identifier:  TBD  
 
 
TITLE:  A Phase 1 Study of AZD8186 in Combination with Docetaxel in patients with PTEN 
mutated or PIK3CB mutated advanced solid tumors, potentially amenable to docetaxel 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator:               Alison Schram 
                                                      Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
646-888-5294 
schrama@mskcc.org  
Participating Organizations: 
  
Part 1 Dose escalation cohort 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
          
         
LAO restricted to: 
• MD017/ JHU Sidney Kimmel Comprehensive Cancer Center 
• NY016 / Memorial Sloan Kettering Cancer Center 
• NY478 / Memorial Sloan Kettering Westchester 
• NJ299/ Memorial Sloan Kettering Monmouth 
 
LAO-TX035/ University of Texas MD Anderson Cancer Center LAO 
LAO restricted to: 
• TX035/ University of Texas MD Anderson Cancer Center 
  
LAO-NCI/ National Cancer Institute LAO 
 
Part 2 Pharmacodynamic expansion cohort/ Part 3 Disease specific expansion cohort 
Open to all sites in LAO Participating Organizations table: 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 

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LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistician: 
 
LAO Protocol Liaison: 
Alexia Iasonos, PhD                                             Stella  Krawiec, M.A. 
485 Lexington Ave                                               Johns Hopkins University 
New York, NY 10017                                           201 N. Broadway, Suite 9200-33 
646-888-8255                                                        Baltimore, MD 21205 
iasonosa@mskcc.org                                             Telephone: (410) 502-1962 
 
 
 
                        skrawie1@jhmi.edu  
 
 
 
NCI-Supplied Agent(s):  AZD8186, NSC# 785347  
Commercially- Supplied Agent: Docetaxel, NSC# 628503   
 
 
IND Sponsor:  DCTD, NCI 
 
 
Protocol Type / Version # / Version Date: 
Original / Version 1 / 04/21/2017 
 
 
 
 
Amendment / Version 2 / 06/22/2017 
Amendment / Version 3 / 07/26/2017 
Amendment / Version 4 / 10/26/2017 
 
 
 
 
Amendment / Version 5 / 12/13/2017 
 
 
 
 
Amendment / Version 6 / 03/23/2018 
      Amendment / Version 7 / 06/12/2018 
      Amendment / Version 8 / 07/05/2018 
      Amendment / Version 9 / 08/02/2018 
      Amendment / Version 10 / 12/06/2018 
      Amendment / Version 11 / 03/18/2019 
      Amendment / Version 12 / 08/29/2019 
      Amendment / Version 13 / 10/08/2019 
      Amendment / Version 14 / 12/03/2019 
      Amendment / Version 15 / 05/20/2021 
 
 
 
 

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SCHEMA 
 
This will be a Phase I, multi-part, multicenter, non-randomized, open-label study designed to evaluate 
the safety, tolerability and preliminary activity of AZD8186 in combination with  
Docetaxel in patients with PTEN mutated or PIK3CB mutated advanced solid tumors. In this study, 
patients who have received any number of prior therapies in the metastatic disease setting will be 
treated with the combination of AZD8186 twice daily (BID) orally (PO), 5 days on, 2 days off every 
week, combined with Docetaxel intravenous (IV) on day 1 of a 21 day cycle, until progression of 
disease (POD), unacceptable toxicity or withdrawal from study. All treatments will be administered 
in the outpatient setting. The primary objectives are to determine the MTD or RP2D of AZD8186 
when administered in combination with docetaxel and assess the safety and tolerability of the 
combination. Secondary endpoints include objective response rate (ORR), clinical benefit rate (CBR) 
at 24 weeks and to investigate the drug-drug interaction between docetaxel and AZD8186. 
 
Per the drug manufacturer AstraZeneca, clinical supply of AZD8186 60 mg tablets will expire on 
April 30, 2022 (based on the planned expiration date extension). Supplies can be used until the 
terminal lot shelf life dating is reached or the NCI inventory is exhausted.  All patients must 
complete their last treatment on or before April 30, 2022, and the study will be closed to accrual and 
treatment to coincide with this expiration date. 
 
Parts 2 and 3 will no longer open following completion of the Part 1 Dose escalation cohort. 
 
Figure 1    Overall Study Schema 
 
 
 
 

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Figure 2    Part 1: Dose escalation cohort schema 
 
(n= 9 -21) 
 
Dose Escalation Schedule 
 
Dose Escalation schema 
Dose Level 
Dose 
AZD8186 
BID PO, 5 days on, 2 days off 
every week 
(mg) 
Docetaxel 
IV on day 1 of a 21-day 
cycle 
(mg/m2) 
-1* 
30 
75 
-1B* 
60 
60 
Starting dose level 1*  
60 
75 
2* 
120† 
75 
Please refer to Section 5.5 for DLT definition. 
†AZD8186 dosed at 90mg bid 5 days on /2 off may be explored, as directed by the emerging 
safety profile of this agent.  
*Prophylactic growth factor support with docetaxel should be administered during the first 
cycle of therapy per institutional guidelines and per the provider’s discretion on subsequent 
cycles. Since the protocol was amended to include the use of prophylactic growth factor during 
DL-1B, patients who experienced a DLT of neutropenia or neutropenic fever at this dose level 
prior to the implementation of prophylactic growth factor maybe replaced. 
Note: DL -1B was added in an amendment based on the emerging safety profile 
 

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Dose Re-escalation:  
The use of prophylactic growth factor with Cycle 1 was added given emerging safety data 
demonstrating neutropenia as the predominant dose-limiting toxicity. In the event that Dose 
Level -1B is deemed tolerable with or without the use of growth factor, dose re-escalation can 
occur to Dose Level 1 and subsequently Dose Level 2 with the ongoing use of prophylactic 
growth factor. 
 
 
Figure 3      Part 2: Pharmacodynamics expansion cohort schema 
 
(n= 10) 
 
Figure 4       Part 3: Disease specific expansion cohort schema 

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(n=36)

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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................ 3 
1. 
OBJECTIVES ................................................................................................................... 10 
1.1 
Primary Objectives ................................................................................................ 10 
1.2 
Secondary Objectives ............................................................................................ 10 
1.3 
Exploratory Objectives .......................................................................................... 10 
2. 
BACKGROUND ............................................................................................................... 10 
2.1 
Study Disease(s) .................................................................................................... 10 
2.2 
CTEP IND Agent .................................................................................................. 13 
2.3 
Other Agent(s) ....................................................................................................... 27 
2.4 
Rationale................................................................................................................ 27 
2.5 
Correlative Studies Background............................................................................ 29 
3. 
PATIENT SELECTION ................................................................................................... 33 
3.1 
Eligibility Criteria ................................................................................................. 33 
3.2 
Exclusion Criteria .................................................................................................. 36 
3.3 
Inclusion of Women and Minorities...................................................................... 37 
4. 
REGISTRATION PROCEDURES ................................................................................... 38 
4.1 
Investigator and Research Associate Registration with CTEP ............................. 38 
4.2 
Patient Registration ............................................................................................... 42 
4.3 
General Guidelines ................................................................................................ 43 
5. 
TREATMENT PLAN ....................................................................................................... 43 
5.1 
Agent Administration ............................................................................................ 43 
5.2 
Part 1: Dose escalation cohort ............................................................................... 45 
5.3 
Part 2: Pharmacodynamic expansion cohort ......................................................... 46 
5.4 
Part 3: Disease specific expansion cohort ............................................................. 47 
5.5 
Definition of Dose-Limiting Toxicity ................................................................... 48 
5.6 
Dose Expansion Cohorts ....................................................................................... 50 
5.7 
General Concomitant Medication and Supportive Care Guidelines ..................... 50 
5.8 
Duration of Therapy .............................................................................................. 51 
5.9 
Duration of Follow Up .......................................................................................... 52 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 52 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS............................ 58 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ................. 58 
7.2 
Adverse Event Characteristics .............................................................................. 61 
7.3 
Expedited Adverse Event Reporting ..................................................................... 62 
7.4 
Routine Adverse Event Reporting......................................................................... 64 
7.5 
Secondary Malignancy .......................................................................................... 64 
7.6 
Second Malignancy ............................................................................................... 65 
8. 
PHARMACEUTICAL INFORMATION ......................................................................... 65 

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8.1 
CTEP IND Agent .................................................................................................. 65 
8.2 
Commercial Agent: Docetaxel .............................................................................. 68 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 70 
9.1 
Exploratory Correlative Studies ............................................................................ 70 
9.2 
Table 7 ................................................................................................................... 72 
10. 
STUDY CALENDAR ....................................................................................................... 76 
11. 
MEASUREMENT OF EFFECT ....................................................................................... 78 
11.1 
Antitumor Effect – Solid Tumors.......................................................................... 78 
11.2 
Antitumor Effect – Prostate cancer, PCWG3 ....................................................... 84 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................ 91 
12.1 
Study Oversight ..................................................................................................... 91 
12.2 
Data Reporting ...................................................................................................... 93 
12.3 
Collaborative Agreements Language .................................................................... 95 
12.4 
Genomic Data Sharing Plan .................................................................................. 95 
13. 
STATISTICAL CONSIDERATIONS .............................................................................. 95 
13.1 
Study Design/Endpoints ........................................................................................ 95 
13.2 
Sample Size/Accrual Rate ..................................................................................... 97 
13.3 
Stratification Factors ............................................................................................. 97 
13.4 
Analysis of Secondary Endpoints ......................................................................... 97 
13.5 
Exploratory Correlative Analysis .......................................................................... 98 
REFERENCES ............................................................................................................................ 100 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................ 104 
APPENDIX B 
Curated list of PTEN variants with the corresponding 
literature to support their loss of function ....................................................................... 105 
APPENDIX C 
Curated list of PIK3CB variants with the corresponding 
literature to support their Gain of function...................................................................... 109 
APPENDIX D PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD .............................................................................................................................. 110 
APPENDIX E 
BIOMARKER REQUEST FORM .......................................................... 112 
APPENDIX F 
Drug Administration Diary for AZD8186 .............................................. 112 
APPENDIX G 
COLLABORATIVE AGREEMENTS LANGUAGE ............................ 116 
APPENDIX H - BIOSPECIMEN COLLECTION AND SHIPPING GUIDELINES ................ 118 
I. 
SUBMITTING FORMALIN-FIXED, PARAFFIN-EMBEDDED (FFPE) 

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TUMOR TISSUES ........................................................................................................ 119 
III. 
SUBMITTING WHOLE BLOODS ............................................................................... 121 
IV. 
SUBMITTING PLASMAS ............................................................................................ 121 
V. 
ORDERING INFORMATION ...................................................................................... 123 
VI. 
SHIPMENT EMAIL NOTIFICATION .......................................................................... 123 
VII. 
SPECIMEN COLLECTION LOG ................................................................................ 123 
APPENDIX I 
TUMOR FROZEN NEEDLE BIOPSY SPECIMEN 
COLLECTION AND HANDLING ............................................................................... 125 
APPENDIX J 
SOP FOR PROCESSING NEEDLE BIOPSIES AT THE 
PADIS LAB  ................................................................................................................. 125 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To determine the MTD or RP2D of AZD8186 when administered in combination with 
docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.  
 
1.1.2 To assess the safety and tolerability of AZD8186 when administered in combination 
with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.  
 
1.2 
Secondary Objectives 
 
1.2.1 To observe and record anti-tumor activity.  Although the clinical benefit of this drug 
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. 
 
1.2.1.1 
To assess the objective response rate (ORR) of AZD8186 when administered in 
combination with docetaxel in patients with PTEN or PIK3CB mutated advanced solid 
tumors.  
1.2.1.2 
To assess the clinical benefit rate at 24 weeks of AZD8186 when administered in 
combination with docetaxel in patients with PTEN or PIK3CB mutated advanced solid 
tumors.  
 
1.2.2 To investigate a drug-drug interaction between docetaxel and AZD8186 and correlate 
drug exposure with pharmacodynamics response  
 
1.3 
Exploratory Objectives 
 
1.3.1 Examine the pattern of co-mutated genes in PTEN or PIK3CB mutated tumors and 
their association with treatment response or resistance. 
 
1.3.2 Describe possible mechanisms of acquired resistance to PI3Kβ inhibition. 
 
1.3.3 Evaluation of protein expression of the PTEN gene and its association with treatment 
response or resistance. 
 
1.3.4 Examine isoform-specific AKT inhibition and other downstream target modulation 
from PI3Kβ inhibition with AZD8186.  
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
This phase I study will be open to patients with all solid tumor types harboring a PTEN or PIK3CB 
mutation.  
 

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PTEN deficiency (from gene loss, frameshift deletions, epigenetic down-regulation or protein 
degradation) is a frequent event in many cancer subtypes including prostate, breast, lung, gastric 
and endometrial cancer, melanoma and glioblastoma.1,2 Among one of the largest institutional series 
(n=15,000) of sequenced metastatic tumors using a CLIA NGS assay called MSK-IMPACT,3  
genomic alterations in PTEN have been identified in 8% of patients (See Figure 5, below, 
Oncoprint from cbioportal.org and Figure 6, below showing the most frequently affected tumor 
types).4,5 In addition the table below Figure 6 illustrates the most frequently altered tumor types as 
identified within the TCGA dataset.2 
 
Figure 5   PTEN oncoprint 
 
 
 
 
Figure 6   Cancer types Summary: PTEN  
 
 
 
 
 
 
 
 
 
 
 
 

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  Frequencies of PTEN genetic lesions across cancer subtypes2 
Cancer Type 
% of tumors with 
PTEN mutation or homozygous loss 
(# altered/total) 
Bladder 
4.1% (4/97) 
Lower Grade Glioma 
5.3% (9/169) 
Breast 
7.47% (57/760) 
Cervical 
13.9% (5/36) 
Colorectal 
6.3% (14/221) 
Glioblastoma Multiforme 
41.9% (99/236) 
Head & Neck SCC 
2.6% (8/302) 
Renal clear cell 
3.4% (10/290) 
Renal papillary 
3% (3/100) 
Lung Adenocarcinoma 
3.9% (5/129) 
Lung SCC 
11.2% (20/179) 
Ovarian 
7.28% (23/316) 
Prostate 
13.6% (14/103) 
Sarcoma 
2.9% (6/207) 
Melanoma 
12.4% (28/225) 
Stomach 
11.3% (13/115) 
Thyroid 
1.9% (6/318) 
Uterine 
66.3% (159/240) 
 

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Mutations in PIK3CB, although rare have been reported6 and out of 15,000 sequenced metastatic 
tumors at MSKCC, ~1.6% patients have been identified to have alterations in PIK3CB. (See Figure 
7, below, Oncoprint from cbioportal.org and Figure 8, below showing the most frequently affected 
tumor types).4,5   
 
 
Figure 7   PIK3CB oncoprint 
 
 
 
 
 
Figure 8    Cancer types Summary: PIK3CB 
 
 
 
 
 
2.2 
 CTEP IND Agent 
 
2.2.1 AZD8186  
 
AZD8186 is a potent selective inhibitor of PI3Kβ/δ being developed as an oral anti-tumor 
agent with an initial focus on patients with PTEN-deficient tumors. For more detail on non-clinical 
and clinical studies with this agent please refer to the most up to date version of the investigator 
brochure. 

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2.2.1.1 
Summary of Non-clinical studies 
 
In nonclinical models, PD activity of AZD8186 manifested as reductions in phospho-AKT, 
phospho-PRAS40 and Foxo-3a nuclear translocation (signaling events downstream of PI3Kβ), 
leading to inhibition of cellular proliferation in cell line assays in vitro and growth inhibition in 
xenografts in vivo. 
 
2.2.1.1.1. 
Pharmacology summary 
 
The principal findings from the non-clinical pharmacology studies are summarized below: 
• AZD8186 targets PI3Kβ and δ. Cells become dependent on PI3Kβ signaling when they lose 
appropriate regulation of the pathway through loss of PTEN function. This can occur at the 
gene level through gene deletion, or mutation, or through down regulation of the protein 
relative to normal levels through transcriptional or post-translational effects. For the 
purposes of this document, the collective drivers of loss of PTEN function are defined as 
PTEN deficient. 
•  Isolated enzymes within the PI3K family bind AZD8186 with tight binding kinetics. As a 
result, cell based assays are more discriminating for the relative potency of the molecule 
versus different PI3K family members. With this caveat, in vitro biochemical enzyme 
studies show AZD8186 to be a potent inhibitor of PI3Kβ (4 nM) with additional activity 
versus PI3Kδ (12 nM), and selectivity over PI3Kα (35 nM), and PI3Kγ (675 nM). Broad 
profiling versus 2 extensive kinase panels covering up to 442 kinases (and including 
multiple lipid kinases) showed AZD8186 to have little potency against any other kinase 
(concentration >1 μM). 
• In vitro cellular assays show AZD8186 to inhibit phosphorylation of protein kinase B, 
pAKT (473) with a concentration giving 50% of the drug-induced inhibitory effect (IC50) of 
3 nM in the PI3Kβ dependent PTEN null, cell line MDAMB-468. AZD8186 inhibited 
phosphorylation of pAKT (thr308) with an IC50 of 725 nM in the PI3Kα dependent PTEN 
wild-type cell line BT474. Additional activity versus PI3Kδ was observed with AZD8186 
inhibiting pAKT (ser473) with an IC50 of 17 nM following stimulation of JEKO cells with 
immunoglobulin M (IgM). AZD8186 showed comparable suppression of pAKT in a range 
of PTEN null cells lines with IC50 ranging from (10 to 460 nM). 
• In a broad cell panel screen (124 cell lines) AZD8186 inhibited the growth of a number of 
cell lines with IC50 ranging from 20 to 1000 nM. While activity was seen in both PTEN null 
and PTEN wild-type cell lines, PTEN null were enriched in the sensitive group.  
• In vivo AZD8186 inhibited growth of PTEN null tumor xenografts following oral treatment. 
Robust anti-tumor activity was observed when animals were dosed in the range of 25 mg/kg 
to 50-mg/kg continuous dosing (all dosed twice daily [BD]). Activity was also achieved 
following treatment with 10 mg/kg to 30 mg/kg BD AZD8186 in the presence of 1-
aminobenzotriazole (ABT). ABT is a cytochrome p450 inhibitor used to reduce the 
clearance of AZD8186, and generate a pharmacokinetic (PK) profile that has a flatter profile 
than that achieved with standard BD dosing. 
• In nonclinical models, AZD8186 was effective when used in combination with docetaxel 
both with continuous and intermittent dosing schedules. 
• AZD8186 gives increased combination benefit with inhibitors of the PI3Kα isoform. 
Increased tumor responses were seen when HCC70 tumors were treated with AZD8186 and 
AZD8835 (a PI3Kα/δ inhibitor). In the human prostate carcinoma cell line (LNCaP) model, 

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AZD8186 combines with BYL719 (a PI3Kα inhibitor) to give increased tumor growth 
suppression. 
• AZD8186 combines with blockade of androgen signaling to give increased anti-tumor 
responses in PTEN protein null androgen-receptor (AR)-positive tumor models. AZD8186 
with surgical castration (in PC346 tumor xenografts) or AZD8186 combined with 
enzalutamide (in the LNCaP model or prostate cancer genetically engineered mouse model 
[GEMM] model) regressed tumors. AZD8186 also combined well in vitro with the androgen 
signaling modulator enzalutamide. A triple combination of AZD8186, BYL719 and 
enzalutamide gave the greatest tumor response, suggesting comprehensive pathway 
suppression in combination with AR inhibition gives greatest benefit in prostate cancer 
models. 
• AZD8186 combines with inhibitors of mammalian target of rapamycin (mTOR) signaling. 
In HCC-70, 786-0 (renal cancer), and Karpas-422 (diffuse large B-cell lymphoma) 
(DLBCL) the combination of AZD8186 and AZD2014 (mTORC1/2 inhibitor) gave tumor 
regressions. In 786-0, the combination of everolimus (RAD001 mTORC1 inhibitor) with 
AZD8186 gave tumor regression. In HCC70, AZD8186 gave increased combination benefit 
when combined with AZD6244, an inhibitor of the mitogen activated protein kinase 
(MAPK)/EKT pathway. 
• Nonclinical data indicates that with intermittent scheduling, efficacy in HCC70 tumors is 
maintained when AZD8186 is dosed 5 days out of 7 days as monotherapy. When used in 
combination, other schedules of AZD8186 are effective, with 4 to 5 days dosing per week 
generally being optimal (25 mg/kg to 50 mg/kg BD). However, in combination with 
AZD2014, it is possible to reduce both dose and duration of exposure further while 
maintaining efficacy. 
• PI3Kβ is important in regulating ligand-induced platelet activation following activation of 
specific G-protein coupled receptors (GPCRs). Consistent with activity versus PI3Kβ, 
AZD8186 inhibited murine and human platelet aggregation in ex vivo assays. 
• One major metabolite (M1) of AZD8186 has been investigated. M1 shows equivalent in 
vitro activity to AZD8186 in PI3Kα, PI3Kβ, PI3Kδ cell based assays. 
• In a secondary pharmacodynamics screen of 186 molecular targets, AZD8186 had activity 
within 30-fold of the highest predicted human free maximum plasma drug concentration 
(Cmax) at 3 targets. Of these, only the inverse agonism at the dopamine D2S receptor may 
have potential to translate into central nervous system (CNS) symptoms if clinical free 
Cmax exposures exceed 5 μM.  
• AZD8186 is active at the human Ether-a-go-go-Related Gene (hERG) cardiac channel in 
vitro, with 39% inhibition of the hERG tail current at a concentration 110μM. 
• In a conscious telemetered dog cardiovascular study, AZD8186 caused minor transient 
increases in PR interval and systolic and diastolic arterial blood pressure, but these changes 
were small in magnitude and considered not to be adverse. 
• In mice, assessments of respiratory function, using whole body plethysmography, and CNS 
function, using a modified Irwin screen, showed no changes related to administration of 
AZD8186. 
• Following single oral dosing, AZD8186 caused dose- related inhibition of stomach 
emptying in mice, with no effects on gastrointestinal (GI) transit. 
 

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2.2.1.1.1. 
Non-clinical pharmacokinetics and drug metabolism 
summary 
 
The absorption, distribution, metabolism, and excretion of AZD8186 have been studied in 
mouse and dog in vivo following oral administration and in mouse, dog, and human in vitro. 
The animal species and strains used were the same as those used in the toxicology program. 
The compound has been used in in vitro studies designed to determine protein binding, cross 
species metabolism and interactions with human cytochrome P450 (CYP) and transporter enzymes. 
Toxicokinetic monitoring of the 1-month toxicology studies were performed according to Good 
Laboratory Practice (GLP). Exposures have been achieved in the clinic equivalent to that required 
for efficacy in mouse xenograft models. 
 
• In mice and dogs oral absorption was rapid with maximum plasma concentrations generally 
10 min to 2 h following administration. Increase in the exposure over the dose range studied 
was less than proportional with dose. In mice, a decrease in exposure on Day 28 compared 
to Day 1 was observed. In dogs exposure was generally higher on Day 28 versus Day 1. 
• Mean percentage free AZD8186 was 9.66, 9.56, 27.6, 33.6 and 15.2% in mouse, rat, rabbit, 
dog, and human plasma respectively. 
• Following incubation with mouse, dog and human hepatocytes, AZD8186 was primarily 
metabolized to oxidized and dealkylated products followed by conjugation to glucuronic 
acid and/or sulphate. All 6 metabolites formed in human hepatocytes were observed in 
incubations with mouse and dog hepatocytes. A demethylated metabolite AZ13472080 
(M1), is equipotent with AZD8186 in vitro, and has been observed in plasma of mice, dogs 
and humans dosed with AZD8186. In vitro CYP3A4 was the principal cytochrome P450 
responsible for human metabolism in a panel of 6 isoforms. AZD8186 related material 
irreversibly binds to human hepatocytes. 
• In vitro, AZD8186 is a reversible inhibitor of human CYP2C9 with an IC50 of 29 μM. 
Reversible inhibition (IC50) of the other human cytochrome P450s (CYP) exceeded 30 μM. 
Time-dependent inhibition of CYP enzymes was not observed. AZD8186 did not inhibit 
human P-glycoprotein (P-gp). AZD8186 inhibited human organic anion transporter protein 
1B1(OATP1B1) with an IC50 of 19 μM. AZD8186 is an inducer of CYP3A4 and to a lesser 
extent CYP2B6 in vitro. No induction of CYP1A1/2 was observed. The induction potential 
of AZD8186 at therapeutic doses is predicted to be low. 
• In conclusion: 
 
o AZD8186 undergoes predominantly Phase 1 metabolism to multiple oxidation and 
dealkylation products followed by conjugation. All metabolites identified in human 
hepatocytes were observed in mouse and/or dog hepatocytes indicating the suitability 
of these species for assessing the toxicology of AZD8186. 
o Dealkylation of AZD8186 to M1 is a major route of metabolism in mouse and dog in 
vitro. M1 is an equipotent metabolite of AZD8186 with a similar selectivity profile 
against other PI3K isoforms. In the 1-month toxicology studies, it was circulating at 
low levels in mouse (generally <20% parent) but higher levels in dog (approximately 
50 to 165% parent). M1 is circulating in plasma of patients dosed with AZD8186 but 
at lower levels than AZD8186. 

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o AZD8186 is cleared/ metabolized predominantly by CYP3A4. There is therefore a 
risk that the PK of AZD8186 may be affected by co-administration with inducers 
and/or potent inhibitors of CYP3A4. 
o AZD8186 is a weak inhibitor of CYP2C9 (IC50 29 μM) and OATP1B1 (IC50 19 
μM). Based on the predicted human exposures of AZD8186 the use of sensitive 
substrates of CYP2C9 and OATP1B1 has been restricted in the clinical study. 
Assessment of the drug-drug interaction risk based on the observed interim human 
plasma concentrations at 240 mg BD supports this assessment for CYP2C9 
interactions but suggests the risk of OATP1B1 interactions is low. 
o AZD8186 is an inducer of CYP3A4 and to a lesser extent CYP2B6 in vitro. 
Currently Day 19 and Day 1 exposures in patients for AZD8186 up to 240 mg BD 
are very similar, suggesting there is no significant induction of CYP3A4. An early 
assessment of the potential of AZD8186 to induce CYP3A4 in the clinical study will 
be conducted using 4-hydroxy-β-cholesterol as a marker of CYP3A4 metabolism. 
o Human free exposures of AZD8186 achieved in the clinic are within the range 
required for efficacy in the nude mouse. 
 
2.2.1.1.2. 
Toxicology summary 
 
Nonclinical safety evaluation studies conducted with AZD8186 include oral toxicology studies of 
up to 1 month in duration in mice and dogs, a battery of in vitro and in vivo genetic toxicity studies 
and an in vitro phototoxicity assessment. 
Key findings from the studies are summarized below: 
• Dosing AZD8186 for up to 1 month was associated with hepatic changes in dogs and mice. 
In dogs, dosing for up to 14 days was associated with minimal hepatocyte degeneration, 
sinusoidal dilatation and increased sinusoidal leucocytes, with associated increases in 
plasma liver enzyme activities (alkaline phosphatase [ALP], aspartate aminotransferase 
[AST], alanine aminotransferase [ALT] and glutamate dehydrogenase [GLDH]). After 
dosing for 1 month at similar dose levels, hepatocellular single cell necrosis, inflammation 
and pigmented macrophages, with more marked increases in plasma liver enzyme activities, 
were seen. Reversibility of the plasma liver enzyme increases and histopathology was 
demonstrated after a1 month recovery period. Pigmented macrophages, inflammation and 
fibrosis noted in the liver of some recovery animals was considered to indicate resolution of 
earlier liver changes in these animals. In mice, inflammatory cell infiltration in the liver, 
sometimes accompanied by areas of hepatocellular degeneration and/or necrosis, was seen 
following dosing for 1 month. Small increases in liver enzymes were seen in some 
individual mice dosed with AZD8186, but did not correlate with the histopathological 
changes in the liver. Similar inflammatory changes of lesser severity were seen in a few 
mice following a 1-month recovery period, suggesting reversibility. 
• Dosing AZD8186 in dogs for up to 1 month was associated with single cell necrosis or 
degeneration of lymphocytes, reduced lymphocytes and/or inflammation in the lymphoid 
tissues in the GI tract, thymus mesenteric lymph node, and tonsils and in the splenic white 
pulp. Changes in the bone marrow (increased myeloid: erythroid ratio, increased or 
decreased cellularity) and thymus (hypocellularity, lymphocyte single cell necrosis), and 
increases in peripheral white blood cell (WBC) counts (especially neutrophils and 
monocytes), were also apparent. In mice, dosing for up to 1 month produced changes in the 
mesenteric and/or mandibular lymph nodes (increased histiocytes, lymphocytolysis, reduced 

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lymphocytes), bone marrow (increased histiocytes) and spleen (hypocellularity) in 
individual animals. Lymphoid organ and hematology changes showed evidence of 
reversibility in both species following a 1-month recovery period. 
• Dosing AZD8186 in dogs and mice for up to 1 month was associated with testicular tubular 
degeneration, with associated reductions in testis weight and changes in the epididymides. 
Following a 1-month recovery period, partial reversibility of the testis changes was seen for 
mice although in dogs testicular tubular degeneration was still apparent. In mice, a reduction 
in ovary weight, with no histopathological correlate, was also seen following dosing 
AZD8186 for 1 month. 
• There was no evidence of rash or any other changes suggestive of potential hypersensitivity 
type reactions in the nonclinical toxicology studies when AZD8186 was dosed continuously 
for up to 1 month in mice and dogs. 
• Dosing AZD8186 to dogs for 1 month was associated with sporadic fecal changes  
• A dose level of 30 mg/kg BD to dogs for 1 month was associated with elevated neutrophils, 
monocytes and C-reactive protein; there were no changes to inflammatory cytokine release 
or lymphocyte subsets noted.  
• At all dose levels in the dog, treatment related findings were present in the lymphoid system 
in the GI associated lymphoid tissue (GALT). The findings were minimal to mild single cell 
necrosis of lymphoid follicles and minimal to mild inflammatory cell infiltration associated 
with the GALT These changes recovered after 28 days off-dose.  
• AZD8186 causes inhibition of adenosine diphosphate (ADP)-stimulated platelet aggregation 
in dog whole blood ex vivo, without any adverse effects on bleeding in dogs or mice in vivo. 
• The majority of these changes were considered likely to be related to pharmacology, in 
particular resulting from inhibition of PI3K β and/or PI3K δ. 
• AZD8186 also caused small increases in plasma glucose in mice and dogs, which suggested 
that plasma exposures in these animals were sufficient to transiently inhibit PI3Kα. 
• AZD8186 was not genotoxic in vitro in the Ames and mouse lymphoma assays or in vivo in 
a mouse bone marrow micronucleus assay. 
• AZD8186 absorbs in the ultraviolet (UV) spectrum (290 to 700 nm) and was positive in an 
in vitro 3T3 Neutral Red Uptake phototoxicity test, indicating a potential phototoxicity risk. 
 
2.2.1.2 
Summary of Clinical Data 
 
AZD8186 is currently under evaluation in 1 ongoing AstraZeneca-sponsored clinical 
study 
(D4620C00001), a Phase 1 study to assess safety, tolerability, PK, and preliminary 
anti-tumour activity in patients with advanced castration-resistant prostate cancer 
(CRPC), 
squamous non-small cell lung cancer (sqNSCLC), triple-negative breast cancer 
(TNBC) and 
patients with known PTEN-deficient advanced solid malignancies, as monotherapy 

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and in 
combination with abiraterone acetate or vistusertib (mTOR inhibitor).  
  
This study dosed its first patient on 10 July 2013 and as of 02 May 2019, 147 patients have been 
dosed with AZD8186 and 7 dose levels have been investigated under 3 different BD dosing 
schedules (5 days on, 2 days off; 2 days on, 5 days off, continuous) either as monotherapy or in 
combination with abiraterone or vistusertib. Patients have received doses ranging from 30 to 360 
mg BID alone and in combination with either AZD2014 or abiraterone. There have been 16 
separate dosing regimens in total (12 monotherapy, 4 combination). Dose limiting toxicities (DLTs) 
of rash have occurred at the 360 mg and 300 mg dose levels. Additionally, Grade 3 diarrhea and 
colitis occurred at 180 mg dose levels. 
 
The most common treatment related, adverse events have been in the Gastrointestinal (GI) tract 
(including diarrhea, nausea, vomiting and potentially abdominal pain), skin, immune 
system/apparent hypersensitivity. These adverse events have been monitorable, reversible and mild 
in nature. 
 
Hypersensitivity, pyrexia/chills, hepatic effects, inhibition of platelet aggregation, phototoxicity, 
reproductive toxicity and drug-drug interaction and lymphoid effects have been identified as 
important potential risks and will continue to be closely monitored as the ongoing phase I clinical 
trial progresses. 
 
The hypersensitivity-like reactions including rash, chills, fever sometimes accompanied by 
gastrointestinal symptoms are of unknown etiology. This group of adverse events has 
substantial overlap with known AEs associated with PI3Kδ inhibitors including fever, rash, 
diarrhoea and anaphylactic reactions. As such, it is possible that the hypersensitivity-like 
events may be pharmacologic mechanism-related, specifically due to PI3Kδ (±PI3Kβ) 
inhibition. 
 
2.2.1.2.1. 
Pharmacokinetics 
 
The preliminary pharmacokinetics of AZD8186 and its N-demethylated active metabolite (M1) have 
been characterized in patients after single and multiple BD dosing (5 days on, 2 days off) over the 
dose range 30, 60, 120, 180, 240, 300 and 360 mg.  
 
AZD8186 appeared rapidly in plasma after single or multiple oral administration with peak 
plasma concentrations attained at around 1.5 h. Following the time to reach maximum plasma 
concentration (tmax), levels declined in a bi-phasic manner with a mean terminal half-life of 1.8 to 
4.3 h following a single dose. 
 
A dose proportional increase in AZD8186 exposure was observed in the dose range tested. 
Geometric mean Cmax and area under the plasma concentration-time-curve from zero to 12h after 
dosing (AUC(0-12)) increased in a dose proportional manner following single and multiple dosing.  
 
Following an intermittent 5 days on; 2 days off schedule there was minimal accumulation with mean 
accumulation ratio (Rac) of 1.17 (Day 19/Day 1 AUC(0-12)). These results are consistent with the 

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short half-life of AZD8186, and further suggest a low likelihood of autoinduction of metabolizing 
enzymes that might affect its own clearance. 
 
The metabolite (M1) was detected in the plasma of all patients with a similar profile to that of the 
parent drug, but at a lower level (approximately 40%, independent of dose, to date). 
 
Overall, the metabolite increased with dose in a similar manner to that of the parent drug after 
single or multiple dosing. 
 
2.2.1.2.2. 
Pharmacodynamics 
 
Acute reduction of pAKT S473 and pGSK3β was observed in platelet-rich plasma of patients 
treated with a single dose of AZD8186. This reduction was maintained for 8 hours in patients 
treated with an AZD8186 single dose (30 or 60 mg), and for 24 hours in patients treated with at 
least 120 mg.7 
 
2.2.1.2.3. 
Safety and efficacy 
 
Preliminary findings from 147 dosed patients from data cut off of 02 May 2019: 
 
Safety and tolerability 
 
Most patients (143/147 [97.3%]) experienced an AE, and most patients 
(117/147 [79.6%]) experienced an AE that was considered by the investigator to be causally 
related to AZD8186. Over half the patients (91/147 [61.9%]) experienced an AE of CTCAE 
Grade 3 or higher. Twenty-six of the 147 patients (17.7%) had an AE leading to 
discontinuation. Of the 147 patients, 61 (41.5%) patients experienced an SAE and 
29 (19.7%) patients experienced an SAE that was considered by the investigator to be 
causally related to AZD8186. The AEs include those from doses that were later deemed to 
be non-tolerable due to dose limiting toxicities (DLTs). 
• 
The most frequently reported AEs (affecting >20% patients) were diarrhoea reported by 
(69/147 [46.9%]), nausea (62/147 [42.2%]), fatigue (54/147 [36.7%]), vomiting (51/147 
[34.7%]), decreased appetite (40/147 [27.2%]), pyrexia (34/147 [23.1%]), increased 
aspartate aminotransferase (31/147 [21.1%]) and increased alanine aminotransferase 
(30/147 [20.4%]). 
• 
In Study D4620C00001 to date, the SOCs with the most SAEs were GI disorders 
(29 events), Infections and infestations (25 events), General disorders and administrative site 
conditions (23 events), and Respiratory, thoracic, and mediastinal disorders (11 events). The 
most frequently occurring PTs (with ≥3 SAEs) were pyrexia (15 events), diarrhoea (8), 
pneumonia (6), colitis (6), vomiting (5), AST increased (5), ALT increased 
(4), anaemia (4), nausea (4), sepsis (4), back pain (4), confusional state (4), haematuria 
(3), pulmonary embolism (3), lower respiratory tract infection (3), and dehydration (3). 
• 
At this early stage of clinical development, patient numbers in each dose group are low, 
and it is difficult to draw conclusions. 

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• 
There have been no AEs leading to death reported in the clinical programme to date. All 
deaths have been reported up to the data cut-off for this IB have been identified as being due 
to disease progression. 
• 
Three patients have experienced confirmed partial responses, according to RECIST. One 
patient was administered AZD8186 as monotherapy, and 1 patient was administered 
AZD8186 in combination with vistusertib, and 1 patient was administered AZD8186 in 
combination with abiraterone 
 
 
 
 
Preliminary efficacy 
 
At this stage, only a small number of patients have been enrolled to determine efficacy, as the 
clinical programme is still evaluating the optimal dose and schedule. 
 
Three patients have experienced confirmed partial responses, according to RECIST, as 
follows: 
 
• 
Highly refractory mCRPC Part A patient with known PTEN and KRAS mutations on 2/5 
schedule at 120 mg BD a (maximal 32% tumour reduction versus baseline). The patient is 
now off-study due to disease progression (on study >83 weeks). 
• 
mCRPC Part D1 patient (germline BRCA-2 and AR mutations) on 5/2 schedule 30 mg BD 
plus vistusertib 100 mg 2/5 schedule. The patient is now off-study due to disease 
progression (on study for >55 weeks). 
• 
Abiraterone/enzalutimide naïve PTEN proficient mCRPC Part C1 cohort 2 patient (120 
mg AZD8186 BD 5/2/ plus 1000 mg abiraterone QD) had confirmed PR by CT (51% 
reduction in target lesions) and PSA. 
 
Investigation of the safety and tolerability of AZD8186 alone and in combination with 
abiraterone acetate is continuing in expansion cohorts in patients with mCRPC. 
 
 
2.2.1.2.4. 
Precautions for use  
 
The risks associated the AZD8186 are as follows from 147 dosed patients from data cut off of 02 
May 2019: 
 
Identified risks 
Rash  
Diarrhea and colitis 
 
Potential risks 
Hypersensitivity 
Possible drug interactions 
Platelet aggregation/bleeding risk 

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Lymphoid effects 
Hepatic effects 
Phototoxic potential 
Reproductive precautions 
 
 
 
 
 
 
 
Summary of previous and ongoing important risks 
 
Risk 
Pre-clinical data 
Clinical data 
Actions  
Identified risks 
Rash 
 
 
No data in pre-clinical 
studies 
Rash has been observed with 
the use of AZD8186 at a 
cumulative frequency of 24% 
(8.8% grade 3) in study 
D4620C00001. All cases 
resolved after dose- 
interruption/dose-reduction. 
 
Recommendations for the 
management of rash 
together with dose 
modification guidance for 
rash grade > 3 are 
included in the clinical 
study protocol. 
Diarrhea/Colitis
 
 
Evidence in genetically 
modified mice with a 
‘kinase-dead’ mutation 
inserted into the PI3Kδ 
gene. These mice 
spontaneously develop 
colitis (Uno et al 2010). 
However, when these 
mice are raised in a 
germ free environment 
they do not develop 
colitis (Steinbach et all 
2014). If the germ-free 
mice are transferred to 
normal environment 
they do get colitis 
(Steinbach et all 2014). 
This data indicates that 
lacking catalytically 
active PI3Kδ is a risk 
factor for colitis, when 
bowel microbiota are 
present 
 
Diarrhea has been observed 
with the use of AZD8186, the 
majority being mild, self-
limited and responsive to anti-
motility agents [cumulatively 
46.9% (All grades); 8.2% 
(grade 3); study 
D4620C00001]. 9  cases of 
grade 3 colitis/entercolitis 
were reported, all of which 
resolved with dose 
interruption, dose 
reduction and/or 
supportive treatment including 
steriods. 
 
Patients with pre-
existing grade 2 or 
higher chronic diarrhea 
are excluded from 
studies with 
AZD8186. 
Recommendations for 
the management of 
diarrhoea together with 
dose modification 
guidance for diarrhoea 
grade >2 are included 
in the clinical study 
protocol. Suspected 
colitis as the cause of 
intermittent, chronic or 
chronic recurrent 
diarrhoea should be 
confirmed and treated 
by standard local 
practice. 
 
Important potential risks 

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Hypersensitivity  No data in pre-clinical 
studies  
Two patient experienced 
hypersensitivity in study 
D4620C00001 (one case was 
Grade 3) and recovered with 
dose reduction/interruption. 
Patients with medically 
confirmed history of 
hypersensitivity or 
allergic reaction to any 
drug (e.g., penicillin), or 
anaphylaxis to food 
allergen(s) are 
excluded from studies 
with AZD8186. 
Hypersensitivity is 
closely monitored as 
part of routine 
pharmacovigilance. 
Guidance on dose 
interruption for patients 
who experience 
hypersensitivity/ allergic 
response is 
included in the clinical 
study protocol. 
 
 
Possible drug 
interactions 
AZD8186 may have 
the potential to induce 
CYP450 enzymes, 
particularly CYP3A4, 
and to inhibit Organic 
Anion Transporting 
Polypeptide 1B1 
(OATP1B1) and 
CYP2C9 enzyme. 
AZD8186 is predominantly 
metabolised by CYP3A4 and 
preliminary PK data from 
study D4620C00001suggests 
there is no auto-induction 
effect following multiple bi-
daily dosing (5 on 2 off 
schedule) over a 3 week 
treatment period. No toxicity 
potentially related to drug-
drug interaction (DDI) has 
been observed so far in study 
D4620C00001. 
 
 
The concomitant use of 
AZD8186 with narrow 
therapeutic index drugs 
that are metabolized by 
CYP3A4 or CYP2C9 
should be avoided. A list 
of these drugs is included 
in the clinical study 
protocol. Strong and 
moderate CYP3A4 
inducers and inhibitors 
are prohibited during 
studies with AZD8186 
and a list of these are 
included in clinical study 
protocols.  
Additional monitoring of 
low-density- lipoprotein 
(LDL) is advised for 
patients receiving 
cholesterol-lowering 
drugs (eg. statins and 
ezetimibe). 
 
Hepatic effects
 
 
AZD8186 
administration was 
associated with 
changes in the liver of 
dogs (including 
Cumulatively 12% of patients 
developed increase in AST 
and/or ALT (Grade 1/2) and 
12% developed a Grade 3 
toxicity in study 
Patients are required to 
have adequate baseline 
hepatic function, with 
liver enzymes and liver 
synthetic function 

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24 
 
hepatocyte 
degeneration/single 
cell necrosis, increases 
in plasma liver 
enzymes) and mice 
(inflammatory cell 
infiltration). These 
changes showed 
evidence of 
reversibility following 
withdrawal of 
AZD8186. 
 
D4620C00001, all of which 
resolved after dose 
interruption/reduction. One 
patient developed Grade 4 
ALT/ Grade 3 AST elevation 
in combination with 
abiraterone, resulting in an 
interruption of study therapy. 
There was negative 
rechallenge with AZD8186, 
and positive rechallenge with 
abiraterone. The event 
resolved upon continuation of 
AZD8186 and discontinuation 
of abiraterone.  
monitored closely 
throughout study 
treatment. Persistent 
grade 2 or higher 
occurrence of elevation of 
transaminases and 
bilirubin or evidence of 
impaired liver function in 
patient will result in 
interruption of treatment 
with AZD8186 
immediately until all 
abnormaities return to 
normal or to their 
baseline state.  
Inhibition of 
Platelet 
Aggregation 
(bleeding risk) 
AZD8186 was shown 
to inhibit ADP-
stimulated platelet 
aggregation in dog 
whole blood, without 
any adverse effects on 
bleeding observed in 
vivo. These changes 
were considered likely 
to be related to 
pharmacology, in 
resulting from 
inhibition of PI3K β 
and/or PI3K δ. These 
changes showed 
evidence of 
reversibility following 
withdrawal of 
AZD8186. 
 
Cumulatively, a total of 14 
events of hematuria (13 grade 
1 or garde 2 severity, 1 grade 3 
severity), 1 report of grade 1 
or grade 2 hemoptysis, and 2 
reports of grade 1 or grade 2 
epistaxis were observed. All of 
these events were assessed as 
unrelated to AZD8186 except 
for 2 events of haematuria 
which were assessed as related 
to AZD8186 by the reporting 
investigator.  
 
Thrombolytic therapy is 
not permitted during the 
study period. Anti-
platelet agents should be 
interrupted in patients 
with significant evidence 
of bleeding, bleeding risk 
or 7 days prior to any 
biopsies or surgical 
procedures and restarted 
afterwards. 
 
Phototoxicity
 
 
AZD8186 absorbs in 
the UV spectrum 
(290 to 700 nm) and 
was positive in an in 
vitro 3T3 Neutral 
Red Uptake 
phototoxicity test at 
the in vitro IC50 for 
a positive 
phototoxicity signal 
(7.7 mg/ml, 16.8 
μmol/L). This 
suggests that 
AZD8186 exhibits a 
No effects observed to date.
 
 
Patients will be required 
to follow UV-light 
precautions, including: 
protective clothing, 
sunglasses and Sun 
Protection Factor (SPF) 
45 or greater sunscreen 
when outdoors; and sun 
bed avoidance. 

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weak phototoxic 
potential. 
Reproductive 
toxicity 
AZD8186 
administration was 
associated with 
testicular tubular 
degeneration in dogs 
and/or mice. The 
changes seen in the 
testis in both species 
may be related to PI3K 
β inhibition, as male 
mice expressing a 
catalytically inactive 
PI3K p110β subunit 
have been shown to 
develop testicular 
hypotrophy and 
impaired 
spermatogenesis, 
leading to defective 
fertility. 
 
No effects observed to date.
 
 
Conception must be 
avoided during exposure 
to AZD8186. Strict 
contraceptive guidance is 
included in the clinical 
study protocols. Women 
of childbearing potential 
and men will be required 
to agree to use adequate 
contraception during the 
study period and for 4 
weeks (women) and 1 
week (men) after the last 
dose of study drug. Male 
subjects should similarly 
abstain from sperm 
donation for 6 months 
after the last dose of 
study drug. 
 
Lymphoid 
Tissue changes 
(Blood and 
lymphatic 
disorders) 
In dogs and mice, 
changes were observed 
in a variety of 
lymphoid tissues 
(including lymphocyte 
single cell necrosis- 
degeneration), 
increases in peripheral 
white blood cell counts. 
PI3K isoforms, in 
particular PI3Ks β, δ 
and γ, have multiple 
non-redundant roles 
within the immune 
system, including 
neutrophil and 
lymphocyte 
development and 
function. The changes 
seen in the primary and 
secondary lymphoid 
organs of mice and/or 
dogs dosed with 
AZD8186 may, 
therefore, be a 
consequence of 
inhibition of PI3K β 
Cumulatively, 
thrombocytopenia, anaemia, 
neutropenia and lymphopenia 
were reported as follow: 
-thrombocytopenia: 3 cases 
(2.04%) of Grade 1/2, 3 cases 
(2.04%) of Grade 3, 1 case 
(0.7%) 
of Grade 4. Of these 7 events, 
3 were assessed as related to 
AZD8186. None of the events 
were serious.  
-anaemia: 18 cases (12.2%) of 
Grade 1/2, 8 cases (5.4%) of 
Grade 3. Of these 26 events, 
13 were assessed as related to 
AZD8186. 4 events were 
serious and 1 was related to 
AZD8186.  
-neutropenia/neutrophil count 
decreased: 8 cases (5.4%) of 
Grade 1/2 and 3 cases (2.0%) 
of Grade 3. Of these 11 
reports, 8 were assessed as 
related to AZD8186. A single 
report was serious and related 
Patients are required to 
have adequate bone 
marrow reserve and organ 
function at study entry 
and these parameters will 
be monitored throughout 
study. 
 

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26 
 
and PI3K δ. 
to AZD8186 therapy. 
-lymphopenia/lymphocyte 
count decreased: 5 cases 
(3.4%) of grade 1/2, 9 cases 
(6.1%) of grade 3, 1 case 
(0.7%) of grade 4. Of these 
15 cases, 6 were assessed as 
related to AZD8186. None of 
the events were serious.  
 
 
2.2.1.2.5. 
Rationale for the proposed starting dose, dose escalation 
scheme. 
 
From the ongoing phase I study, AstraZeneca has declared a RP2D of AZD8186 at 60 mg po bid on 
a 5 day on/2 off weekly schedule. AZD8186 was tested on this schedule at doses as high as 340 mg 
po bid.  Toxicities of rash, fever, chills, and colitis were seen with these higher doses. Across the 
ongoing phase I study, doses as high as 340 mg BD AZD8186 have been explored on the 5/2 
monotherapy schedule and as high as 120 mg BD on the continuous (declared as tolerated) and 240 
mg BD on the 2/5 schedule (also declared as tolerated). In addition AZD8186 at 120mg BD is 
currently being explored with full dose abiraterone and vistusertib (AZD2014, TORC1/2 inhibitor). 
Based on pharmacodynamic data, 30mg is considered to be the lowest effective dose, as a result the 
proposed starting dose for combination with docetaxel is 60mg. 
 
   Dose Escalation Schedule 
Dose Escalation schema 
Dose Level 
Dose 
AZD8186 
BID PO, 5 days on, 2 days off 
every week 
(mg) 
Docetaxel 
IV on day 1 of a 21-day 
cycle 
(mg/m2) 
-1* 
30 
75 
-1B* 
60 
60 
Starting dose level 1*  
60 
75 
2* 
120† 
75 
 
Please refer to Section 5.5 for DLT definition. 
†AZD8186 dosed at 90mg bid 5 days on /2 off may be explored, as directed by the emerging 
safety profile of this agent.  
*Prophylactic growth factor support with docetaxel should be administered during the first 
cycle of therapy per institutional guidelines and per the provider’s discretion on subsequent 
cycles. Since the protocol was amended to include the use of prophylactic growth factor during 
DL-1B, patients who experienced a DLT of neutropenia or neutropenic fever at this dose level 
prior to the implementation of prophylactic growth factor maybe replaced. 
Note: DL -1B was added in an amendment based on the emerging safety profile 

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2.3 
Other Agent(s) 
 
Docetaxel 
 
Docetaxel, a semi-synthetic analog of paclitaxel, acts by disrupting the microtubule network leading 
to apoptosis and cell death. Docetaxel is used as a single agent and in combination with multiple 
other chemotherapies in the treatment of many solid tumors including Breast, ovarian, lung, head & 
neck, bladder, esophageal, cervical, and endometrial cancers.  
The most common adverse events with the administration of docetaxel ate infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, 
constipation, anorexia, nail disorders, fluids retention, asthenia, pain, nausea, diarrhea, vomiting, 
mucositis, alopecia, skin reactions and myalgia (Taxotere product information). 
An established standard of care dose (75mg/m2 Docetaxel on day 1 of a 21-day cycle) was chosen 
as the starting dose level for this agent. This dose is used in most solid tumors treated with 
docetaxel either as a single agent or in combination with other chemotherapies.  
 
2.4 
Rationale 
 
The PI3K/AKT/mTOR signaling network is a critical regulator of many cellular processes, 
including proliferation, survival and transformation. PI3K–AKT pathway dysregulation is a 
hallmark of various cancers, seen in up to 50% of all solid tumors.10-12 Among other mechanisms, 
aberrant pathway activation can arise from somatic mutations in PIK3CA, AKT1 or from 
loss/inactivation of the PTEN suppressor gene.13-15  
 
The lipid kinases PI3Kα, β, γ & δ are key regulators of this network.16 Different isoforms of PI3Ks 
have been shown to play key roles in distinct tumor types, often linked with genetic alterations in 
genes encoding other components of the network. Furthermore, the PI3K enzymes are critically 
controlled by the tumor suppressor PTEN, a lipid phosphatase that reverses the action of PI3Ks.17  
PTEN additionally has a nuclear role in promoting chromosome stability and DNA repair and 
therefore, loss of PTEN function increases genomic instability.2,18,19 Indeed, PTEN has been linked 
to poor outcome and therapeutic resistance in a number of cancers and as such offers a potential 
therapeutic target.1,2,20-29 
 
PTEN deficient tumors may have increased dependence on PI3Kβ activity requiring p110β for 
growth and signaling through the PI3K pathway and thus may be sensitive to PI3Kβ inhibition.30 
31,32 AZD8186 is a potent and selective small molecule inhibitor of PI3Kβ with additional activity 
against PI3Kδ. PTEN-deficient tumors have been identified to have dependency on AKT2 for 
survival.33 AZD8186 has been shown to inhibit AKT pathway activation, modulate pathway 
biomarkers and inhibit growth of breast and prostate tumor models.34  Although AZD8186 has 
demonstrated limited single-agent activity in PTEN-null and PI3Kβ-driven preclinical models, it is 
likely to be more clinically effective in combination with other targeted agents or cytotoxic 
chemotherapy. Indeed, AZD8186 administered on an intermittent schedule with a single dose of 
docetaxel improved tumor growth inhibition in both PTEN-deficient prostate cancer and triple-
negative breast cancer (TNBC) xenograft mouse models (Figure 9, below).34  

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2.5 
Correlative Studies Background 
 
2.5.1 Targeted genomic sequencing of formalin-fixed, paraffin-embedded tumor and 
tumor-derived plasma cell free (cf) DNA samples with the MSK-IMPACT 
assay 
2.5.1.1 
Background  
2.5.1.1.1. 
The MSK-IMPACT platform is an enterprise-grade targeted 
hybrid-capture next generation sequencing (NGS) assay examining 468 
genes (current panel version) commonly mutated in cancer,3 with a proven 
track record of generating high coverage (>500X) data in formalin-fixed 
paraffin-embedded (FFPE) specimens with as little as 15ng of genomic 
DNA.37 Using a version of MSK-IMPACT optimized for cfDNA-based 
studies, the Center for Molecular Oncology (CMO) at MSKCC has 
successfully prepared sequence libraries with as little as 2ng cfDNA.38 This 
platform has readily detected somatic mutations in cfDNA, captured tumor 
heterogeneity and provided a real-time readout of clonal and subclonal 
dynamics and evolution.39 
2.5.1.2 
DNA extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue from fresh 
pre-treatment biopsies or archival specimens and post-progression tumor biopsies along 
with a matched normal blood specimen collected pre-treatment will be evaluated for 
mutations in established cancer-related genes using the MSK-IMPACT assay. Serial 
cfDNA samples collected on study will also be evaluated for emerging mutations using 
MSK-IMPACT. cfDNA will be isolated from the plasma compartment of blood 
collected in Streck tubes. 
2.5.1.3 
Integrated biomarker  
2.5.1.3.1. 
Retrospective central confirmation of the molecular alteration (an 
inactivating PTEN mutation or activating PIK3CB mutation) in pre-
treatment biopsy specimens or archival tumor specimen (pre-treatment 
biopsy required if archival tumor tissue is unavailable) 
2.5.1.4 
Exploratory biomarker  
2.5.1.4.1. 
Hypotheses: 
2.5.1.4.1.1. 
Co-mutational profile will potentially modify response to 
AZD8186 in PTEN/ PIK3CB mutated tumors  
2.5.1.4.1.2. 
In patients that initially respond to AZD8186, the durability of 
these responses will be limited by mutations that drive acquired 
resistance.  
2.5.1.4.1.3. 
Aims: 
2.5.1.4.1.3.1. 
Examine the pattern of co-mutated genes in pre-
treatment biopsy specimens or archival tumor specimens of 
patients with PTEN/ PIK3CB mutated tumors and their 
association with treatment response or resistance 
2.5.1.4.1.3.2. 
Monitor the emergence of new somatic alterations or 
resistant subclones in the cfDNA and post-progression tumor 
biopsies of patients with PTEN/ PIK3CB mutated tumors who 
initially respond to AZD8186, thereby describing potential 
mechanisms of acquired resistance to therapy. 
 

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2.5.2 Multiplex quantitation of Akt pathway signaling proteins in flash frozen pre- and 
on-treatment biopsy specimens with the Luminex multiplex assay (Integrated 
biomarker)  
 
2.5.2.1 
Background:  
2.5.2.1.1. 
Investigators (Dr Srivastava, lab PI) at the Pharmacodynamics 
Assay Development and Implementation Section (PADIS) laboratories of 
DCTD, NCI have extensive experience in developing validated multiplex 
immunoassays suitable for quantifying apoptotic biomarkers.40 Using 
validated immunoassays for pharmacodynamic biomarkers of MET 
signaling, they succeeded in quantifying pharmacodynamic response of the 
MET/HGF receptor to MET inhibitors.41 Dr Srivastava’s group have since 
developed Luminex multiplex assays to monitor the pharmacodynamics of 
multiple classes of drugs targeting the PI3K-AKT-mTOR-rpS6 pathway. 
This multiplex assay examines isoform-specific AKT inhibition and other 
downstream target modulation from PI3Kβ inhibition.  
 
2.5.2.1.2. 
The preclinical time-course study of this assay evaluating the 
molecular target responses to AZD8186 in PTEN mutant cell lines HCC70 
and PC3 is ongoing at the Biological Testing Branch, NCI, the results of 
which will be presented at AACR-NCI-EORTC (Herrick, Srivastava et al 
2017). First, highly selective isoform- or phospho-specific antibodies were 
developed for AKT1/2/3 and pRPS6(S235) and their specificity validated 
using a combination of techniques involving isoform-specific CRISPR 
knock-out cell lines, cancer cells treated with selective drugs and epitope-
peptide competition. Multiplex sandwich immunoassays were then 
developed on the Luminex platform by using isoform-specific antibodies for 
capture and biotinylated antibodies for detection of total protein or 
phosphorylated residues. Recombinant proteins were used as calibrators. Dr 
Srivastava’s lab multiplexed the analysis of biomarkers in the PI3K-AKT-
rpS6 pathway  (Table 1 below) 
 
Prelimanry results:  
• Using PTEN-null cancer cell lines (HCC70, MDA-MB-468, PC-3) 
treated with AZD8186, they found that the multiplex assays measure 70-
90% reduction in target phosphorylation with high precision (CV < 15%). 
They also demonstrated that the AKT and rpS6 phospho-signals appear to 
be stable and quantifiable when biopsies are processed according to 
clinically-validated biopsy collection and extraction protocols established 

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previously for phospho c-MET (Appendix I). 
• Changes in AKT and rpS6 phosphorylation in AZD8186 treated PC3 
xenografts – Changes in biomarker levels were analyzed 2, 4, 7 and 24 
hours post dose 1 in mice implanted with PC3 xenografts.  No significant 
changes in the total protein levels were detected except for a small change 
in total rpS6 in the 50 mg/kg treatment group (p< 0.05).  Significant 
changes in phosphorylation were observed at 7h for pS473 AKT1 and at 
4 and 7h for pThr308 AKT1 (p<0.05) for the 50 mg/kg dose.  AKT2 
phosphorylation at pS473 significantly decreased at 4h and 7h and after 
7h for pThr308 AKT2 (p< 0.05).  Both pS473 and pThr308 AKT3 
phosphorylation was reduced at 7h (p< 0.01 and p< 0.5 
respectively).  Reduction in rpS6 phosphorylation at pS235 and 
pS240/244 was observed at 2h, 4h and 7h post dose 1 50 mg/kg (p<0.05 
2-4h Phospho A, p<0.01 7h PhosphoA, p< 0.01 2h Phospho B, p< 0.05 
25 and 50 mg/kg at 4h and p<0.001 7h).  
 
 
 

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2.5.2.2 
Hypothesis: Testing paired tissue biopsies with this multiplex assay will provide 
quantitative measurements of the magnitude of drug-induced target suppression and 
indicate the effectiveness of AZD8186 in suppressing downstream pathway 
signaling.PI3Kβ inhibition of PTEN-deficient tumors will lead to changes in AKT 
pathway signaling and downstream target modulation. 
2.5.2.3 
Aim: Examine isoform-specific AKT inhibition and other downstream target modulation 
from PI3Kβ inhibition with AZD8186 in patients with PTEN/ PIK3CB mutated tumors 
enrolled in the pharmacodynamic expansion cohort only, using pre- and on-
treatment [window: Between C1D -5 to C1D -3, (2-3 hrs post dose)] flash frozen 
biopsy specimens. Methods as previously described.40,41 
 
2.5.3 Immunohistochemistry-scoring of PTEN protein expression (Exploratory 
biomarker) 
2.5.3.1.1. 
Hypothesis:  Loss of PTEN surface expression will be associated 
with inactivating/loss of function mutations in the PTEN gene and predict 
for response to therapy 
2.5.3.1.2. 
Immunostaining of FFPE sections from pre-treatment or archival 
specimens and post-progression biopsies will be performed with tumor 
PTEN expression using the H-score formula: 3 × percentage of strongly 
staining cells+2 × percentage of moderately staining cells+percentage of 
weakly staining cells, giving a range of 0 to 300.42 A H-score >10 will be 
considered positive for PTEN protein expression.43,44 
2.5.3.1.3. 
 
2.5.4 Docetaxel and AZD8186 Pharmacokinetics (Integrated biomarker) 
2.5.4.1.1. 
Background:  Clinical Pharmacology of Docetaxel and AZD8186 
and Drug-Drug Interaction Potential: Docetaxel is metabolized primarily by 
CYP3A4 to at least four inactive metabolites and is susceptible to drug-drug 
interactions.45 46  Docetaxel is also a substrate for the drug transporter 
ABCB1 (P-glycoprotein), encoded by the MDR1 gene.47 AZD8186 may be 
a substrate for and induce CYP3A4. Given docetaxel is a narrow 
therapeutic-index drug with ~40% intersubject variability in drug 
clearance,48 there is a potential for reduced docetaxel concentrations when 
co-administered with AZD8186. Therefore, pharmacokinetic (PK) 
characterization would help confirm the potential clinical consequences of 
concurrent docetaxel and AZD8186. 
 
2.5.4.1.2. 
Hypothesis:  The interaction between AZD8186 and docetaxel 
will not result in clinically meaningful alterations in exposure. 
2.5.4.1.3. 
Aims: To investigate a drug-drug interaction between docetaxel 
and AZD8186. To correlate drug exposure with pharmacodynamics 
response. 
 
 
 
 
 

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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically confirmed malignancy that is metastatic or 
unresectable and for which standard curative or palliative measures do not exist or are 
no longer effective. 
 
3.1.2 Patients must be able to swallow and retain oral medications and be without 
gastrointestinal illnesses that would preclude absorption of AZD8186.  
 
3.1.3 Unlimited prior therapies allowed  
 
3.1.4 Docetaxel appropriate 
3.1.4.1 
Patients who have not received prior docetaxel (or other taxane therapy) in the advanced 
setting are eligible for all cohorts 
3.1.4.2  
Patients who have previously received docetaxel(or other taxane therapy) in the 
 
advanced setting are eligible for the dose escalation cohort only, if anticipated to have
 
maintained taxane sensitivity and in the opinion of the investigator would still benefit 
 
from further docetaxel therapy.   
 
3.1.5 Age ≥18 years.   
3.1.5.1 
Because no dosing or adverse event data are currently available on the use of AZD8186 
in combination with Docetaxel in patients <18 years of age, children are excluded from 
this study, but will be eligible for future pediatric trials. 
 
3.1.6 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.7 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
hemoglobin 
 
 
≥8 g/L 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin* 
within normal institutional limits  
− 
AST(SGOT)/ALT(SGPT) 
≤1.5 × institutional upper limit of normal 
− 
creatinine 
within normal institutional limits 
OR 
− 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 

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3.1.8 PTEN or PIK3CB mutated advanced solid tumor. 
3.1.8.1 
PTEN loss of function mutation or PIK3CB gain of function mutation identified by local 
CLIA certified next generation sequencing (NGS). 
3.1.8.1.1. 
A curated list of PTEN variants with the corresponding literature 
to support their loss of function is found in Appendix B of this LOI. 
3.1.8.1.2. 
A curated list of PIK3CB variants with the corresponding 
literature to support their gain of function is found in Appendix C of this 
LOI 
 
3.1.8.2 
Breast cancers patients enrolled on this study must have either: 
3.1.8.2.1. 
Estrogen receptor positive and HER2 negative breast cancer 
3.1.8.2.2. 
Triple negative breast cancer 
 
 
3.1.9 Adequate archival tissue (metastatic tissue sample is preferable but primary tumor 
tissue will be acceptable) or willing to undergo pre-treatment biopsy (for central 
confirmation of molecular alteration and PTEN immunohistochemical assessment) if 
adequate archival tissue is unavailable. 
 

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3.1.10 The effects of AZD8186 on the developing human fetus are unknown.  For this reason, 
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 and for 
the duration of study participation.  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 AZD8186 administration. 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
3.1.12 Cohort specific eligibility: 
3.1.12.1 
Dose escalation cohort:  
3.1.12.1.1. 
Prior receipt of docetaxel is permitted (see 3.1.4.2) 
3.1.12.1.2. 
Measurable disease is not required for enrollment 
3.1.12.2 
Pharmacodynamic expansion cohort: 
3.1.12.2.1. 
Prior receipt of docetaxel is not permitted (see 3.1.4.1) 
3.1.12.2.2. 
Patients must have measurable disease, defined as at least one 
lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal 
lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT 
scan, MRI, or calipers by clinical exam.  See Section 11 for the evaluation of 
measurable disease.  
3.1.12.2.3. 
Consent to allow mandatory paired (pre- and on- treatment) fresh 
tissue biopsies if deemed safe to do so for quantitation of Akt pathway 
signaling proteins 
3.1.12.3 
Disease specific expansion cohorts 
3.1.12.3.1. 
Prior receipt of docetaxel is not permitted (see 3.1.4.1) 
3.1.12.3.2. 
Patients (excepting the prostate cancer patients) must have 
measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest 
x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical 
exam.  See Section 11 for the evaluation of measurable disease.  
3.1.12.3.3. 
Breast cancers patients enrolled on this study must have: 
3.1.12.3.3.1. Metastatic or advanced (incurable and unresectable) HER2 
negative breast cancer regardless of estrogen receptor status (both 
hormone receptor positive and triple negative patients are eligible) 
3.1.12.3.3.2. Received hormonal therapy, as appropriate based on their 
hormone receptor status. Hormone receptor positive patients who have 
not received endocrine therapy for recurrent/metastatic disease are 
eligible, permitted their physician feels they are not appropriate for first 
line endocrine therapy, for example for high risk visceral metastatic 
disease.  
3.1.12.3.4. 
Prostate cancers patients enrolled on this study (applies to all 
prostate cancer patients treated on parts 1, 2, and 3) must have: 
3.1.12.3.4.1. Metastatic or advanced (incurable and unresectable) castration 
resistant metastatic cancer 

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3.1.12.3.4.2. Received at least one additional line of anti-androgen therapy with 
abiraterone or enzalutamide.  
3.1.12.3.4.3. Measurable disease is not required for enrollment 
 
3.2 
Exclusion Criteria 
 
3.2.1 HER2 positive breast cancer. 
 
3.2.2 Prior treatment with PI3K/AKT inhibitors. 
 
3.2.3 Any known concurrent RAF or PIK3CA mutation. 
 
3.2.4 Patients who have had chemotherapy, radiotherapy, immunotherapy or anticancer 
agents within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of the first dose of 
study treatment, except hormonal therapy with LHRH analogues for medical castration 
in patients with prostate cancer and breast cancer, which are permitted 
 
3.2.5 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > Grade 1)   
 
3.2.6 Patients who are receiving any other investigational agents. 
 
3.2.7 Patients with known, untreated or unstable 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. Patients with treated brain metastases are eligible if the 
metastases have been radiographically and clinically stable for at least one month. If 
on steroids for this indication, the patient must be on a stable dose for at least one 
month.  
 
3.2.8 History of clinically significant allergic reactions attributed to compounds of similar 
chemical or biologic composition to AZD8186 or Docetaxel or to Docetaxel itself. 
 
3.2.9 Patients receiving any medications or substances that are strong inhibitors and/or 
strong or moderate inducers of CYP3A4 are ineligible. Because the lists of these 
agents are constantly changing, it is important to regularly consult a frequently-
updated medical reference. 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.  [Appendix D: patient information sheet] 
 
3.2.10 Existing bleeding or condition associated with increased risk of bleeding  
3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 

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Documentation Required 
IVR 
NPIV
R 
AP 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and 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).     
 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm >. For questions, please contact the RCR 
Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
4.1.1 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 

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be processed, the Signatory Institution must inform the CTSU which CIRB-approved institutions 
aligned with the Signatory Institution are participating in the study. 
 
Participating Organizations: 
  
Part 1 Dose escalation cohort 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
                           
LAO restricted to: 
• MD017/ JHU Sidney Kimmel Comprehensive Cancer Center 
• NY016 / Memorial Sloan Kettering Cancer Center 
• NY478 / Memorial Sloan Kettering Westchester 
• NJ299/ Memorial Sloan Kettering Monmouth 
 
LAO-TX035/ University of Texas MD Anderson Cancer Center LAO 
 LAO restricted to: 
• TX035/ University of Texas MD Anderson Cancer Center 
 
LAO-NCI/ National Cancer Institute LAO 
 
Part 2 Pharmacodynamic expansion cohort/ Part 3 Disease specific expansion cohort 
Open to all sites in LAO Participating Organizations table: 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
4.1.2 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the [NCI protocol #10131] 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 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.  

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41 
 
• 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, then select LAO-MD017  and 
protocol #10131. 
• Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.  (Note: For sites under the CIRB initiative, IRB 
data will load to RSS as described above.) 
 
4.1.3 Requirements For NCI protocol #10131 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)  
• A Site initiation visit (SIV) is required for each participating site prior to activation. 
The local site PI must participate on the call as well as their research nurse, study 
coordinator, and pharmacist. To schedule a SIV, please email the Protocol Liaison 
and crocc@jhmi.edu and reference the protocol in the subject line of the email.   
 
4.1.4 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. 
 
4.1.5 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 to the members’ area 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 #:10131 
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42 
 
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. 
 
4.2 
Patient Registration 
 
4.2.1 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. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.2.2 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. If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
• 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. 
 
4.2.3 Patient Enrollment Instructions   
 
Sites must reserve a slot in IWRS and then submit documentation to the study team before 
their slot request will be approved and they are able to enroll the patient in OPEN. 
 
• A biomarker request form of the patient’s mutation must be been signed and 
approved for eligibility by the Principal Investigator. (Appendix E) 

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4.2.4 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 at 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.3 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 28 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 
 
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 intent to treat the patient's malignancy. 
 
Enrolled patients will initiate treatment with AZD8186 and Docetaxel beginning Day 1 of Cycle 1, 
excepting in the pharmacodynamic expansion cohort where patients will begin AZD8186 only on 
Day -7 (AZD8186 monotherapy lead-in). A cycle is 21 days. See below for details regarding 
administration of each agent.  
 
Per the drug manufacturer AstraZeneca, clinical supply of AZD8186 60 mg tablets will expire on 
April 30, 2022 (based on the planned expiration date extension).  Supplies can be used until the 
terminal lot shelf life dating is reached or the NCI inventory is exhausted.  All patients must 
complete their last treatment on or before April 30, 2022, and the study will be closed to accrual and 
treatment to coincide with this expiration date. 
 
Prophylactic growth factor support (i.e., G-CSF or peg G-CSF) with docetaxel should be 
administered during the first cycle of therapy per institutional guidelines and per the provider’s 
discretion on subsequent cycles. 
 
While on study, patients will return for assessments every week during the first cycle, then every 3 
weeks.  
 

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Patients that require discontinuation of one study agent (AZD8186 or Docetaxel), but meet criteria 
to continue the other study agent (AZD8186 or Docetaxel) may do so after discussion with the 
study chair. 
 
Docetaxel can be discontinued and AZD monotherapy continued if the patient develops intolerable 
G2 or greater toxicity deemed related to docetaxel (including but not limited to nail toxicity, edema, 
weight gain, and neuropathy). 
 
During screening, every 6 weeks (±7 days) for the first 24 weeks then every 12 weeks (±7 days), 
and at the end of study, patients will have tumor imaging studies (a CT or MRI of the abdomen and 
pelvis and a CT of the chest) performed.  
 
A patient will be permitted to have a new cycle of therapy delayed up to 7 days (without this being 
considered to be a protocol violation) for major life events (e.g., serious illness in a family member, 
major holiday, vacation which is unable to be re-scheduled). Documentation to justify this decision 
should be provided.   
 
Beyond the DLT period, it will be acceptable for a new cycle of therapy (and all associated tests 
and procedures) to be delivered within a 3 day window before and after the protocol defined date. 
 
Table 2 Regimen Description 
 
Regimen Description 
Agent 
Premedications; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Docetaxel 
 
Premedicate according to 
institutional guidelines. 
Recommended pre-medication 
with dexamethasone  
8 mg orally twice daily x 3 
days (or at the discretion of the 
investigator), to begin the day 
before treatment (6 doses) 
 
Recommend close observation 
for hypersensitivity reactions, 
especially during the first and 
second infusions, including an 
assessment of vital signs (body 
temperature, pulse rate, 
respiration rate, blood 
pressure) and weight prior to 
administration and monitoring 
of patient continuously during 
and up to 2 hours from the end 
of the the infusion on C1D1 
and C2D1. 
**  in 
NS or 
D5W 
 
IV over 1 
hour  
Day 1 
21 days  
(3 weeks) 
 
 
 

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AZD8186 
 
Taken at approximately the 
same time each day on an 
empty stomach and 
approximately 12 hours apart  
** tablet PO in the 
a.m. and 
p.m. (water 
only for at 
least 2 
hours prior 
and 1 hour 
after each 
dose) 
Starting on 
Day 1, 
administered 
for 5 days on, 
2 days off, 
every week, 
 
(Pharmacody
namic 
expansion 
cohort only, 
start on Day 
-7) 
**Doses as appropriate for assigned dose level. 
 
The patient will be requested to maintain a medication diary of each dose of medication (Appendix 
F).  The medication diary will be returned to clinic staff at the end of each course. Missed doses 
should be recorded in the pill diary but will not be considered deviations to the protocol. 
 
 
5.2 
Part 1: Dose escalation cohort  
 
Figure 2 Dose escalation cohort schema 
  
 
(n= 9 -21) 
 
 
 
 
 

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   Dose Escalation Schedule 
 
Dose Escalation schema 
Dose Level 
Dose 
AZD8186 
BID PO, 5 days on, 2 days off 
every week 
(mg) 
Docetaxel 
IV on day 1 of a 21-day 
cycle 
(mg/m2) 
-1* 
30 
75 
-1B* 
60 
60 
Starting dose level 1*  
60 
75 
2* 
120† 
75 
Please refer to Section 5.5 for DLT definition. 
†AZD8186 dosed at 90mg bid 5 days on /2 off may be explored, as directed by the emerging 
safety profile of this agent.  
*Prophylactic growth factor support with docetaxel should be administered during the first 
cycle of therapy per institutional guidelines and per the provider’s discretion on subsequent 
cycles. Since the protocol was amended to include the use of prophylactic growth factor during 
DL-1B, patients who experienced a DLT of neutropenia or neutropenic fever at this dose level 
prior to the implementation of prophylactic growth factor maybe replaced. 
Note: DL -1B was added in an amendment based on the emerging safety profile 
 
 
• 
DLT evaluation period: 21 days (i.e. the duration of cycle 1) 
• 
Patients will be evaluated weekly during the DLT evaluation period: 
– C1D1, C1D8 (± 1 day), C1D15 (± 1 day), C2D1 (± 1 day). 
 
 
5.3 
Part 2: Pharmacodynamic expansion cohort: NO LONGER OPEN   
 
Figure 3 Pharmacodynamic expansion cohort schema 

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(n= 10) 
 
5.4 
Part 3: Disease specific expansion cohort: NO LONGER OPEN 
 
Figure 4 Disease specific expansion cohort schema 
 
(n=36) 
 

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5.4.1 AZD8186  
 
Please refer to the regimen description, Table 2.  
Note that for the pharmacodynamic expansion cohort specifically, patients will begin 
AZD8186 only on Day -7 (AZD8186 monotherapy lead-in).  
 
AZD8186 will be taken orally twice daily at approximately the same time each day on an 
empty stomach (water only for at least 2 hours prior and 1 hour after each dose) and 
approximately 12 hours apart for 5 days on, 2 days off every week. 
 
5.4.2 Docetaxel  
 
Please refer to the regimen description, Table 2.  
 
Administration of Docetaxel will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
Anaphylactic precautions should be observed during Docetaxel administration.  
Premedication in order to prevent the onset of hypersensitivity reaction (HSR) and to reduce 
and/or delay the occurrence of skin toxicity and fluid retention related to docetaxel, will be 
according to institutional guidelines with recommendations detailed in the regimen 
description, Table 2. Additional antiemetic premedication may be employed at the 
discretion of the investigator. 
 
Sites should consult the manufacturer’s instructions for docetaxel for complete prescribing 
information (including warnings, precautions, contraindications and adverse reactions) and 
follow institutional procedures for the administration of docetaxel. 
 
5.5 
Definition of Dose-Limiting Toxicity 
 
A DLT is defined as any treatment related toxicity (i.e., not attributable to the disease or 
disease-related processes under investigation) during the first 21 days of multiple dosing 
(i.e. from dosing on cycle 1, day 1 until dosing would be due on day 22), which includes: 
 
1. Hematological toxicities as follows: 
a. Grade 4 neutropenia (ANC < 500 cells/mm3) lasting longer than 7 consecutive 
days despite growth factor support  
b. Grade 3 neutropenia of any duration accompanied with fever ≥ 38.5°C and/or 
systemic infection 
c. Grade 3 thrombocytopenia with bleeding 
d. Any other confirmed and clinically significant hematological toxicity ≥ Grade 4 
(a repeat test may be required for confirmation of an isolated abnormality in the 
absence of clinical signs, symptoms or other abnormal investigations, i.e., a 
suspected spurious value). 
 
 

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2. Non-hematological toxicity ≥ Grade 3 including: 
a. Laboratory abnormalities (a repeat test may be required for confirmation of an 
isolated abnormality in the absence of clinical signs, symptoms or other 
abnormal investigations, i.e., a suspected spurious value). 
b. QTc prolongation (> 500 msec corrected using Fridericia’s formula) in the 
presence of normal serum potassium 
 
3. Hepatotoxicities as follows: 
a. Elevations of ALT or AST by 3-fold or greater above the upper limit of normal 
with elevation of serum total bilirubin of greater than 2× the upper limit of 
normal, without findings of cholestasis (defined as serum alkaline phosphatase 
activity less than 2× the upper limit of normal). 
b. No other reason can be found to explain the combination of increased 
aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, 
ischemia, preexisting liver disease, or another drug capable of causing the 
observed injury. 
4. Any other toxicity i.e., greater than at baseline, is clinically significant and/or 
unacceptable, does not respond to supportive care and results in a disruption of the 
dosing schedule of more than 14 days. 
5. Any event, including significant dose reductions or omissions, judged to be a DLT by 
the Investigator. 
A DLT excludes: 
1. 
Alopecia of any grade 
2. 
Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea 
(all patients should receive optimal anti-emetic and/or anti diarrheal prophylaxis and/or 
treatment). 
All participating sites are expected to notify the Principal Investigator when a DLT has occurred. 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-limiting 
toxicity (DLT) is defined above. Patients who do not complete 75% of the study drug (AZD8186) 
during the DLT period due to reasons other than drug toxicity will be replaced. 
 
Table 4 Dose escalation decision rules 
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 

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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 maximally tolerated dose (MTD)/ 
recommended phase 2 dose (RPD2). At least 6 patients 
must be entered at the recommended phase 2 dose. 
* If  Dose Level -1B is not deemed tolerable due to neutropenia, 3 more patients can be treated at 
this dose level with growth factor support.  
 
5.6 
Dose Expansion Cohorts 
 
Once Part 1: Dose escalation cohort of the study is completed and the MTD/RP2D is reached, parts 
2 and 3 will be opened concurrently and an additional 46 patients will be treated at the MTD. For 
the expansion cohorts, patients will continue to be monitored for occurrence of DLT during the 
DLT period (cycle 1, as defined for the dose escalation cohort above).  
DLT data from the first 6 consecutively enrolled subjects to Parts 2 or 3 will be combined with DLT 
data from the 6 subjects treated at the MTD in Part 1. If, at any point, 4 or more total DLTs are 
observed across the combined 12 patients, further enrollment will be halted as the safety stopping 
rule will have been met. At this point, the study would be amended in consultation with the board to 
ensure ongoing subject safety.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 
Medidata Rave using the Web Reporting Module.  All participating sites are expected to notify the 
Principal Investigator when a DLT has occurred. 
 
 
5.7 
General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant therapy includes any prescription medications or over the counter preparations used by 
a patient between the 7 days preceding the screening evaluation and the treatment discontinuation 
visit.  
 
Because there is a potential for interaction of AZD8186 with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs (including the use of 
supportive care medications or premedications such as dexamethasone), 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. For example, the 
potential targets for drug interaction can involve, but are not limited to CYP450, glucuronidation, P-
glycoprotein, protein binding, or reduced absorption from proton-pump inhibitors.   

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It is probable that AZD8186 is predominantly eliminated via CYP3A4 metabolism; therefore 
CYP3A4 inhibitors or inducers may increase or decrease exposure to AZD8186, respectively. 
Strong and moderate inhibitors or inducers of CYP3A4/5 should not be combined with AZD8186. 
Weak inhibitors or inducers of CYP3A4/5 are permitted but caution should be exercised and 
patients monitored closely for drug interactions. Dexamethasone is a weak CYP3A4 inhibitor but is 
required per standard of care premedication for docetaxel. Dexamethasone 8 mg orally twice daily x 
3 days is recommended to decrease both HSR and fluid retention rate in patients receiving 
docetaxel every 21 days ( Table 2 Regimen). 
 
Check the study agent Investigator’s Brochure for potential sources of drug interactions.  The study 
team should check a frequently-updated medical reference for a list of drugs to avoid or minimize 
use of.  Appendix D (Patient Drug Information Handout and Wallet Card) should be provided to 
patients if available. 
 
Any concomitant therapy intended for the treatment of cancer, whether health authority-approved or 
experimental, is prohibited. This includes but is not limited to the following: Chemotherapy, 
hormonal therapy (except LHRH analogues for medical castration in patients with breast or prostate 
cancer, which are permitted), immunotherapy, radiotherapy, investigational agents, or herbal 
therapy.  
 
Supportive care and other medications considered necessary for the patient’s well being may be 
given at the discretion of the investigator. 
 
5.7.1 Anticoagulation or thrombolytic therapy 
The use of  vitamin K antagonists is not permitted on the study. Patients requiring anti-
coagulation should be given standard or low molecular weight heparins, or factor Xa 
inhibitors. 
 
5.7.2 Recombinant Granulocyte Colony Stimulating Factor (G-CSF) 
Primary prophylactic administration should be given with Cycle 1 and with subsequent 
cycles per investigator discretion  
 
5.7.3 Blood transfusions  
No primary prophylactic administration (for or during the first cycle) is permitted. 
Blood transfusions may be administered during subsequent cycles. 
 
5.7.4 Bone modifying agents 
The use of bisphosphonates and RANK ligand inhibitors are permitted on the study.  
 
5.8 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for until one of 
the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 

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• 
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 
 
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). 
 
5.9 
Duration of Follow Up 
 
Patients will be followed for a minimum of 30 days after removal from protocol treatment or until 
death, whichever occurs first.   
 
Patients removed from protocol treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event.  
 
Patients who discontinue for reasons other than progression should be imaged when they come off 
protocol treatment and then every 3 months until progression of disease or beginning of alternative 
anticancer therapy. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Investigator judgment is required for all dose modifications. Reductions in AZD8186 and/or 
docetaxel may be appropriate depending on the clinical context. If the adverse event is more clearly 
related to Docetaxel based on the known toxicity profile of this drug, then dose reductions of 20% 
decrements (where dose level -1 is 60mg/m2 and dose level -2 is 45/mg/m2) according to the 

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approved product information (prescribing information) should be used, whilst maintaining the 
AZD8186 dose and schedule. Patients cannot be dose reduced to dose level -1. When patients 
require dose modification due to toxicity possibly related to AZD8186, the dose should be 
decreased by 60 mg (i.e., 120 mg BID can have a single dose reduction to 60 mg BID). If more than 
2 dose reductions are required, AZD8186 should be discontinued.  
 
If a patient experiences several adverse events and there are conflicting recommendations, the 
investigator should use the recommended dose adjustment that reduces the dose to the lowest level. 
 
If a patient experiences any of the following listed below, dosing will be interrupted and supportive 
therapy administered as required in accordance with local practice/guidelines: 
• Any of the following AEs not attributable to the disease or disease-related processes under 
investigation: CTCAE grade 2 or higher maculopapular rash, chills, fever, 
hypersensitivity/allergic response, or any other immune mediated AE such as colitis 
• And/or any other CTCAE grade 3 
• And/or unacceptable toxicity including a DLT not attributable to the disease or disease-
related processes under investigation (refer to Section 5.5 for DLT definition). 
 
If the toxicity resolves or reverts to ≤ CTCAE grade 1 within 21 days of onset and there are no 
safety concerns for retreatment, AZD8186 and/or Docetaxel may be restarted at the same dose or a 
lower dose using the rules below for dose modifications. 
 
 
If the toxicity does not resolve to ≤ CTCAE grade 1 after 21 days of dose interruption, then the 
patient should be permanently discontinued from AZD8186 and Docetaxel (withdrawn from the 
study) and observed until resolution of the toxicity. NOTE: Patients that require discontinuation of 
one study agent but meet criteria to continue the other study agent may do so after discussion with 
the study chair.  
 
On resolution of toxicity within 21 days: 
− 
If a further episode of the same AE subsequently requires dose interruption, 
AZD8186 and/or Docetaxel must restart at one dose level lower on 
improvement of the AE. 
− 
If a different AE subsequently requires dose interruption, AZD8186 and/or 
Docetaxel may restart at the same or one dose level lower on improvement of 
the AE at the discretion of the Investigator and agreement with the Principal 
investigator. 
 
Table 6 Dose modifications 
 
Nausea 
Management/Next Dose for 
AZD8186 
Management/Next Dose for 
Docetaxel  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose  
 
No change in dose  
 

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Nausea 
Management/Next Dose for 
AZD8186 
Management/Next Dose for 
Docetaxel  
May consider holding 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 >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
 
Vomiting 
Management/Next Dose for 
AZD8186 
Management/Next Dose for 
Docetaxel  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose  
 
May consider holding until ≤ 
Grade 1.  Resume at same dose 
level. 
No change in dose  
 
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 >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Recommendations for treatment of diarrhea/colitis 
 
Patients should be made aware of the risk of diarrhea while receiving treatment with 
AZD8186. Patients should be advised to drink sufficient fluids and have a supply of 
loperamide available throughout treatment. However, loperamide should not be administered 
prophylactically. 
 
As soon as the first liquid stool occurs, patients should start treatment with loperamide 
immediately (to be administered per package information and usual clinical practice) and also 
take electrolyte-containing fluids. Patients should inform their study doctor. Loperamide 
should not be administered for more than 48 consecutive hours. 
 
Infectious diarrhea should be excluded by standard of care investigations, for example, 
caused by infections with C. difficile or Salmonella. If positive, patients must be treated 
according to local practice. 
 
Hospitalization is recommended for management of diarrhea under the following 
circumstances: 
• Diarrhea associated with fever 

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• Diarrhea requiring intravenous hydration 
• Diarrhea persisting beyond 48 hours following the initiation of high-dose loperamide 
therapy. 
Suspected drug-induced colitis as the cause of diarrhea of chronic (i.e. >3 loose stools per 24 
hours for more than 4 weeks), intermittent or chronic recurrent course, should be confirmed 
by standard of care investigations including colonic tissue biopsy and treated by standard local 
practice including high-dose steroids with tapering down of the dose over 3-4 weeks. 
 
Diarrhea 
or colitis  
 
Management/Next Dose for 
AZD8186 
Management/Next Dose for 
Docetaxel  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold, reassess 24-48 hrs later. 
Once ≤ Grade 1 (within 21 days), 
resume at same dose level. 
No change in dose 
Grade 3 
Hold, reassess 24-48 hrs later. 
Once ≤ Grade 1 (within 21 days), 
resume at one dose level lower.** 
If unresolved , hospitalize (if not 
already) with GI consult 
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 >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours). Should not be administered for more 
than 48 consecutive hours. 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Recommendations for treatment of rash 
 
Patients who develop Grade 1 or 2 changes in their skin condition should be treated with the 
Investigator’s choice of antihistaminergic drugs, over the counter moisturizing cream or ointment, 
local antihistamines and/or topical or systemic steroids. If bacterial infection is suspected, local 
and/or systemic antibiotics may be added. 
 
For Grade 3 rash, topical and/or systemic steroids with or without topical and/or systemic 
antibiotics (to be considered if bacterial infection is suspected) are indicated, together with 
dose modifications as described in section 5.9.2; short courses (mod days) of corticosteroid 
treatment at doses that do not exceed 100 mg per day of prednisone or equivalent may be 
given. 
 
Example treatments: 
• Topical steroids: triamcinolone acetonide 0.025%; desonide 0.05%; fluticasone proprionate 
0.05%, alclometasone 0.05% 
• Topical antipruritics: pramoxine 1%; doxepin 5% cream 

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• Oral antihistamines: loratidine, cetirizine, fexofenadine; diphenhydramine 25-50 mg every 
8h; hydroxyzine 25 mg every 8h 
• Topical antibiotics: clindamycin 1-2%; erythromycin 1-2%; metronidazole 1%; silver 
sulphadiazine1% 
• Oral antibiotics: doxycycline 100 mg BD; minocycline 100 mg BD; tetracycline 500 mg 
 
 
 
Hematologic Dose Modifications 
 
Neutropenia 
Management/Next Dose for 
AZD8186 
Management/Next Dose for 
Docetaxel  
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
No change in dose  
Hold* until ≤ Grade 1.  Resume at 
one dose level lower and/or initiate 
G-CSF, if not given 
prophylactically.** 
Grade 4 
Hold* until ≤ Grade 2.  Resume at 
one dose level lower and/or initiate 
G-CSF if not given 
prophylactically. ** 
Hold* until ≤Grade 1.  Resume at 
one dose level lower and/or initiate 
G-CSF if not given 
prophylactically..** 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should permanently discontinue docetaxel. 
 
 
Thrombocytopenia 
Management/Next Dose for 
AZD8186 
Management/Next Dose for 
Docetaxel 
≤ 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 1.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower.** 
Hold* until ≤ Grade 1.  Resume at 
one dose level lower.** 
*Patients requiring a delay of >3 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
With recurrence of G4 neutropenia/thrombocytopenia or a G3 febrile neutropenia event despite one 
docetaxel dose reduction, the participant should be removed from docetaxel chemotherapy. 
 
Additional hemostatic criteria for AZD8186 dosing 
 
Patients requiring anti-coagulation should be given standard or low molecular weight heparins, or 
factor Xa inhibitors. Vitamin K antagonists are not permitted during the study period. If the patient 
is on an anti-platelet agent, this will be interrupted in line with the investigator’s usual practice if 

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there is significant evidence of bleeding or bleeding risk. Similarly, during the study period, anti-
platelet agents should be stopped 7 days prior to any biopsies or surgical procedures and restarted 
afterwards. 
 
If the patient is showing clinical benefit and the above improve to baseline or to the normal range 
treatment with AZD8186 may be permitted to restart at a de-escalated dose at the discretion of the 
Investigator. 
 
Hepatic Toxicity 
• Hold docetaxel if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with 
alkaline phosphatase > 2.5 x ULN.  If laboratory abnormalities improve sufficiently to 
resume, decreased docetaxel dose by 1 dose level. 
• Hold AZD8186 for Grade 2 bilirubin, or Grade 3 ALT and/or AST elevation.  If the toxicity 
resolves or reverts to ≤ CTCAE grade 1 within 21 days of onset and there are no safety 
concerns for retreatment, AZD8186 and may be restarted at the same dose or a lower dose 
using the rules for dose modifications. 
• If no recovery after 3 weeks, participant will be removed from study treatment. 
 
Dose Modifications for Docetaxel Infusion (Allergic/Hypersensitivity) Reactions 
 
• In the event of an infusion reaction, follow the Institutional Guidelines of each site and/or 
the recommendations shown in the tables below, based on the grade of the reaction. 
• To identify the grade of a reaction, refer to the list below adapted from the General 
Disorders and Administration Site Conditions section of the NCI CTCAE Version 4.0: 
o Grade 1: Mild transient reaction; infusion interruption not indicated; intervention 
not indicated. 
o Grade 2: Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids indicated 
for ≤24 hours). 
o Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical sequelae Note: any infusion 
that is interrupted and not resumed within the visit will be considered a Grade 3 
reaction. 
o Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Docetaxel Infusion 
Reactions 
Management/Next Dose for [Agent Name] 
≤ Grade 1 
Interruption or intervention not indicated. Slow the rate of infusion of 
the drug until resolution of symptoms, then resume at the planned 
infusion rate. 
Grade 2 
Interrupt the infusion. Follow institutional guidelines or give steroids 
(e.g. Dexamethasone 8 mg IV), diphenhydramine 50 mg IV, and/or an 
H2 blocker (e.g. Ranitidine 50 mg IV) after consultation with the 
attendant physician. Resume after recovery of symptoms at a slower 

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Docetaxel Infusion 
Reactions 
Management/Next Dose for [Agent Name] 
rate, and then increase incrementally toward the initial rate. If the 
reaction reoccurs, stop the infusion and do not administer the 
remaining volume. 
Grade 3 or 4 
Stop the infusion. Treat the participant as per grade 2 reaction above. 
Discontinue docetaxel permanently. 
 
 
Docetaxel Dose Modifications for Neurotoxicity 
 
• For grade 4 neurotoxicity, the participant should be removed from study treatment. 
• For grade 3 neurotoxicity, docetaxel should be held until toxicity resolves to ≤ grade 1. 
Resume docetaxel at a dose reduction of one level. 
 
Docetaxel Dose Modifications for Fluid Retention 
 
• There are no dose reductions for fluid retention. Participants should be treated with salt 
restrictions and diuretics.  
• More aggressive therapy depends on the clinical situation. In severe situations, the 
Investigator, with the participant, should determine if it is in the participant’s best interest to 
continue or discontinue study treatment. 
 
Docetaxel Dose Modifications for Mucositis  
 
• For grade 4 mucositis (life-threatening), the participant should be removed from study 
treatment. 
• For grade 3 mucositis present on Day 1 of a cycle, docetaxel should be held until toxicity 
resolves to grade 1. Resume docetaxel at a dose reduction of one level. 
• If the grade 3 mucositis does not resolve within 3 weeks, the participant should be removed 
from study treatment. 
 
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 and 7.3) 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 Lists (CAEPRs) 
 
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).   

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• Hepatic: increased transaminase, alkaline phosphatase, and bilirubin, hepatic failure, 
hepatic drug reaction. 
• Pulmonary: dyspnea with restrictive pulmonary syndrome, pleural effusions. 
• Other: asthenia, dysgeusia, anorexia, conjunctivitis, arthralgia, muscle aches, 
myopathy, peripheral edema, fluid retention syndrome, ascites, fever, flu-like 
symptoms. 
 
Please refer to the package insert for the comprehensive list of adverse events with this 
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 5.0 
will be utilized for SAE reporting only. This study will continue to utilize CTCAE version 
4.0 for routine toxicity reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0 and 5.0. A copy of the CTCAE version 4.0 and 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. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
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 
 
7.3.1 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.h
tm).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
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 

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notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 
7.3.2 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.  
 
7.3.3 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” in 
the system organ class (SOC) “General disorders and afministration 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.  
 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS 
recognizes this event as a patient death.  
 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
 
 
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 

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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.  
 
Loading of the pathology report is required. 
 
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 or commercial 
agent administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent 
 
8.1.1 AZD8186  (NSC #785347) 
 
Chemical Name: 8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholino-4-oxo-
chromene-6-carboxamide 
 
Other Names: none 
 
Classification: PI3K beta and delta inhibitor 
 
Molecular Formula: C24H25F2N3O4  
 
M.W.: 457.42 
 
Approximate Solubility: AZD8186 solubility is 0.16 mg/mL at pH 1.5, 0.08 mg/mL at pH 6.6 
and 0.11 mg/mL in Fasted State Simulated Intestinal Fluid. 
Mode of Action: AZD8186 is a potent and oral inhibitor of phosphatidylinositol 3-kinase 
(PI3K), selective for beta and delta isoforms.  The PI3K/AKT/mTOR signaling pathway is a 
critical regulator of proliferation, survival and transformation of cells. This pathway is 
frequently de-regulated is human cancers and is suitable to targeted therapy.  
 
Description: AZD8186 is a crystalline powder. 

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How Supplied: AstraZeneca supplies and CTEP, NCI, DCTD distributes AZD8186 as film-
coated tablets containing 30 mg and 60 mg of AZD8186. Tablets are packaged in 36-count 
HDPE bottles with an induction seal and child-resistant cap. Supplies of 30 mg tablets can be 
used until the terminal lot shelf life dating of  November 30, 2021 is reached or the NCI 
inventory is exhausted. Supplies of 60 mg tablets can be used until the terminal lot shelf life 
dating of April 30, 2022 is reached or the NCI inventory is exhausted. 
 
Tablet excipients include mannitol, colloidal silicon dioxide, di-calcium phosphate 
(anhydrous), sodium starch glycolate, microcrystalline cellulose, sodium lauryl sulfate and 
magnesium stearate. The tablets are film coated with Opadry.  
 
Storage: Store intact bottles below 30° C.  
 
 
If a storage temperature excursion is identified, promptly return AZD8186 to less than 30° C 
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:  Stability studies are ongoing. 
 
Repackaging is not allowed and tablets must be dispensed in the original container. If exact 
quantity must be dispensed, then extra tablets should be removed, documented as waste and 
destroyed immediately. 
 
Route and Method of Administration: Oral. Take on an empty stomach with water only for 
at least 2 hours prior and 1 hour after each dose. 
 
Potential Drug Interactions:  In vitro studies demonstrate AZD8186 is predominantly 
metabolized by CYP3A4/5 and CYP1A2 and to a lesser extent by CYPs 2C8, 2C9, 2D6 and 
2C19. Avoid concomitant administration of potent CYP3A4/5 and CYP1A2 
inducers/inhibitors.  
 
In vitro studies suggest AZD8186 is a weak inhibitor of CYP2C9 and OATP1B1 and an 
inducer of CYP3A4/5 and to a lesser extent for CYP2B6. No enzyme induction was 
observed for CYP1A1/2 and no inhibition was observed for CYP 1A2, 2C8, 2B6, 2C19, 
2D6, 3A4/5 and P-glycoprotein. Avoid concomitant administration of sensitive substrates of 
CYP2C9, CYP3A4/5, CYP2B6 and OATP1B1 since there is a potential for drug-drug 
interaction.  
 
Patient Care Implications: Based on preclinical toxicology, AZD8186 is expected to affect 
platelet aggregation. Bleeding risk should be considered before starting treatment and 
monitored throughout study treatment, both clinically and with standard hematology and 
coagulation testing. Anti-coagulants or thrombolytic therapy should be restricted. Anti-
platelet agents may be permitted, but these should be interrupted if there is significant 
evidence of bleeding or bleeding risk. Anti-platelet agents should be stopped 7 days prior to 
any biopsies or surgical procedures and restarted afterwards. 

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Patients will be required to follow UV-light precautions, including use of protective 
clothing, sunglasses and sunscreen with SPF 45+ when outdoors and should be counseled to 
avoid tanning beds. 
 
Availability 
 
AZD8186 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
AZD8186 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
 
8.1.2 Agent Ordering and Agent Accountability  
 
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, a “current” password and active person 
registration status.  Questions about IB access may be directed to the PMB IB 
coordinator via email.   
 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, 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 
participating investigator at that institution. 
 
Study agent must be ordered after patient is registered to the treatment arm as no starter 
supplies are available for this study. 
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, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   

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8.1.2.2 
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. 
 
8.1.2.3 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP 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 
 
8.2 
Commercial Agent: Docetaxel 
 
Docetaxel  
 
Please refer to the FDA approved and appropriate package insert for the standard 
comprehensive mixing instructions and adverse drug reaction information for Docetaxel. 
 
Provided below are the details for Taxotere®, but sites may use the docetaxel formulation 
that is available to them, either concentrate or solution (brand or generic) and refer to the 
appropriate package insert. 
 
Product description: 
 
Taxotere® is a semisynthetic analog of paclitaxel using a precursor extracted from the 
needles of the European yew tree. Taxotere®’s high affinity for binding to microtubules 
enhances tubular polymerization, leading to inhibition of mitosis and cell division. 
Taxotere® is a cell-cycle specific agent with activity in the mitotic phase. Taxotere® is a 
member of the taxoid family. The molecular weight is 861.94 Da. 
 
Product form: Taxotere® is formulated in polysorbate 80 and commercially available. 
Solution preparation: 
Storage and Stability: Storage and stability may vary by manufacturer, refer to specific 
prescribing information. Follow USP 797 recommendations for beyond use dates based on 
the level of risk for preparation. 

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Docetaxel 10 mg/mL: Store intact vials between 2°C to 25°C (36°F to 77°F).Protect from 
bright light. Multi-use vials (80 mg/8 mL and 160 mg/16 mL) are stable for up to 28 days 
after first entry when stored between 2°C to 8°C (36°F to 46°F) and protected from light. 
Solutions diluted for infusion should be used within 4 hours of preparation, including 
infusion time. 
Docetaxel 20 mg/mL concentrate/solution: 
Taxotere: Store intact vials between 2°C to 25°C (36°F to 77°F). Protect from bright light. 
Solutions diluted for infusion in D5W or NS in non-PVC containers should be used within 6 
hours of preparation, including infusion time, when stored between 2°C to 25°C (36°F to 
77°F) or within 48 hours when stored between 2°C to 8°C (36°F to 46°F). 
Generic formulations: Store intact vials between 2°C to 25°C (36°F to 77°F). Protect from 
light. Multi-use vials are stable for up to 28 days after first entry when stored between 2°C 
to 8°C (36°F to 46°F) and protected from light. Solutions diluted for infusion in D5W or NS 
should be used within 6 hours of preparation, including infusion time. Actual 
recommendations may vary by generic manufacturer; consult manufacturer’s labeling. 
Non-alcohol formulation: Store intact vials at 20°C to 25°C (68°F to 77°F). Protect from 
light. After the first use and following multiple needle entries and withdrawals, multi-use 
vials (80 mg/4 mL and 160 mg/8 mL) are stable for up to 28 days when stored between 2°C 
to 8°C (36°F to 46°F) and protected from light. Solutions diluted for infusion in NS or D5W 
are stable for 24 hours when stored between 2°C to 8°C (36°F to 46°F). 
Docetaxel lyophilized powder (Docefrez): Store intact vials between 2°C to 8°C (36°F to 
46°F). Protect from light. Allow vials (and provided diluent) to stand at room temperature 
for 5 minutes prior to reconstitution. After reconstitution, may be stored refrigerated or at 
room temperature for up to 8 hours. Solutions diluted for infusion in D5W or NS should be 
used within 6 hours of preparation, including infusion time. According to the manufacturer, 
physical and chemical in-use stability of the infusion solution (prepared as recommended) 
has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C 
(36°F and 46°F). 
Two-vial formulation (generic; concentrate plus diluent formulation): Reconstituted 
solutions of the two-vial formulation are stable in the vial for 8 hours at room temperature or 
under refrigeration. Solutions diluted for infusion in NS or D5W in polyolefin containers 
should be used within 4 hours of preparation, including infusion time. 
 
Handling: Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
 
Preparation:  
One-vial formulations: Further dilute for infusion in 250 to 500 mL of NS or D5W in a 
non-DEHP container (eg, glass, polypropylene, polyolefin) to a final concentration of 0.3 to 
0.74 mg/mL. Gently rotate and invert manually to mix thoroughly; avoid shaking or 
vigorous agitation. 

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Non-alcohol formulation: Use a 20 gauge needle to withdraw docetaxel from the vial; 
dilute in 250 mL of NS or D5W to a final concentration of 0.3 to 0.74 mg/mL. If docetaxel 
dose is >200 mg, use a larger volume of infusion fluid to maintain a final concentration of 
0.3 to 0.74 mg/mL. Mix by gentle manual rotation. 
Taxotere: Use only a 21 gauge needle to withdraw docetaxel from the vial (larger bore 
needles, such as 18 gauge or 19 gauge needles, may cause stopper coring and rubber 
precipitates). If intact vials were stored refrigerated, allow to stand at room temperature for 5 
minutes prior to dilution. Inspect vials prior to dilution; solution is supersaturated and may 
crystalize over time; do not use if crystalized. 
Two-vial formulation (generic; concentrate plus diluent formulation): Vials should be 
diluted with 13% (w/w) polyethylene glycol 400/water (provided with the drug) to a final 
concentration of 10 mg/mL. Do not shake. Further dilute for infusion in 250 to 500 mL of 
NS or D5W in a non-DEHP container (eg, glass, polypropylene, polyolefin) to a final 
concentration of 0.3 to 0.74 mg/mL. Gently rotate to mix thoroughly. Do not use the two-
vial formulation with the one-vial formulation for the same admixture product. 
 
Route of administration:  
 
The Taxotere® dilution for infusion should be administered intravenously over 
approximately 1-hour per institutional standards, under ambient room temperature (below 
25°C) and lighting conditions. 
Use non-PVC (polyvinylchloride) tubing only; filter not required. 
Infusion control device required for all infusions. 
Agent Ordering:   
 
Taxotere® is commercially available and will not be provided. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Biospecimen collections will be performed in accordance with the Schedule of Procedures detailed 
in the study calendar (Section 10). All specimens should be processed, packaged and shipped 
according to Table 7 and the Specimen Collection and Shipping Guidelines and SOPs in (Appendix 
H and Appendix I). Memorial Sloan Kettering (PI: Michael F. Berger, PhD; Michael Roehrl, MD), 
the Pharmacodynamics Assay Development and Implementation Section (PADIS) laboratories of 
DCTD, NCI (PI: Apurva Srivastava, PhD) and the Analytical Pharmacology Core Laboratory at the 
Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins (PI: Michelle Rudek, 
PharmD, PhD) will act as the receiving sites for biomarker specimens as outlined in Table 7, 
below.  
 
Archival and/or Fresh Tumor Tissue:  
Fresh pretreatment (screening) and/or archival tumor tissues are mandatory for central confirmation 
of the required molecular alteration and PTEN IHC analysis. 

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Fresh pre- and on-treatment biopsies are mandatory for the pharmacodynamic expansion cohort. 
Post-progression biopsies are optional but strongly encouraged for all cohorts. 
 
Tumor samples should be provided in the form of a formalin-fixed paraffin-embedded block. 
Alternatively, unstained slides (as detailed in Appendix H sample requirements) should be 
provided. Bone metastases, final needle aspirates, cytology specimens and alcohol-fixed specimens 
are not suitable. 
 
Whole Blood for Germline DNA:  
Blood will be obtained during the study (preferably acquired during screening, at the same time as 
hematology, serum chemistry, and plasma samples are taken).  
 
Note: Paired analysis of tumors and patient-matched normal samples will be performed for the sole 
purpose of unambiguous detection of somatic mutations. Germline DNA will not be annotated for 
pathogenic mutations. Testing will not be conducted in a CLIA lab but at the MSKCC centre for 
molecular oncology and as such, results will not be returned to the patient. 
 
Plasma for Biomarker Analysis of cfDNA:  
Serial plasma samples for subsequent exploratory biomarker analyses will be collected from each 
patient at every study visit.  
 
Guidelines for whole blood collection for germline DNA and plasma cfDNA are provided in the 
Appendix H.  
 
 
9.1 
Exploratory Correlative Studies 
 
9.1.1 Targeted genomic sequencing with MSK-IMPACT of formalin-fixed, paraffin-
embedded tumor and tumor-derived plasma cell free (cf) DNA samples. 
 
MSK uses a custom, hybridization-based capture panel (MSK-IMPACT)3 to detect single 
nucleotide variants, small indels, copy number alterations, and structural variants from 
matched tumor-normal sequence data. There have been three versions of the panel: version 1 
containing 341 genes, version 2 containing 410 genes, and the current version containing 
468 genes. Specimens are reviewed by a pathologist to ensure tumor cellularity of at least 
10%. Tumors are sequenced to an average unique depth of coverage of approximately 750X. 
Reads are aligned using BWA, flagged for duplicate read pairs using GATK, and locally 
realigned using ABRA. Sequence mutations are called using MuTect and reported for >5% 
allele frequency (novel variants) or >2% allele frequency (recurrent hotspots). Copy number 
alterations are called using a custom pipeline and reported for fold-change >2. Structural 
rearrangements are called using Delly. All somatic mutations are reported without regard to 
biological function. Testing is performed for patients with advanced metastatic cancer across 
all solid tumor types. 
 

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9.1.1.1 
Pre-treatment biopsy specimens or archival tumor specimen (pre-treatment biopsy 
required if archival tumor tissue is unavailable) will be sequenced to: 
9.1.1.1.1. 
Retrospective central confirmation of the molecular alteration (an 
inactivating PTEN mutation or activating PIK3CB mutation) [Integrated 
Biomarker] 
9.1.1.1.2. 
Examine the pattern of co-mutated genes in PTEN/ PIK3CB 
mutated tumors [Exploratory Biomarker] 
 
9.1.1.2 
Post-progression biopsy specimens and serial cfDNA samples will be sequenced to: 
9.1.1.2.1. 
Monitor the emergence of new somatic alterations or resistant 
subclones [Exploratory Biomarker] 
 
9.1.2 Immunohistochemistry-scoring of PTEN protein expression [Exploratory 
Biomarker] 
9.1.2.1 
Of pre-treatment biopsy specimens or archival specimens and post-progression biopsies 
specimens using previously described methods.50 
 
9.1.3 Multiplex quantitation of Akt pathway signaling proteins with the Luminex 
multiplex assay [Integrated biomarker] 
9.1.3.1 
Of flash frozen pre- and on-treatment biopsy specimens using previously described 
methods (Appendix J).40,41 
 
9.1.4 Docetaxel and AZD8186 Pharmacokinetics [Integrated biomarker] 
9.1.4.1 
Docetaxel blood levels will be measured by LC-MS/MS in the blood at the following 
time points: C1D1**:Pre-treatment; C2D1 Pre-treatment, 30 min. 55 min. after the start 
of the docetaxel infusion, and 2 hours (~3 hours), 5 hours (~6 hours) post- end of 
infusion docetaxel infusion, and C2D2 ~24 hours after the start of infusion. 
**For Part 2 PD study, this should be pre-study or Day -7 
9.1.4.2 
AZD8186 blood levels will be measured by LC-MS/MS in the blood at the following 
time points: C1D1**: Pre-treatment; C2D1 Pre-treatment, 1 hour, 3 hours, and 6 hours 
post-dosing; C2D2 ~24 hours after the C2D1 dose and prior to the next AZD8186 dose; 
Starting Cycle 3, a Day 1 Pre-treatment sample should be collected at every scheduled 
study visit. 
**For Part 2 PD study, this should be pre-study or Day -7 
 
Optional samples may be obtained in the event of chronic (lasting ≥7 days) or serious (≥G3 
non-hematological, ≥G4 hematological) toxicity, a blood sample should be drawn as close 
as possible to the time of the event with documentation of the last docetaxel and AZD8186 
dose administered. 
 
 
9.2 
Table 7        
 
Collection, Handling and Shipping of biomarker specimens to sites performing 
correlatives studies 
 

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Required Specimen (Specimen Code) 
Collection Time Point 
Ship To 
Pre-treatment biopsy specimen 
FFPE Metastatic Tumor (FM01)   
 (Refer to Appendix H – Specimen Guidelines) 
Prior to any treatment 
Pre-treatment biopsy is 
mandatory if adequate 
archival tissue is 
unavailable. 
Precision Pathology Biobanking 
Center at MSKCC  
 
Memorial Sloan Kettering Cancer 
Center 
Precision Pathology Biobanking Center 
(PPBC) 
411 E 67th Street 
Room C-573 
New York, NY  10065 
 
Phone: 212-639-2296 / 6737 
 
 
 Archival tumor specimen 
FFPE Metastatic Tumor (FM02)     
 (Refer to Appendix H – Specimen Guidelines) 
Prior to any treatment 
Not required if  FM01is 
submitted 
Archival tumor specimen  
FFPE Primary Tumor (FP01) 
 (Refer to Appendix H – Specimen Guidelines) 
 
Prior to any treatment 
Not required if  FM01 or 
FM02 is submitted 
Whole Blood (WB01) 
7-10mL drawn into purple top (EDTA) or 
PaxGene tube (s)  
(Refer to Appendix H – Specimen Guidelines) 
Prior to or after starting 
study treatment 
Blood for Plasma cfDNA (PL-SCR, PL-01, PL-
02,….) 10mls of blood drawn in 2 x Streck tubes 
 (Refer to Appendix H – Specimen Guidelines) 
Screening (SCR) and at 
every treatment cycle 
(01,02,…) 
 
 
Lab Medicine, MSKCC within 2 days 
of specimen collection  
 
Memorial Sloan Kettering Cancer 
Center  
 
Center for Laboratory Medicine 
327 East 64th Street 
Room C2-004 
New York, NY 10065 
ATTN: cfDNA Lab  
 
Phone: 646-608-1034 
E-mail: zzPDL_LAB_CFDNA_LAB 
 
 
 
 

NCI Protocol #:10131 
Version Date: 05/20/2021 
 
74 
 
Docetaxel PK†# 
4 or 5 mL green top sodium heparin vacutainer 
tubes 
 
Blood Draw: 
-  Obtain venous blood by standard phlebotomy 
technique from a peripheral access point.  
NOTE:  Suggest using a minimum 18G needle 
to avoid sample hemolysis. 
- Fill-up the tubes as much as possible until 
blood flow stops. 
- GENTLY invert each tube several times (8-10 
times) immediately after collection to avoid 
sample hemolysis. 
- Place samples immediately on ice after 
collection; samples must be processed within 30 
minutes. 
 
Processing instructions: 
1. Invert sample 8-10 times immediately before 
processing.   
2. Centrifuge at 2500-3000 rpm for 10 minutes 
in swinging bucket (SW) or 15 minutes in a 
fixed angel (FA) rotor at 4ºC in a refrigerated 
centrifuge.  Make sure that the centrifuge 
reaches speed and is maintained throughout 
the entire spin. 
C1D1**: Pre-treatment; 
C2D1:Pre-treatment, 30 
min. 55 min. after the start 
of the docetaxel infusion, 
and 2 hours (~3 hours), 5 
hours (~6 hours) post- end 
of docetaxel infusion, and 
C2D2~24 hours after the 
start of infusion. 
 
**For Part 2 PD study 
only, this should be pre-
study or Day -7 
 
Specimens should be stored and 
shipped as a batch by participant (more 
than 1 participant/shipment is 
acceptable if the site has >1 participant 
on-study). A participant's samples 
should be shipped to the APC lab 
within 1 month of the last sample's 
collection date. (i.e., if C3D1 sample is 
collected on 1/1/2017, all of that 
participant's samples should be at the 
APC lab by 2/1/2017). The APC lab 
may contact the study team to request 
shipment off-schedule. The PK 
(docetaxel and AZD8186) specimens 
can be shipped in the same shipment. 
Please ship 1-2 aliquots to the APC 
laboratory. Once receipt is 
confirmed, the back-up aliquot may 
be shipped.  The back-up can be 
shipped later 
Preparing the shipment  
-Samples should be stored in cardboard 
boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
-Please organize the samples by Patient 
and Time point in the box.  

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75 
 
AZD8186 PK†# 
 
As for Docetaxel PK above 
C1D1**: Pre-treatment;  
C2D1Pre-treatment, 1 
hour, 3 hours, and 6 hours 
post-dosing; C2D2 ~24 
hours after the C2D1 dose 
and prior to the next 
AZD8186 dose;  
Starting Cycle 3, a Day 1 
Pre-treatment sample should 
be obtained at every 
scheduled study visit  
 
**For Part 2 PD study only, 
this should be pre-study or 
Day-7 
 
 
-Do not store in plastic bags (they break 
on dry-ice and labels will detach).  
-A copy of each of the pharmacokinetic 
sample collection forms for the 
respective patients or a sample list 
should be included with each shipment. 
To prevent problems with illegible 
writing on tubes, consider numbering 
them (in addition to sample label) and 
numbering samples on the sample sheet.  
-Note the study number, PI, and the 
drugs used/to be measured.  
-A name, phone number and email 
address should be included with samples 
so that receipt can be acknowledged.  
-Please notify the lab by email (onc-
pharmacology@lists.johnshopkins.edu) 
or telephone (410-502-7192 or 410-955-
1129) at least 24 hours prior to shipment. 
 
Shipping  
- All samples should be shipped via 
overnight express courier in insulated 
containers with enough dry ice to 
maintain the samples in a frozen state.  
- Overnight shipments should occur on 
Monday through Wednesday (Tuesday is 
the preferred day) except when the 
following day is a holiday. 
 
Analytical Pharmacology Core 
Laboratory* 
Attn: NCI10131 Docetaxel + AZD8186 
Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 
Pre-treatment biopsy specimen 
Flash frozen Metastatic Tumor (FZM01)   
1-2 cores (Refer to Appendix I) 
 
Prior to any treatment 
(before Cycle 1 Day -7) 
Mandatory  
 
Memorial Sloan Kettering Cancer 
Center 
Precision Pathology Biobanking Center 
(PPBC) 
411 E 67th Street 
Room C-573 
On-treatment biopsy specimen 
Flash frozen Metastatic Tumor (FZM02)  
1-2 cores (Refer to Appendix I) 
 
On-treatment window: 
Between C1D -5 to C1D -
3 biopsy, (2-3 hrs post 
dose).  

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76 
 
Post-progression biopsy specimen 
FFPE Metastatic Tumor (FM03)  
(Refer to Appendix H – Specimen Guidelines) 
 
After progression on 
study. 
 
New York, NY  10065 
 
* Label samples as cfDNA, including study number (NCI10131), unique patient ID (assigned by the consortium), 
initials, date of collection, draw time, and time point for e.g. SCR (screening), Cycle 1, 2 etc 
† Label samples as docetaxel or AZD8186 PK, including study number (NCI10131), unique patient ID (assigned by 
the consortium), initials, date of collection, draw time, and time point for e.g. SCR (screening), Cycle 1, 2 etc 
# Optional samples may be obtained in the event of chronic (lasting ≥7 days) or serious (≥G3 non-hematological, 
≥G4 hematological) toxicity, a blood sample should be drawn as close as possible to the time of the event with 
documentation of the last docetaxel and AZD8186 dose administered. 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Baseline 
radiographic tumor assessment must be done within 30 days prior to the start of therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. It will be acceptable for a new cycle of 
therapy (and all associated tests and procedures) to be delivered within a 3 day window before and 
after the protocol defined date (see Section 5.1). 
 
 
Pre- 
Study 
Cycle 1, 
Day -7* 
Cycle 1, 
Day 1 (±1) 
 
Cycle 1, 
Day 8 (±1) 
 
Cycle 1, 
Day 15 
(±1) 
Cycle 2, 
Day 1 
(±1) 
 
Cycle 2, 
Day 2  
Cycle 3 (and 
beyond), 
Day 1 (±3) 
Off Studyc 
AZD8186 
 
A* 
A 
A 
A 
A 
A 
A 
 
Docetaxel 
 
 
D 
 
 
D 
 
D 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
     X--------------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
 
X 
X 
Performance status 
X 
X 
X 
 
X 
 
 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
PT (INR)/PTT  
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Urinalysis  
X 
X 
X 
X 
X 
X 
 
X 
X 

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77 
 
EKG  
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Adverse event evaluation  
X 
    X---------------------------------------------------------------------------------------------------X 
X 
 
Tumor assessments 
X 
 
 
 
Tumor measurements with CT 
and/or MRI and Bone scan (required 
for prostate cancer patients only) are 
repeated every 6 weeks (+/- 7 days) 
for 24 weeks, then every 12 weeks 
(+/- 7days) thereafter.  
Documentation (radiologic) must be 
provided for patients removed from 
study for progressive disease. 
PSA measurement on Day 1 of 
every cycle as below (required for 
prostate cancer patients only) 
X 
PSA (required for prostate 
cancer patients only) 
X 
 
X 
 
 
X 
 
X 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
Plasma Collection for 
cfDNA Biomarker 
Analysisd 
X 
 
X 
 
 
X 
 
X 
X 
Whole blood sample for 
germline DNAe 
X 
 
 
 
 
 
 
 
 
Docetaxel PK f 
X 
 
 
 
 
X 
X 
 
X 
AZD8186 PK g 
X 
 
 
 
 
X 
X 
X 
X 
 
Fresh Pre-Treatment 
Biopsy or Archived FFPE 
Submissionh  
Xd 
 
 
 
 
 
 
 
 
 
On-Treatment Biopsy i 
 
Xe 
 
 
 
 
 
 
 
 
Post-Progression Biopsy j 
 
 
 
 
 
 
 
 
Xf 
 
 
 
A: AZD8186 assigned dose, BID PO, 5 days on, 2 days off every week,. *Patients enrolled in the 
pharmacodynamic (PD)cohort will begin on Day -7 
D: Docetaxel 75mg/m2 on Day 1 of a 21-Day cycle 
a: Na, K, Cl, CO2, BUN, creatinine, Ca, glucose (fasting for 8 hours), total bilirubin, total protein, 
albumin, alkaline phosphatase, AST, ALT  
b: Serum pregnancy test (women of childbearing potential).  
c: Off-study evaluation (30 days +/- 7 days after last dose). Patients who discontinue for reasons 
other than progression should be imaged when they come off study and then every 3 months until 
progression of disease or beginning of alternative anticancer therapy. 
d: Plasma will be collected for cfDNA biomarker analysis at every study visit 
e: Whole blood sample for research (single collection) obtained during study, preferably during 
screening or within the first cycle of  therapy.  
f: Docetaxel PK: Pre-study or Day -7 (for PD study) or C1D1 pre-treatment (1 sample; overall pre-
treatment)  C2D1:Pre-treatment, 30 min. 55 min. after the start of the docetaxel infusion, and 2 
hours (~3 hours), 5 hours (~6 hours) post- end of docetaxel infusion, and C2D2~24 hours after the 
start of infusion.  
g: AZD8186 PK: Pre-study or Day -7 (for PD study) or C1D1: Pre-treatment (1 sample; overall pre-
treatment); C2D1: Pre-treatment; C2D2~24 hours after the C2D1 dose and prior to the next 
AZD8186 dose; Starting Cycle 3, a Day 1 Pre-treatment should be collected at every scheduled study visit  
h: Archived formalin fixed paraffin embedded (FFPE) tissue or Fresh Pre-Treatment Biopsy 
specimen  (1-2 cores in FFPE along with an additional 1-2 cores flash frozen for the PD cohort 
only). Biopsy is mandatory for the PD cohort and for patients with insufficient archival material 
i: Mandatory on-treatment biopsy for the PD cohort, Window:C1D -5 to C1D -3 biopsy, (2-3 hrs. 
post dose). (1-2 cores flash frozen). 
j: Optional Fresh Post-progression Biopsy specimen (1-2 cores in FFPE). 
 
 
 

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78 
 
11. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of this drug 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.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated every 6 weeks for the first 24 weeks and every 12 weeks thereafter. 
In addition to a baseline scan, confirmatory scans will also be obtained 4 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 6 weeks for the 
first 24 weeks and every 12 weeks thereafter. In addition to a baseline scan, confirmatory scans 
should also be obtained 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 AZD8186 and Docetaxel. 
 
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). 
 

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79 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
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 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.  
 
 
 
 

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80 
 
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. 
 
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.   
 

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81 
 
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 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 

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82 
 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches 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. 
 

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83 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
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. 
**    Confirmation of response is required for non-randomized trials with response as primary 
endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  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 

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84 
 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘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. 
 
11.2 
Antitumor Effect – Prostate cancer, PCWG3 
 
Therapeutic Response for Prostate Cancer patients 
 
Response and progression will be evaluated in this study using a combination of the 
international  criteria  proposed  by  the  Response  Evaluation  Criteria  in  Solid  Tumors 
(RECIST) Committee (Version 1.1) as described by Eisenhauer et al. 2009 and the guidelines 
for prostate cancer endpoints developed by the Prostate Cancer Clinical Trials Working 
Group (PCWG3) described by Scher, et al. 2016. 
 
A short summary is given below. 
 
Measurable Disease: 
 
Tumor lesions: measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) with the following: 
 
• A minimum size of 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 
• A minimum size of 10 mm caliper measurement by clinical exam (lesions that 
cannot be accurately measured with calipers should be recorded as nonmeasurable) 
 
• A minimum size of 20 mm by chest X-ray 

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85 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be not greater than 5 mm). At baseline and in follow-
up, only the short axis will be measured and followed. 
 
 
Nonmeasurable Disease: 
 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques. 
 
Bone Lesions 
 
For the purposes of this study, bone metastatic lesions should be recorded at baseline and 
followed during treatment using PCWG3 criteria. Bone lesions should not be recorded as 
target or nontarget lesions according to RECIST 1.1 criteria. 
 
Lesions with Prior Local Treatment 
 
Tumor lesions situated in a previous irradiated area or in an area subjected to other 
locoregional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 

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Target Lesions 
 
All measurable lesions up to a maximum of 5 lesions per organ (per PCWG3), 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) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
 
Nontarget Lesions 
 
RECIST Version 1.1 criteria require unequivocal quantification of the changes in tumor 
size for adequate interpretation of the sum of target lesions. Consequently, when the 
boundaries of the primary are difficult to delineate, this tumor should not be considered a 
target lesion. 
 
Guidelines for Evaluation of Measurable Disease 
 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a ≤ 5 mm contiguous reconstruction algorithm. If a 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. 
 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable. 
Ultrasound (US), endoscopy and laparoscopy should not be used to measure tumor lesions. 
Cytology and histology can be used to differentiate between PR and CR in rare cases (eg, 
after treatment to differentiate between residual benign lesions and residual malignant 
lesions. 
 
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 when both methods have 
been used to assess the antitumor effect of a treatment.

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Evaluation of Target Lesions 
 
Complete 
Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to
< 10 mm. 
Partial 
Response 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD 
since the treatment started. 
Progressive 
Disease 
At least a 20% increase in the sum of the LD 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. The appearance of one or 
more new extra-skeletal lesions is also considered progression. 
For bone lesions, refer to PCWG3 criteria for determining 
progressive disease. 
 
Evaluation of Nontarget Lesions 
 
Complete 
Response 
Disappearance of all nontarget lesions and normalization of 
tumor marker level. 
Stable 
Disease/Inco
mplete 
Response 
Persistence of 1 or more nontarget lesion(s) or/and 
maintenance of tumor marker level above the normal limits. 
Progressive 
Disease 
Appearance of 1 or more new extra-skeletal lesions and/or 
unequivocal progression of existing nontarget lesions. For bone 
lesions, refer to PCWG3 criteria for determining progressive 
disease. 
 
If tumor markers are initially above the institutional ULN, they must normalize for a 
patient to be considered a complete responder. 
 
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 PD the smallest measurements 
recorded since the treatment started). 
 
 
 
 

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Evaluation of Best Overall Response: Patients with Target (+/- NonTarget-) 
Disease 
  
Target Lesions 
  
Nontarget 
  
New Lesions 
  
Overall 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Evaluation of Best Overall Response: Patients with NonTarget- Disease Only 
Nontarget Lesions 
New Lesions 
Overall 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as endpoint for assessment of efﬁcacy in some trials so to assign 
this category when no lesions can be measured is not advised. 
 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspiration/biopsy) prior to confirming the complete 
response status. 
 
 
 
 
 

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Duration of Response 
 
Imaging is required for this study at baseline and after every 2 cycles (6 weeks) thereafter. 
Patients who have been on study at least 24 weeks, may decrease the frequency of disease/ 
tumor assessments to every 3 cycles (12 weeks). There is a +/- 7 day window for all scans. 
 
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 PD is 
objectively documented (taking as reference for PD the smallest measurements recorded 
since the treatment started), including progression in bone per PCWG3 criteria. 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented.  
 
Duration of Stable Disease 
SD 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 

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PCWG3 Criteria for Assessment of Bone Disease 
 
PCWG3 criteria will be used to document evidence of disease progression in bone 
lesions as described by Scher, et al. 2016 
 
Imaging of Baseline Bone Disease 
 
The use of bone scan as the standard for bone imaging is retained in PCWG3, with the 
presence or absence of metastasis recorded first. A quantitative measure of disease 
burden, such as lesion number, the bone scan index, or lesion area, is also suggested, 
recognizing that these measures require further analytical and prospective clinical 
validation. Changes in lesions considered metastatic on bone scintigraphy should be 
followed and assessed serially using a bone scan assessment form. Areas/lesions on bone 
scintigraphy that are suggestive can be assessed further with CT or MRI and followed 
separately, but such supplemental imaging should not be used to establish indicator 
lesions for the purposes of a trial. 
 
Different modalities for imaging bone metastases can provide different information for 
the same patient. However, because of the lack of standards for reporting disease presence 
or changes after treatment, positron emission tomography imaging with sodium fluoride, 
fluorodeoxyglucose, choline, or prostate-specific membrane antigen, bone marrow MRI 
(body MRI), and other modalities that are in use to image bone, should be approached as 
new biomarkers subject to independent validation. 
 
Criteria for progression in bone at study entry 
 
• 
Two new lesions observed on 99mTc-methylene diphosphonate 
radionuclide bone scintigraphy 
 
• 
Confirm ambiguous results by other imaging modalities (eg, CT or MRI) 
however only positivity on the bone scan defines metastatic disease to bone 
 
 
Documentation of baseline bone disease 
 
• 
Presence or absence of metastasis recorded first 
 
• 
A quantitative measure of disease burden, such as lesional number, the bone scan 
index, or lesion area, is required 
 
• 
Changes in lesions considered metastatic on bone scintigraphy should be followed 
and assessed serially using a bone scan assessment form. Areas/lesions on bone 
scintigraphy that are suggestive can be assessed further with CT or MRI and followed 
separately, but such supplemental imaging should not be used to establish indicator 
lesions for the purposes of a trial 
 
Following for bone progression during the study 
 
• 
Exclude pseudoprogression in the absence of symptoms or other signs of progression. 
• At least two new lesions on first post-treatment scan, with at least two additional lesions 
on the next scan (2+2 rule). 

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• If at least two additional new lesions are seen on the next (confirmatory) scan, the date 
of progression is the date of the first post-treatment scan, when the first two new lesions 
were documented. 
• For scans after the first post-treatment scan, at least two new lesions relative to the first 
post- treatment scan confirmed on a subsequent scan. 
• 
Changes in intensity of uptake alone do not constitute either progression or regression 
  
Controlling for Flare by Applying the 2+2 Rule using the First Post- 
treatment  Scan as Baseline 
 
 
 
Date 
Progression 
Detected 
(Visit) 
  
Criteria for Progression in 
Bone 
  
Criteria for Confirmation of 
Progression in Bone 
 
Week 9 
(1st on-
treatment scan) 
 
Two or more new lesions on 
bone scan compared to 
baseline bone scan by 
PCWG3 
Two or more new bone lesions 
compared to Week 9 on bone scan 
obtained at least 6 weeks after 
progression identified (or at Week 17 
assessment) 
 
Week 17 
(2nd on-
treatment scan) 
 
Two or more new lesions 
on bone scan compared to 
Week 9 bone scan. 
Persistent or increase in number of bone 
lesions compared to Week 17 
assessment on bone scan obtained at 
least 6 weeks after progression 
identified (or at Week 25 assessment) 

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PCWG3 Criteria For Confirmation of Radiographic Progression in Bone by 
Investigator Assessment (to be used in conjunction with modified RECIST 1.1 criteria 
for visceral and nodal disease) 
 
REFERENCES 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009;45(2):228-47. 
 
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and 
Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the 
Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016. 
 
 
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). 
 
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. 
 
Week 25 and 
after (3rd on-
treatment scan 
and after) 
 
Two or more new 
lesions bone scan 
compared to Week 9  
bone scan 
Persistent or increase in number of bone 
lesions compared to prior assessment on 
bone scan obtained at least 6 weeks 
after progression identified (or at next 
scheduled assessment) 

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All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
Investigators (or, when unavailable, a qualified representative from each institution) will meet 
via teleconference every 2 weeks. 
 
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. If the study has a DTL, individuals requiring write 
access to Rave must also be assigned the appropriate Rave tasks on the DTL  
 
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 
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. 
 
In addition, the lead Principal Investigator will have at least bi-weekly conference calls with the 
site Study Investigators and study teams to review accrual, progress, adverse events, and 
unanticipated problems.  
 
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 three times annually (one annual site visit and two data 

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audits).  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) 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. 
 
 

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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 
Collaborative Agreements Language 
 
See Appendix G 
 
12.4 
Genomic Data Sharing Plan 
 
N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Primary Objectives 
13.1.1.1 
To determine the MTD or RP2D of AZD8186 when administered in combination 
with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.  
13.1.1.2 
To assess the safety and tolerability of AZD8186 when administered in combination 
with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors. 
 
13.1.2 Secondary Objectives 
13.1.2.1 
To assess the objective response rate (ORR) of AZD8186 when administered in 
combination with docetaxel in patients with PTEN or PIK3CB mutated advanced 
solid tumors.  
13.1.2.2 
To assess the clinical benefit rate (CBR) at 24 weeks of AZD8186 when administered 
in combination with docetaxel in patients with PTEN or PIK3CB mutated advanced 
solid tumors.  
13.1.2.3 
To investigate a drug-drug interaction between docetaxel and AZD8186 and correlate 
drug exposure with pharmacodynamics response  
 
13.1.3 Exploratory Objectives 
13.1.3.1 
Examine the pattern of co-mutated genes in PTEN or PIK3CB mutated tumors and 
their association with treatment response or resistance. 
13.1.3.2 
Describe possible mechanisms of acquired resistance to PI3Kβ inhibition. 
13.1.3.3 
Evaluation of protein expression of the PTEN gene and its association with treatment 
response or resistance. 
13.1.3.4 
Examine isoform-specific AKT inhibition and other downstream target modulation 
from PI3Kβ inhibition with AZD8186.  
 
13.1.4 Statistical Considerations for Primary objectives:  
 
In the dose escalation cohort/ portion of the study, a standard 3+3 design will be used to find the 
maximum tolerated dose (MTD) for the combination of AZD8186 and docetaxel. Initially, three 
patients will be treated with AZD8186 at dose level 1 [the RP2D identified in the ongoing phase 

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I study (NCT01884285)] combined with standard approved dose (75mg/m2) of docetaxel.  At 
any given dose level, if none of the initial 3 patients experience DLT by the end of cycle 1 (Day 
21), the next dose level will be studied. If one of the initial 3 patients has DLT, 3 additional 
patients will be treated at the same dose level. Escalation will continue only if there is no 
additional DLT observed. If 2 or more patients experience DLT at any dose level, the previous 
dose will be declared the MTD. Should 2 or more patients experience DLTs at the lowest dose 
level, the study will stop and the treatment regimen will be re-evaluated. If only 3 patients are 
treated at a dose declared to be the MTD, 3 additional patients will be enrolled and treated at that 
dose to confirm the MTD. Therefore, at the completion of the dose escalation cohort/ portion, 6 
patients will have been treated at the MTD. Patients who withdraw before completing at least 
75% of the assigned dose during cycle 1 for reasons other than development of a DLT will be 
replaced. (See Section 5.2, Dose escalation schedule/scheme, Section 5.5 for Definition of a DLT 
and Table 4 for Dose escalation decision rules and MTD definition) 
 
Patient safety and tolerability will be described according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4. All patients who 
receive any amount of the study drug will be evaluable for toxicity. 
 
Safety evaluation will be conducted throughout the expansion cohort of this study (i.e. the 
pharmacodynamic expansion cohort and disease specific dose expansion cohorts 1, 2, 3). DLT 
data from the first 6 consecutively enrolled subjects to Parts 2 or 3 will combined with DLT data 
from the 6 subjects treated at the MTD in Part 1. If, at any point, 4 or more total DLTs are 
observed across the combined 12 patients, further enrollment will be halted as the safety 
stopping rule will have been met. At this point, the study would be amended in consultation with 
the board to ensure ongoing subject safety. 
 
So if DLT’s are seen in: 
 
• 0/6 at MTD in part 1 combined with 4/6 in part 2+3.  
• 1/6 at MTD in part 1 combined with 3/6 seen in part 2+3. 
The probability of stopping the trial under hypothetical true DLT rates denoted as p is shown 
below  
 
p probstop 
0.10 
0.00710 
0.15 
0.02720 
0.20 
0.06611 
0.25 
0.12549 
0.30 
0.20383 
0.35 
0.29725 
0.40 
0.40038 

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97 
 
p probstop 
0.45 
0.50717 
0.50 
0.61161 
0.55 
0.70835 
0.60 
0.79315 
 
 
13.2 
Sample Size/Accrual Rate 
 
Proposed Sample Size Minimum: 55 Maximum: 67 
 
Projected yearly accrual rate is estimated at 1-2 patients per month. 
 
 
13.3 
Stratification Factors 
 
N/A 
 
13.4 
Analysis of Secondary Endpoints 
 
Antitumor activity: 
The secondary objective of this phase I study is to obtain preliminary data of antitumor activity 
in disease specific cohorts and overall across all cohorts. Efficacy will be measured by the 
objective response rate (ORR) and Clinical benefit rate (CBR) at 24 weeks of AZD8186 when 
administered in combination with docetaxel in patients with PTEN or PIK3CB mutated advanced 
solid tumors.  
 
Given the sample size per cohort, only descriptive statistics will be computed for the secondary 
objectives. Patient response to AZD8186 and docetaxel will be assessed with Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 evaluations of computed tomography 
(CT) scans performed every 6 weeks (and bone scans and PSA measurement by Prostate 
Working Group 3 (PCWG3) criteria for the Prostate cancer patients).  
 
A response is defined as any of the following: a response according to RECIST v 1.1, PCWG3 
(for patients with measurable visceral and/or nodal disease at baseline) or a reduction in the PSA 
level of 50% or more (for prostate cancer patients without visceral and/or nodal disease at 
baseline), with a confirmatory assessment at least 4 weeks later. 
 
Clinical benefit rate (CBR) is defined as the proportion of patients with CR, PR, and SD at 24 
weeks as defined by modified RECIST Version 1.1. A 90% confidence interval on CBR will be 
calculated assuming binomial proportions. All patients will be followed up for 24 weeks. 
Patients who are lost to follow up before 24 weeks will be evaluable for response and counted as 
non responders. 

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Efficacy and safety will be reported separately for each disease cohort (cohort 1, 2, 3) as part of 
the primary analysis and overall when all cohorts are combined (secondary analysis). All patients 
treated at the MTD will be included in an attempt to answer the question whether this treatment 
regimen is tolerable and has antitumor activity in this preselected patient population regardless of 
disease type. 
 
Exposure/response relationships:  
 
Docetaxel51 and AZD8186 (method TBD) concentrations in subject samples will be 
quantitatively measured using liquid chromatography/tandem mass spectrometric (LC/MS/MS) 
method in the Analytical Pharmacology Core Laboratory at the Sidney Kimmel Comprehensive 
Cancer Center (SKCCC) at Johns Hopkins. For docetaxel, a limited sampling schema will be 
employed to assess for total exposure since AZD8186 may decrease docetaxel concentrations.  
For docetaxel, individual PK parameters will be estimated for Cmax, AUC, T1/2, Cl, and V 
using non-compartmental or compartmental PK methods with the software WinNonlin. For 
AZD8186, trough concentrations will be assessed to elucidate a minimum exposure. Advanced 
population PK methods may be employed to assess the link between drug exposure and 
biological effects and efficacy. The PK variables will be tabulated and descriptive statistics (e.g., 
geometric means and coefficients of variation) calculated for each dose level. PK parameters 
(i.e., T½, Cl, and AUC) will be compared across dose level using nonparametic statistical testing 
techniques. Exploratory correlative studies with pharmacodynamic (biological endpoints, 
toxicity and efficacy) will be analyzed using nonparametric statistics. Significance for 
comparisons will be at the p<0.05 level. 
 
13.5 
Exploratory Correlative Analysis  
 
Correlative studies will be performed and summarized using descriptive statistics and graphical 
displays at pre and post treatment time points. All correlative studies will be considered 
exploratory.  
 
Retrospective central confirmation of the molecular alteration (an inactivating PTEN mutation 
or activating PIK3CB mutation) will be described (Integrated biomarker) 
Out of all patients enrolled on the study a number/rate of centrally confirmed PTEN and PIK3CB 
mutated tumors will be reported. 
 
Examine the pattern of co-mutated genes and association with treatment response.  
At the patient level, associations of pre-treatment pattern of co-mutated genes (grouped by 
pathway for e.g. mutations affecting the PI3K-Akt-mTOR pathway – binary covariate) and 
response (CR/PR at 6 weeks; binary covariate defining responders and non responders) will be 
assessed. These associations will be performed using non parametric methods such as the Mann 
Whitney U test due to the small targeted sample size of this proposed study.  
 
Describe possible mechanisms of acquired resistance to PI3Kβ inhibition.  
Sequencing data from pre- and post-treatment specimens of patients that initially responded to 
AZD8186 will be compared to identify newly acquired mutations or DNA copy number 
alterations. Given that the number of patients and recurrence rate of specific events will be low, 
this analyses will be primarily descriptive with graphical representation in order to uncover any 

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99 
 
trends such as a pathway specific clustering of resistance mutations or second-site mutations or 
focal amplifications, that might inform potential mechanisms of acquired resistance. Results will 
be used to generate future hypotheses that will be tested in larger patient samples. 
 
Evaluation of protein expression of the PTEN gene and its association with treatment response 
or resistance.  
We will summarize the expression pattern of PTEN by immunohistochemistry at baseline 
(archival/pre-treatment specimen) and post-progression on therapy to provide a preliminary 
assessment on the predictive capacity of this marker in determining responders versus non-
responders. 
 
Examine isoform-specific AKT inhibition and other downstream target modulation from PI3Kβ 
inhibition with AZD8186.  
 
• The proposed number of participants in the PD cohort is accounting for the fact that adequate 
tissue obtained under the optimal conditions (Appendix I) is unlikely to be achieved in all 10 
patients. Tumor heterogeneity, biological variability and inadequate tumor content in pre- 
and post-treatment biopsies could affect interpretation of lysate based assays. It is estimated 
that 20-30% of biopsies could be challenging and may influence biomarker interpretation and 
that biological inter-tumor variability of phospho-proteins will be in the range of 50-70% (for 
different markers).  
• Dr Srivastava (lab PI) has addressed some of the issues related to tumor heterogeneity,40,41 
especially the variable mouse cell infiltration (from 20% to 50% of tumor was mouse 
content) of tumor and how to use variability data to derive valid interpretation. In addition, to 
help with interpretation of potential aberrant results due to tumor heterogeneity, Dr 
Srivastava plans to consider two factors: 1) Using total levels of all biomarkers (AKT1, 
AKT2, AKT3, and rpS6) as denominator assay to express changes in all phospho-
measurements (expressed as ratio of total as done previously); 2) Monitoring if all markers in 
the multiplex (12 markers) are changing in one direction, if this is the case, results would be 
interpreted accordingly.  
• Determination of exact cut-off above/below which a change in biomarker is considered drug 
(AZD8186) induced and not due to biological variability is currently underway in Dr 
Srivastava’s preclinical time-course study in two models, PC3 and HCC70 xenografts 
(detailed in section 2.5.2.1.2) The determination is based on both inter- and intra-tumor 
variability (n=5-6 mice) and calculated as a “critical difference” using a criterion similar to 
that defined in clinical laboratories (methodology and cut-off values described in 
Supplementary data of cited publications).40,41  
• Dr. Srivistava has observed an effect size modulation of the phosphoproteins of 70-90%, 
with a relatively high precision (CV < 15%).  Given the fact that the AKT isoform studies are 
highly novel and important, that there are good controls of total protein for AKT1, AKT2, 
and AKT3, to compare with the phophoepitopes, and that the effect of AZD8186 on all 3 
phospho-isoforms seemed to track together with in vivo studies, we have confidence that this 
small cohort of 10 patients may demonstrate convincing evidence of target modulation. 
• In this study we will collect paired (pre- and on-treatment) biopsies and measure percent 
inhibition on a continuous scale (0-100) aiming to show a 70%-80% decrease in the on-
treatment samples. 

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• 10 patients provide 72-80% power (assuming one sided one sample test for change in the 
mean with Type I error=0.05) to show a 70%-80% decrease respectively. 
• The minimum effect size of 70% incorporates intra-tumor variability 
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B 
CURATED LIST OF PTEN VARIANTS WITH THE 
CORRESPONDING LITERATURE TO SUPPORT THEIR LOSS OF FUNCTION 
 
Gene 
Alteration 
Oncogenicity 
Mutation 
Effect 
PMIDs for Mutation Effect 
PTEN 
A121E 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A126D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A126G 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A126S 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A126V 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A34D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A39P 
Oncogenic 
Loss-of-function 
25527629 
PTEN 
C124N 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
C124R 
Oncogenic 
Loss-of-function 
9467011, 10866302, 21828076 
PTEN 
C136Y 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
C71Y 
Oncogenic 
Loss-of-function 
10866302, 11051241 
PTEN 
D162G 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
D162H 
Oncogenic 
Loss-of-function 
23840064 
PTEN 
D24Y 
Oncogenic 
Loss-of-function 
17213812 
PTEN 
D252G 
Oncogenic 
Loss-of-function 
25527629 
PTEN 
D326N 
Oncogenic 
Loss-of-function 
25527629, 21828076 
PTEN 
D92A 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
D92E 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
D92G 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
D92H 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
D92V 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
Deletion 
Oncogenic 
Loss-of-function 
21430697 
PTEN 
E157G 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
F154L 
Oncogenic 
Loss-of-function 
19329485 
PTEN 
F241S 
Oncogenic 
Loss-of-function 
25527629, 21828076 
PTEN 
F341V 
Oncogenic 
Loss-of-function 
10866302, 11051241 
PTEN 
F347L 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
G127E 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
G127N 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
G129D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
G129E 
Oncogenic 
Loss-of-function 
9811831, 25527629, 9467011, 10866302, 21828076 
PTEN 
G129R 
Oncogenic 
Loss-of-function 
9811831, 25527629, 10866302, 21828076 
PTEN 
G165E 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
G165V 
Oncogenic 
Loss-of-function 
9467011, 21828076 
PTEN 
G36R 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
G44D 
Oncogenic 
Loss-of-function 
21828076 

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106 
 
PTEN 
H118P 
Oncogenic 
Loss-of-function 
25527629, 21828076 
PTEN 
H123D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H123Q 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H123Y 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H61D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H93D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H93Q 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H93R 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
H93Y 
Oncogenic 
Loss-of-function 
10866302, 21828076 
PTEN 
I122L 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
I122S 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
I168F 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
K125E 
Oncogenic 
Loss-of-function 
20926450, 21828076 
PTEN 
K125L 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
K125M 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
K128N 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
K128Q 
Oncogenic 
Loss-of-function 
25447541 
PTEN 
K128R 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
K128T 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
K62R 
Oncogenic 
Loss-of-function 
20926450, 19457929 
PTEN 
L112P 
Oncogenic 
Loss-of-function 
25527629, 10866302 
PTEN 
L112R 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
L181P 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
L23F 
Oncogenic 
Loss-of-function 
17213812 
PTEN 
L325F 
Oncogenic 
Loss-of-function 
19329485 
PTEN 
M199del 
Oncogenic 
Loss-of-function 
11051241 
PTEN 
M35R 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
N48K 
Oncogenic 
Loss-of-function 
25527629, 21828076 
PTEN 
N94I 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
P169H 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
P95L 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
P95S 
Oncogenic 
Loss-of-function 
19329485 
PTEN 
P96Q 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
R130* 
Oncogenic 
Loss-of-function 
24721394 
PTEN 
R130A 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
R130G 
Oncogenic 
Loss-of-function 
9811831, 25527629, 10866302, 21828076, 11051241 
PTEN 
R130K 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
R130L 
Oncogenic 
Loss-of-function 
25527629, 9467011, 10866302 
PTEN 
R15K 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
R15S 
Oncogenic 
Gain-of-function 
17213812 

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PTEN 
R161G 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
R173H 
Oncogenic 
Loss-of-function 
24721394, 10866302 
PTEN 
R335* 
Oncogenic 
Loss-of-function 
23475934 
PTEN 
R335L 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
S170R 
Oncogenic 
Loss-of-function 
9467011, 10866302 
PTEN 
T131A 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
T131I 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
T131L 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
T160I 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
T167A 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
V217D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
V343E 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
V343L 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
Y155C 
Oncogenic 
Loss-of-function 
10866302, 21828076, 11051241 
PTEN 
Y65C 
Oncogenic 
Loss-of-function 
20926450, 19457929 
PTEN 
Y68D 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
A121P 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
C105F 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
C124S 
Likely 
Oncogenic 
Loss-of-function 
9811831, 25527629 
PTEN 
C136R 
Likely 
Oncogenic 
Loss-of-function 
23475934 
PTEN 
D107Y 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
D24N 
Likely 
Oncogenic 
Likely Loss-of-
function 
17213812 
PTEN 
D331G 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
D92N 
Likely 
Oncogenic 
Loss-of-function 
21828076 
PTEN 
F21A 
Likely 
Oncogenic 
Loss-of-function 
17213812 
PTEN 
G165R 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
G20E 
Likely 
Oncogenic 
Loss-of-function 
10866302, 17213812 
PTEN 
G251C 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
H61R 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
I32del 
Likely 
Oncogenic 
Loss-of-function 
10560660, 22817889, 24904117, 9326929, 24293293 
PTEN 
K289E 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
K342N 
Likely 
Oncogenic 
Loss-of-function 
10866302 

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PTEN 
L108P 
Likely 
Oncogenic 
Loss-of-function 
25527629 
PTEN 
L345Q 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
L42R 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
M134L 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
N276S 
Likely 
Oncogenic 
Loss-of-function 
25527629 
PTEN 
R130Q 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
R173C 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
R173P 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
S10N 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
S170N 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
S227F 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
T401I 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
Truncating 
Mutations 
Likely 
Oncogenic 
Likely Loss-of-
function 
17218262, 11237521 
PTEN 
V133I 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
Y16C 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
Y174N 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
Y27S 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
Y369G 
Likely 
Oncogenic 
Loss-of-function 
10866302 
PTEN 
Y68H 
Likely 
Oncogenic 
Loss-of-function 
9467011, 23840064, 10866302 
 
 
 

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APPENDIX C 
CURATED LIST OF PIK3CB VARIANTS WITH THE 
CORRESPONDING LITERATURE TO SUPPORT THEIR GAIN OF FUNCTION 
 
 
Gene 
Alteration 
Oncogenicity 
Mutation Effect 
PMIDs for Mutation Effect 
PIK3CB 
E552K 
Likely 
Oncogenic 
Gain-of-function 
16339315 
PIK3CB 
D1067Y 
Oncogenic 
Gain-of-function 
26759240 
PIK3CB 
N553S 
Likely 
Oncogenic 
Likely Gain-of-function 
18755892, 26000489 
PIK3CB 
Amplification 
Oncogenic 
Gain-of-function 
26442967, 16432180, 25533673 
PIK3CB 
D1067V 
Oncogenic 
Gain-of-function 
25982275 
PIK3CB 
E663K 
Likely 
Oncogenic 
Likely Gain-of-function 
23734178, 20668451 
PIK3CB 
E1051K 
Likely 
Oncogenic 
Likely Gain-of-function 
18755892, 26000489 
PIK3CB 
ACPP-PIK3CB 
Fusion 
Likely 
Oncogenic 
Likely Gain-of-function 
26000489, 16432180 
PIK3CB 
D1067A 
Likely 
Oncogenic 
Gain-of-function 
26759240 
PIK3CB 
R48W 
Likely 
Oncogenic 
Likely Gain-of-function 
18755892, 26000489 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D 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, AZD8186.  This clinical trial is sponsored by the National Cancer 
Institute.  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 healthcare provider need to know: 
  
AZD8186 interacts with CYP 3A4/5, 1A2, 2C9 and 2B6 and transport protein OATP1B1. 
 
• AZD8186 is broken down by CYP 3A4/5 and 1A2, enzymes that may be affected by other 
drugs that inhibit or induce these enzymes.  
• AZD8186 inhibits CYP2C9 and induces CYP 3A4/5 and 2B6. These enzymes may affect 
the levels of other drugs in the body that are cleared by these enzymes.    
• The protein in question is OATP1B1 and is inhibited by AZD8186 which may affect the 
ability of other drugs to move 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.   
 
AZD8186 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 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 providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
AZD8186 must be used very carefully with other medicines that use certain liver enzymes or 
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 CYP 3A4/5, 
1A2 or sensitive substrates of CYP 3A4/5, 2C9 and 2B6 and transport protein OATP1B1. 
 
• 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.  

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• Avoid taking blood thinners or anticoagulants with checking with the study doctor.  
• Avoid ingesting grapefruit juice, grapefruit and Seville oranges while taking AZD8186. 
• 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 study drug 
AZD8186.  This clinical trial is sponsored by the NCI.  AZD8186 
may interact 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 any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or 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. 
 Avoid ingesting grapefruit juice, grapefruit, and Seville oranges 
while taking AZD8186. 
AZD8186 interacts with specific liver enzymes called CYP 3A4/5, 
1A2, 2C9, 2B6 and transport protein, OATP1B1, and must be used 
very carefully with other medicines that interact with these enzymes 
and transporter.  
 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 3A4/5 and 1A2 or sensitive substrates of 
CYP 3A4/5, 2C9 and 2B6 and transport protein OATP1B1.” 
 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 E 
BIOMARKER REQUEST FORM 
 
Please email this form to the Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX F 
DRUG ADMINISTRATION DIARY FOR AZD8186 
 
 
Participant ID:  _________ Participant Initials:  _____ Dose Level:  _____ 
To be completed by Investigator 
 
 
1. Request date: 
- 
- 20  
 
DD 
MMM 
YY 
 
 
2. Site ID: 
 
/   
  
  
 
(country #) 
(Site #) 
 
 
 
3. Tumor Type:   
 
 
 
4. Specify the PTEN/PIK3CB  mutation:    
 
 
 
5. Attach the genomic test report ONLY if the patient has signed generic 
hospital/institution consent. 
 
Note: Slot request and patient enrollment cannot be approved until 
after the Principal Investigator has approved the mutation 
 
Investigator: 
Date: 
- 
- 20  
 
Signature                                                   DD 
  MM 
      YY 
To be completed by study Principal Investigator 
 
Mutation and/or Amplification Approved: Yes 
No 
 
 
 
Sponsor or study PI: 
Date: 
- 
- 20  
 
Signature                                                   DD 
  MM 
      YY 
 

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Cycle #:  ___ Cycle Start Date: __________ 
 
Instructions: 
• Use this diary to record each dose of AZD8186 that you take – write in the date, the 
number of tablets and the time taken as well as any comments 
 
• Your AZD8186 dose is: _____ mg twice a day for 5 days on and 2 days off every week 
o Take _____ 60mg tablets and_____ 30mg tablets. 
o AZD8186 should be taken on an empty stomach (water only for at least 2 hours 
prior and 1 hour after each dose) and swallowed whole. Do not split, crush or 
chew the tablets. 
o If you miss a dose of AZD8186 (not taken within 4 hours of scheduled time), skip 
the dose and resume taking AZD8186 at the next scheduled time; do not “double 
up” doses to make up a missed dose. 
o If you vomit after taking AZD8186, do not retake the dose. Mark the vomited 
dose in the diary. Resume taking AZD8186 at the next scheduled time. 
 
• Whenever possible, all doses should be taken at approximately the same time each day. 
 
• On days that you come to clinic, wait to dose until instructed by your doctor 
 
• Use the comments section to record any side effects or anything else you would like to 
tell the doctor/research nurse. 
 
• Please bring the empty bottle or any leftover tablets and this diary to your next 
clinic visit. 
 
 

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APPENDIX G 
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 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.  

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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/ 
proprietary information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX H - BIOSPECIMEN COLLECTION AND SHIPPING GUIDELINES 
IMPORTANT NOTES:  
• Before packing, please be sure to fill out and include the Specimen Collection Log (template 
provided in the last page) with each shipment and please keep paperwork dry and separate 
from specimens. 
• Samples may be rejected for analysis if the samples are thawed, container is broken or leaking. 
 
 Overview of specimen types and shipment locations 
Biospecime
n Type 
Specimen and Container 
Type 
Shipment 
Temperatur
e 
Documents and 
information to be sent 
Shipment 
Location 
Frozen 
Tumor 
Tissue (PD 
cohort only) 
 
Fresh Frozen or 
OCT, 1.5ml 
eppendorf tube 
 
 
 
Dry Ice 
- Email notification to PPBC 
- Print out of Specimen 
Collection Log with 
shipment (Appendix H) 
- Print out of Pathology 
Report with the shipment or 
email to PPBC 
- Print out of Batch Record 
(Appendix 1) 
Precision Pathology 
Biobanking Center, 
PPBC 
Memorial Sloan 
Kettering Cancer 
(MSKCC) 
FFPE Tumor 
Tissue 
 
FFPE blocks in 
clear specimen 
bags, FFPE slides 
in slide box/cassette 
Ambient 
- Email notification to PPBC 
- Print out of Specimen 
Collection Log with the 
shipment (Appendix H) 
- Print out of Pathology 
Report with the shipment 
box 
Precision Pathology 
Biobanking Center, 
PPBC 
Memorial Sloan 
Kettering Cancer 
(MSKCC) 
Whole 
Blood 
 
PAXgene™ blood 
tube (prefered) or 
EDTA purple top 
Ambient 
- Email notification to PPBC 
- Print out of Specimen 
Collection Log with the 
shipment 
Precision Pathology 
Biobanking Center, 
PPBC 
Memorial Sloan 
Kettering Cancer 
(MSKCC) 
Plasma 
blood for 
cell-free 
DNA 
(cfDNA) 
 
Streck tube (x2) 
Ambient 
- Print out of Specimen 
Collection Log with the 
shipment 
Department of Lab 
Medicine 
Memorial Sloan 
Kettering Cancer 
(MSKCC) 

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I. 
SUBMITTING FORMALIN-FIXED, PARAFFIN-EMBEDDED (FFPE) TUMOR TISSUES 
A. Sample Requirements: 
a. FFPE tumor block requirements 
i. Resection or core needle biopsy specimens preferred 
ii. >150 micron thickness in size 
iii. Contain >30% tumor content 
b. FFPE unstained slides requirements 
i. 
Total of 22 slides: 2 unstained charged slides and 20 unstained uncharged 
(if uncharged slides not possible, all slides can be provided as charged). 
All 5 micron thickness. 
ii. 
Slides should be unbaked and without cover slips. Baked and cover slipped 
slides will not be accepted. 
iii. 
Contain >30% tumor content 
iv. 
1 corresponding hematoxylin and eosin (H&E) slide should be provided, if 
available 
v. 
All sections must come from the same tissue block 
Pathology Report corresponding to the submitted block should be either provided within the shipment box 
or emailed to PPBC (skibiobank@mskcc.org). Pathology report should contain below information: 
i. 
Tissue fixative used and fixative time 
ii. 
Specimen type (resection, core needle biopsy, fine needle aspirate etc) 
iii. 
Tumor histiotype 
iv. 
Anatomic site (primary, metastatic) 
v. 
% tumor content and % necrosis 
B. Format for Labeling the Specimen: 
Label the FFPE tissue specimens with Patient ID, and original collection date (mm/dd/yyyy). 
This specimen may also be labeled with the pathology accession number and block identifier. 
Each tissue specimen should be accompanied by pathology report.  
C. Shipping Instructions – Ambient 
During the warmer months (June – August), it is advisable to ship the block(s) with a frozen 
gel ice-pack to prevent the melting of paraffin-embedded tissue blocks during the transit.  
Please complete the forms/notifications below before the shipment: 
1. Email notification to PPBC 
2. Print out of Specimen Collection Log with shipment (Appendix H) 
3. Print out of Pathology Report with the shipment or email to PPBC 
4. Print out of Batch Record (Appendix 1)  
All samples should be shipped to: 
Memorial Sloan Kettering Cancer Center 
Precision Pathology Biobanking Center (PPBC) 
411 E 67th Street 
Room C-573 
New York, NY  10065 
212-639-2296 / 6737 
 
! Samples should be sent Monday through Thursday for priority overnight delivery. Do not ship on Friday 
or before a Federal holiday.   

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II. 
SUBMITTING FROZEN TUMOR TISSUES (FOR PD COHORT ONLY) 
 
A. Format for Labeling the Specimen:  
Label the tubes of the flash frozen tissue specimens with Patient ID, and original collection 
date (mm/dd/yyyy).  
 
B. Shipping Instructions – Dry Ice 
Frozen tumor tissues should be shipped in dry Ice in styrofoam box in an insulated cardboard 
box to avoid the loss of dry ice. Shipments in only styrofoam boxes will not be accepted.  
 
Please complete the forms/notifications below before the shipment: 
1. Specimen Collection Log (Appendix H, last page) 
2. Batch record (Appendix 1) 
3. Shipping manifest (Appendix 2)  
  
Frozen Tumor Tissue samples should be shipped to: 
Memorial Sloan Kettering Cancer Center 
Precision Pathology Biobanking Center (PPBC) 
411 E 67th Street 
Room C-573 
New York, NY  10065 
212-639-2296 / 6737  
 
 
! Samples should be sent Monday through Wednesday for priority overnight delivery. Do not 
ship on Friday or before a Federal holiday.   
 
 
 
 
 
 

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III. 
SUBMITTING WHOLE BLOODS 
 
A. Instructions for Collecting and Submitting Whole Blood in PAXgene Blood DNA 
Tubes: 
 
PAXgene™ Blood DNA Tubes (Qiagen Catalog No. 761115) are preferred for whole blood 
collections, which offer optimal collection, storage, and subsequent isolation of genomic DNA. 
An EDTA (purple top) tube is also acceptable. 
1. Ensure that the tube is at room temperature (18-25oC) prior to use and properly labeled 
with the appropriate Patient ID, and Collection Date information. 
2. Collect approximately 8 ml of blood into the tube using your institution’s recommended 
procedure for standard venipuncture technique. Note that PAXgene™ blood tube has 
an 8.5 ml draw volume. 
3. Store the upright at room temperature until shipment 
 
B. Shipping Instructions – Ambient 
Whole blood specimens should be shipped at ambient temperature on the day the specimen 
is collected. If shipment is not possible immediately, whole blood specimens may be stored 
at room temperature until the shipment, which should be within the 48 hours of collection. 
Please complete the Specimen Collection Log (template provided in the last page) and 
include with each shipment.  
 
All samples should be shipped ideally on the same day of collection to: 
Memorial Sloan Kettering Cancer Center 
Precision Pathology Biobanking Center (PPBC) 
411 E 67th Street 
Room C-573 
New York, NY  10065 
212-639-2296 / 6737 
 
! Samples should be sent priority overnight delivery. When avoidable, do not ship on Friday.  
 
! When shipping whole blood specimens, please be aware that your institution must comply 
with IATA standards (www.iata.org). To ship whole blood specimens you will need (1) a sturdy 
shipping container (e.g., an cardboard or Styrofoam box), (2) a leak proof shipping bag with 
absorbent material*, (3) a puncture and pressure resistant envelop (e.g., Tyvek envelope), 
(4) and an Exempt Human Specimen Sticker. 
! If you will be shipping whole blood specimens from more than one patient, please put each 
specimen in a separate plastic zip-lock bag before placing the specimens in the shipping bag. 
 
 
 
 
 

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IV. SUBMITTING PLASMAS 
A. Purpose: 
Plasma will be isolated from whole blood drawn into Streck tubes, and cell-free DNA (cfDNA) 
will be extracted from plasma and used for biomarker research.  
B. Instructions for Collecting and Submitting Plasma Blood for Cell-Free DNA: 
Plasma cell-free DNA should be collected using Streck Cell-Free DNA Blood Collection tubes 
(BCT) (Streck Catalog no. 218962). For each time point, two Streck Cell-Free DNA BCT tubes 
will be drawn (total 20 mL). 
1. Ensure that the Cell-Free DNA BCT tubes is adjusted to room temperature (18-25oC) 
rior to use and labeled with the appropriate Patient ID, and collection date. 
2. Collect blood into the Cell-Free DNA BCT tube using your institution’s recommended 
procedure for standard venipuncture technique. Fill the tube completely with blood. 
3. Store the Cell-Free DNA BCT tubes upright at room temperature until ready for 
shipment. 
 
C. Format for Labeling the Specimen: 
Plasma should be labeled with the Patient ID, timepoint (e.g. cycle number), and collection 
date (mm/dd/yyyy). 
 
D. Shipping Instructions – Ambient 
All plasma blood specimens should be shipped at ambient temperature on the day of the 
specimen collection. Bloods collected on Fridays can be stored at ambient temperature and 
shipped on Monday. Do not store the Streck tubes in fridge or freezer. 
 
Plasma blood samples should be shipped ideally on the day of collection to: 
Memorial Sloan Kettering Cancer Center 
Department of Laboratory Medicine 
327 East 64th Street, Room # C2-004 
New York, NY 10065 
646-608-1034 / 1035 
 
! Samples should be sent Monday through Thursday for priority overnight delivery. Do not 
ship on Friday or before a Federal holiday.  
 
 
 
 
 
 
 

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V. 
ORDERING INFORMATION 
 
Cell-Free DNA BCT Streck tube  
Company:  STRECK https://www.streck.com/ 
Catalog Number:  218962 (100 pack of 10ml tubes) 
 
PAXgene™ Blood DNA Tubes 
Company: PreAnalytix http://www.preanalytix.com 
Catalog Number:  761115 (100 pack of 8.5ml tubes) 
 
VI. SHIPMENT EMAIL NOTIFICATION 
For the sample shipments to PPBC (FFPE blocks/slides, frozen tissue and whole blood) please 
send an email notification to skibiobank@mskcc.org using the email template below. Do not 
send email notification to PPBC for STRECK-Blood for plasma cfDNA samples or for samples 
going to other tests. 
 
Subject: NCI Protocol #:10131 shipment notification 
 
Email body:  
 
Site Name: 
Patient Study ID: 
Collection date (MM/DD/YYYY): 
Specimen Type: (select the ones that apply) FFPE block, FFPE slides, Frozen tissue. Whole 
blood (PAXgene) 
Number of samples/tubes:  
Shipping Tracking Number: 
 
VII. SPECIMEN COLLECTION LOG 
Template Specimen Collection Log is provided in the following page for printing. Each 
sample/specimen should be listed in a separate row. Please provide the completed and printed 
collection log with the specimens in the shipment box. 
 

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APPENDIX I 
TUMOR FROZEN NEEDLE BIOPSY SPECIMEN COLLECTION 
AND HANDLING 
 
https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/SOP340507_Biopsy_Frozen.pdf 
 
 
APPENDIX J 
SOP FOR PROCESSING NEEDLE BIOPSIES AT THE PADIS LAB 
 
https://dctd.cancer.gov/ResearchResources/biomarkers/docs/met/SOP341201 METIA Tumor
E   xtraction.pdf