Conditions: Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative Progesterone Receptor Negative Progesterone Receptor Positive Stage IV Breast Cancer Triple-Negative Breast Carcinoma
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This partially randomized phase Ib/II trial studies the side effects and best dose of taselisib when given together with enzalutamide and to see how well they work in treating patients with androgen receptor positive triple-negative breast cancer that has spread to other places in the body. Taselisib is a PI3K inhibitor. The PI3K pathway is involved is cancer growth. Androgen may cause the growth of tumor cells. Enzalutamide may stop the growth of tumor cells by blocking the androgen receptor from working. Giving taselisib with enzalutamide may be a better treatment for patients with breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1). (Phase Ib) II. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Determination of the maximally tolerated dose (MTD) of taselisib given in combination with enzalutamide. (Phase Ib) III. To evaluate the efficacy, as measured by clinical benefit rate (CBR), of enzalutamide + taselisib in patients with androgen receptor positive (AR+) triple negative (TN) metastatic breast cancer (MBC). (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival (PFS) of enzalutamide + taselisib in patients with AR+ TN MBC.

II. To assess the pharmacokinetics (PKs) of taselisib and enzalutamide in patients with AR+ TN MBC.

TERTIARY OBJECTIVES:

I. To explore predictors of biomarker response and mechanisms of resistance based on exploratory analysis of tumor tissue obtained through biopsies.

II. Levels of phosphatase and tensin homolog (PTEN) expression by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qPCR).

III. Presence of mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene.

IV. Human epidermal growth factor receptor 2 (HER2) (IHC, fluorescence in situ hybridization \[FISH\]) and estrogen receptor (ER)/progesterone receptor (PR) levels (IHC) in tumor biopsy from a metastatic site.

V. Levels of mitogen-activated protein kinase kinase (MEK) activity measured by phosphorylated extracellular-signal-regulated kinases (p-ERK1/2) (IHC) and phosphorylated p-ribosomal protein S6 (S6) (S235/236 and S240/244) at baseline and upon progression of disease.

VI. Levels of phosphorylated v-akt murine thymoma viral oncogene homolog 1 (p-AKT) (IHC) at baseline and upon progression of disease.

VII. Gene expression profiling to assign a triple negative subtype. VIII. Whole exome deoxyribonucleic acid (DNA)-sequencing (seq) on DNA isolated at baseline and upon progression.

IX. Plasma for circulating tumor DNA (ctDNA) analysis to assess PIK3CA mutation status in response and resistance.

X. To assess the predictive effects of PIK3CA mutations and PTEN loss on PFS and CBR.

XI. To evaluate the ability of multi-parametric magnetic resonance imaging (MRI) performed early in therapy to predict both biological and clinical response.

OUTLINE: This is a phase Ib, dose-escalation study of taselisib followed by a randomized phase II study.

PHASE IB: Patients receive taselisib orally (PO) once daily (QD) on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive taselisib PO QD and enzalutamide as in Phase Ib. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib.

ARM II: Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may crossover to Arm I.

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

Arms:
arm 1: Patients receive taselisib PO QD on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib. arm 2: Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may crossover to receive Enzalutamide + Taselisib arm 3: Patients receive taselisib PO QD on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib. arm 4: Patients receive taselisib PO QD on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib. arm 5: Patients receive taselisib PO QD on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib. arm 6: Patients receive enzalutamide PO QD starting on day 1 of cycle 1, and will receive Taselisib PO QD starting on day 1 of cycle 2. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 7: Upon progression of disease, patients on the enzalutamide only arm will be allowed to crossover to enzalutamide + taselisib (must begin no later than 21 days after the clinic visit at which disease progression is determined) Enzalutamide and Taselisib will be taken PO QD

Interventions: intervention 1: Biomarker Analysis intervention 2: Enzalutamide intervention 3: Pharmacological Study intervention 4: Taselisib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Correlative studies intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
 VICC BRE 1374: A Phase Ib/II Trial of Taselisib (GDC-0032), a PI3K Inhibitor, in Combination With 
Enzalutamide in Patients With Androgen Receptor Positive Triple Negative Metastatic Breast Cancer 
 
NCT02457910 
 
Version:  4/5/2017 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
1 
Protocol version:  04/05/2017 
 
 
BRE 1374: A Phase Ib/II trial of taselisib (GDC-0032), a PI3K inhibitor, in combination 
with enzalutamide in patients with androgen receptor positive triple negative metastatic 
breast cancer 
 
 
Protocol Number   
VICC BRE 1374 
 
 
Other Protocol IDs:   
TBCRC 032 
 
Primary Investigators   
Vandana G. Abramson, MD (Protocol Chair) 
 
  
  
  
Vanderbilt-Ingram Cancer Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
 
 
 
Jennifer Pietenpol, PhD 
Vanderbilt-Ingram Cancer Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
 
u 
 
Co-Investigators 
Medical Oncology: 
 
  
  
  
 
Carlos L. Arteaga, MD  
  
  
  
 
  
  
  
  
Vanderbilt-Ingram Cancer Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
 
 
 
Laboratory Correlatives: 
 
  
  
  
 
Brian Lehmann, PhD   
  
  
 
  
  
  
  
Vanderbilt-Ingram Cancer Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
2 
Protocol version:  04/05/2017 
E-mail: brian.d.lehmann@vanderbilt.edu 
 
Advanced Imaging Correlative: 
Richard G. Abramson, M.D. 
Vanderbilt-Ingram Cancer Center 
Department of Radiology and Radiological Sciences 
1161 21st Ave South, CCC-1121 MCN 
Nashville, TN 37232-2675 
Phone: 615-322-6759 
E-mail: richard.abramson@vanderbilt.edu 
 
H. Charles Manning, Ph.D. 
Vanderbilt University Institute of Imaging Science (VUIIS) 
Department of Radiology and Radiological Sciences 
1161 21st. Avenue South, MCN AA-1105 
Nashville, TN 37232 
Phone: 615-322-3793 
Email: henry.c.manning@vanderbilt.edu 
 
Pathology: 
Melinda Sanders, MD 
Vanderbilt-Ingram Cancer Center 
Department of Pathology 4912 TVC 
1301 22nd Ave South 
Nashville, TN 37232-5310 
Phone: 615-343-9115  
E-mail: melinda.sanders@vanderbilt.edu 
 
Biostatistics:  
Yu Shyr, PhD 
Vanderbilt-Ingram Cancer Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
Phone:  (615) 322-4967 
Fax:  (615) 343-7602 
E-mail: yu.shyr@vanderbilt.edu 
 
 
Sujata Patil, PhD 
 
Memorial Sloan Kettering Cancer Center 
 
Department of Epidemiology & Biostatistics 
 
1275 York Avenue 
 
New York, NY 10065 
 
Phone: 646-735-8182 
 
patils@mskcc.org 
 
Supporters 
Genentech  


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
3 
Protocol version:  04/05/2017 
   
Translational Breast Cancer Research Consortium (TBCRC) 
 
Coordinating Center  
Vanderbilt-Ingram Cancer Center (VICC) 
 
Study Liaison: 
 
 
VICC-CTSR Multi-Institutional Department 
2141 Blakemore Avenue 
Nashville, TN 37212 
 
  


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
4 
Protocol version:  04/05/2017 
A Phase Ib/II trial of taselisib (GDC-0032), a PI3K inhibitor, in combination with 
enzalutamide in patients with androgen receptor positive triple negative metastatic breast 
cancer 
 
 
- Protocol Revision Record - 
 
 
Original Protocol:  
 January 27, 2015  
 
Protocol Revision 1:  
  
December 15, 2015 
 
Protocol Revision 2:  
 
January 12, 2016 
 
Protocol Revision 3:  
  
May 10, 2016 
 
Protocol Revision 4:  
  
July 12, 2016 
 
Protocol Revision 5:  
  
April 5, 2017 
 
 
 
 
 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
5 
Protocol version:  04/05/2017 
Table of Contents 
PHASE I SCHEMA: ................................................................................................................................................... 7 
PHASE II SCHEMA: .................................................................................................................................................. 7 
STUDY CALENDAR:  ENZALUTAMIDE +/- TASELISIB .................................................................................. 8 
STUDY CALENDAR: ENZALUTAMIDE + TASELISIB (CROSSOVER) ....................................................... 
11 
1. STUDY DESIGN/SUMMARY ........................................................................................................................ 
13 
2. OBJECTIVES ................................................................................................................................................... 
13 
2.1 
PRIMARY OBJECTIVES................................................................................................................................. 
13 
2.2 
SECONDARY OBJECTIVES 
............................................................................................................................ 
13 
2.3 
EXPLORATORY OBJECTIVES 
........................................................................................................................ 
13 
3. BACKGROUND ............................................................................................................................................... 
14 
3.1 
PI3K PATHWAY AND BREAST CANCER 
....................................................................................................... 
14 
3.2 
CORRELATIVE SCIENCE BACKGROUND 
....................................................................................................... 
14 
3.3 
BACKGROUND ON STUDY TREATMENT 
....................................................................................................... 
17 
3.4 
RATIONALE 
................................................................................................................................................. 
20 
4. PARTICIPANT SELECTION ........................................................................................................................ 
20 
4.1 
I
NCLUSION CRITERIA 
................................................................................................................................... 
20 
4.2 
EXCLUSION CRITERIA 
................................................................................................................................. 
23 
4.3 
I
NCLUSION OF UNDERREPRESENTED POPULATIONS 
.................................................................................... 
25 
5. REGISTRATION PROCEDURES ................................................................................................................. 
25 
5.1 
PRE-S
CREENING 
.......................................................................................................................................... 
25 
5.2 
AR TESTING FOR REGISTRATION 
................................................................................................................. 
25 
AR TESTING CAN BE PERFORMED ON A PRIOR BREAST CANCER BIOPSY (
PRIMARY OR LOCAL RECURRENCE),
 
SURGICAL SPECIMEN,
 OR BIOPSY OF A METASTATIC SITE. 
........................................................................................ 
25 
5.3 
BIOPSY OF METASTATIC LESION 
.................................................................................................................. 
26 
5.4 
SHIP ALL PARAFFIN MATERIAL,
 RNALATER TUBES OR SLIDES AS DETAILED IN THE LAB MANUAL.
  
**SPECIMENS SHOULD BE MAILED TO ARRIVE AT VUMC FROM MONDAY 8AM THROUGH FRIDAY 
1PM**REGISTRATION 
............................................................................................................................................. 
27 
6. TREATMENT PLAN ....................................................................................................................................... 
28 
6.1 
OVERVIEW 
.................................................................................................................................................. 
28 
6.2 
PHASE I
B COMPONENT OF THE TRIAL 
.......................................................................................................... 
28 
6.3 
PHASE II
 COMPONENT OF THE TRIAL 
........................................................................................................... 
34 
6.4 
CONCOMITANT TREATMENT AND SUPPORTIVE CARE GUIDELINES 
............................................................. 
35 
6.5 
ASSESSMENTS DURING TREATMENT 
........................................................................................................... 
36 
6.6 
CROSS-
OVER POST-
PROGRESSION ............................................................................................................... 
37 
6.7 
DURATION OF THERAPY 
.............................................................................................................................. 
37 
6.8 
DURATION OF FOLLOW-U
P 
......................................................................................................................... 
37 
6.9 
CRITERIA FOR REMOVAL FROM STUDY 
....................................................................................................... 
37 
7. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS..................................... 
38 
7.1 
DOSE MODIFICATIONS/
 DELAYS 
................................................................................................................. 
38 
7.2 
TASELISIB 
................................................................................................................................................... 
39 
7.3 
ENZALUTAMIDE 
.......................................................................................................................................... 
45 
7.4 
SPECIAL CONSIDERATIONS ......................................................................................................................... 
46 
8. DRUG FORMULATION/STORAGE/SUPPLY ............................................................................................ 
47 
8.1 
TASELISIB 
................................................................................................................................................... 
47 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
6 
Protocol version:  04/05/2017 
8.2 
ENZALUTAMIDE 
.......................................................................................................................................... 
47 
8.2 
DRUG ACCOUNTABILITY............................................................................................................................. 
47 
9. CORRELATIVE/SPEIAL STUDIES ............................................................................................................. 
47 
9.1 
ADVANCED IMAGING CORRELATIVE (V
ANDERBILT ONLY) ......................................................................... 
48 
9.2 
TISSUE SAMPLES (A
LL PARTICIPATING SITES)............................................................................................. 
50 
9.3 
BLOOD/
PLASMA COLLECTION (A
LL PARTICIPATING SITES) ........................................................................ 
54 
9.4 
TISSUE SPECIMEN AND BLOOD/
PLASMA LABELING AND DOCUMENTATION ................................................. 
54 
9.5 
PHARMACOKINETIC SAMPLING 
................................................................................................................... 
54 
9.6 
SPECIMEN BANKING ................................................................................................................................... 
55 
9.7 
BIOPSY QUESTIONNAIRE 
............................................................................................................................. 
55 
10. 
MEASUREMENT OF EFFECT ................................................................................................................. 
56 
10.1 DEFINITIONS 
............................................................................................................................................... 
56 
10.2 DISEASE PARAMETERS 
................................................................................................................................ 
56 
10.3 RESPONSE CRITERIA 
................................................................................................................................... 
59 
10.4 DURATION OF RESPONSE 
............................................................................................................................ 
60 
10.5 CENTRAL TUMOR MEASUREMENTS ............................................................................................................. 
61 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................ 
62 
11.1 GENERAL 
.................................................................................................................................................... 
62 
11.2 DEFINITIONS 
............................................................................................................................................... 
62 
11.3 REPORTING PROCEDURES 
........................................................................................................................... 
64 
12. 
DATA SAFETY AND MONITORING ...................................................................................................... 
67 
12.1 DATA MANAGEMENT AND REPORTING 
....................................................................................................... 
67 
12.2 MEETINGS 
................................................................................................................................................... 
68 
12.3 MONITORING .............................................................................................................................................. 
68 
12.4 DATA HANDLING AND RECORD KEEPING 
................................................................................................... 
69 
13. 
REGULATORY CONSIDERATIONS ...................................................................................................... 
69 
13.1 I
NFORMED CONSENT AND CONFIDENTIALITY 
............................................................................................. 
69 
13.2 ETHICS AND GCP ........................................................................................................................................ 
71 
14. 
MULTI-CENTER GUIDELINES ............................................................................................................... 
71 
14.1 PROTOCOL REVIEW AND AMENDMENTS 
..................................................................................................... 
71 
14.2 STUDY DOCUMENTATION 
........................................................................................................................... 
71 
14.3 RECORDS RETENTION 
................................................................................................................................. 
72 
14.4 PUBLICATION 
.............................................................................................................................................. 
72 
15. 
STATISTICAL CONSIDERATIONS ........................................................................................................ 
72 
15.1 STUDY DESIGN/
 ENDPOINTS ....................................................................................................................... 
72 
15.2 PHASE I
B STUDY 
......................................................................................................................................... 
72 
15.3 PHASE II
 STUDY 
.......................................................................................................................................... 
73 
15.4 SAMPLE SIZE 
............................................................................................................................................... 
73 
15.5 REPORTING 
................................................................................................................................................. 
74 
15.6 ANALYSIS OF SECONDARY ENDPOINTS 
....................................................................................................... 
74 
15.7 REPORTING AND EXCLUSIONS .................................................................................................................... 
75 
16. 
REFERENCES ............................................................................................................................................. 
75 
 
 


       


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
8 
Protocol version:  04/05/2017 
STUDY CALENDAR:  ENZALUTAMIDE +/- TASELISIB 
 
Evaluation
a 
Screeningb 
Treatment period 
 
Every 2 
cycles 
from 
C1D1 
Post treatment 
 
 
Daily 
Cycle 1  
(28-days) 
Cycle 2  
(28-days)c  
Addition
al cyclesc Cycle 
4 
 
End-of-
treatment
d  
 
30 day 
follow-upd 
Day-28 – 
Day 1 
Day 
1 
Day 
15 
Day 
1 
Da
y 8t  
Day 
15 
Day 
1 
Day 
1   
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
Brain imaging (MRI or CT scan)
 e 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics/ medical history 
X 
 
 
 
 
 
 
 
  
 
 
Physical exam/signs & 
symptoms
b,f 
X 
 
X 
X 
X X X 
X 
 
 
X 
 
Vital signs (including oxygen sat) 
X 
 
X 
X 
X X X 
X 
 
 
X 
 
12-lead ECG
g 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
X 
X 
X X X 
X 
 
 
X 
 
Blood 
collection 
Clinical laboratory 
tests
h 
X 
 
X 
X 
X X X 
X 
 
 
X 
 
Fasting plasma 
glucosei 
X 
 
X 
X 
X X 
 
X 
 
 
X 
 
Pregnancy testj 
X 
 
 
 
 
 
 
 
 
 
 
 
HbA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
PT (or INR)/PTT  
X 
 
 
 
 
 
 
 
 
 
 
 
PK assessmentsk 
 
 
 
 
X  
X 
 
X 
 
 
 
Circulating tumor 
DNA 
 
 
 
 
X  
X 
 
 
 
X 
 
Tumor assessment CTs, bone scanl 
X 
 
 
 
 
 
 
 
 
X 
 
 
Archived tumor blocks/slidesm 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy (metastatic site)n  
X 
 
 
 
 
 Day 
14-21 
 
 
 
X 
 
Imaging Correlate: CEST-MRIo 
X 
 
 
 
 
 Day 
14-21 
 
 
 
X 
 
Enzalutamide administration 
(oral)
p 
 
X 
Oral, once-daily administration 
 
 
 
Taselisib administration (oral): if 
on taselisib arm 
 
X 
 
 Oral, once-daily administration, 
starting cycle 2, day 1 
 
 
 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
9 
Protocol version:  04/05/2017 
Evaluation
a 
Screeningb 
Treatment period 
 
Every 2 
cycles 
from 
C1D1 
Post treatment 
 
 
Daily 
Cycle 1  
(28-days) 
Cycle 2  
(28-days)c  
Addition
al cyclesc Cycle 
4 
 
End-of-
treatment
d  
 
30 day 
follow-upd 
Day-28 – 
Day 1 
Day 
1 
Day 
15 
Day 
1 
Da
y 8t  
Day 
15 
Day 
1 
Day 
1   
Pill Diaryq 
 
X 
 
 
 
 
Concomitant medicationsr 
X 
 
X 
X 
X X X 
X 
 
 
 
 
Adverse events 
X 
 
X 
X 
X X X 
X 
 
 
 
X 
Biopsy questionnaires 
 
 
 
 
 
 
 
X 
 
 
 
 
AE = adverse event; BSA = body surface area; CX = Cycle X, where X is the cycle number; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; HbA1C = glycosylated hemoglobin; IMP = investigational medicinal product; INR = international normalized ratio; PT = prothrombin time; 
PTT = partial prothrombin time; SAE = serious adverse event 
a Evaluation assessments should be performed prior to administration of IMP unless otherwise indicated. Results should be reviewed by the Investigator prior to the 
administration of the next dose. All visits should occur within 3 days of scheduled visit unless otherwise noted. 
b Screening must occur within 28 days of dosing. The following procedures must be repeated at the day 1 visit: Medical and cancer history, physical examination, weight 
measurement, vital signs, hematology (see h), serum chemistry panel (see h). Lab values must still meet eligibility criteria on cycle 1, day 1. Tumor assessments must be 
repeated at the baseline visit only if determined to be changed by clinical exam or other clinical observations. SOC procedures performed prior to consent but within the 
protocol defined screening window for each assessment can be used for study purposes. All research only procedures must be performed after the consent date.  
c Patients may continue with daily dosing of enzalutamide with or without taselisib in the absence of unacceptable toxicities after C2 (or if the toxicity has resolved) and with no 
clinical evidence of disease progression.  
d The 30-day follow-up assessments should be done 30 (±3 days) days after the last dose of enzalutamide and taselisib.  30 day follow-up can be done by phone or by a clinic 
visit.  Any ongoing toxicities should be documented.  Any ongoing serious adverse events will be followed every 3 months until resolution. Any AEs or SAEs considered 
possibly or probably related to IMP that have not stabilized, returned to baseline, or are considered irreversible will continue to be monitored as per the protocol in Section 7.   
e MRI should be completed only if CT is unclear and a lesion can only be followed on MRI imaging. The CT  scan should be completed with contrast.  This is considered a 
research procedure if the patient does not have any signs or symptoms of brain metastases. If the patient must undergo brain imaging for the sole purpose of screening for this 
study, it is expected that a CT of the head will be done. 
f The physical examination will include measurements of height and weight at screening.  Weight will be measured on day 1 of each cycle and at the End-of-treatment visit. 
Physical examination will include examination of major body systems including neurologic, cardiac, respiratory, gastrointestinal, and skin. Clinically relevant signs and 
symptoms will be reported as AEs. 
g ECG will be performed at screening  
h Clinical laboratory tests will include hematology and serum chemistry panel including white blood cell count, differential, hemoglobin, platelet count, sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium, SGOT, SGPT, and total serum bilirubin, albumin, and total protein. Additional tests will be 
performed when clinically appropriate. In case of Grade 3 or higher abnormal liver function results, additional testing will be done weekly until recovery to baseline value (see 
section 7.2).  For all other timepoints, labs can be performed up to 3 days prior to each timepoint indicated in the study calendar (other than required C1D1 timepoint). Results 
from labs obtained on C1D1 do have to meet eligibility criteria.   
i
 FPG (fasting plasma glucose) will be collected at screening , on Days 1 and 15  of C1, on CXD1 of subsequent cycles, and at the End-of-treatment visit. FPG will also be 
monitored if patients experience Grade ≥1 hyperglycemia during the course of the study per the hyperglycemia management guidelines provided in the protocol.  FPG can be 
obtained up to 3 days prior to each timepoint indicated in the study calendar (other than required C1D1 timepoint).Fasting plasma glucose is the same as serum glucose on days 
that the patient is fasting. On days the patient is getting non-fasting labs, it should be serum glucose only.  (See Table 3 under section 7.2.1.5) 
j
 Serum pregnancy test: women of child bearing potential must have a negative serum pregnancy test result within 28 days prior to the initial dose of IMP.  


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
10 
Protocol version:  04/05/2017 
k PKs for patients in the phase Ib portion: plasma sample should be obtained on Cycle 1, day 8 at: 0-4 hours prior to dose of taselisib and 1, 3,  and 6 hours post administration 
taselisib.  On Cycle 2, day 15 at:  0-4 hours prior to dose of taselisib and enzalutamide and 1, 3, and 6 hours post administration taselisib and enzalutamide.  On Cycle 4, day 1, 
plasma sample should be obtained 0-4 hours before taselisib and enzalutamide administration, and 3 hours post-administration of both drugs. PKs in phase II will occur for 10 
patients at the Vanderbilt site only and should be obtained on patients receiving both enzalutamide and taselisib: C2D1, C2D15, and C4D1 at 0-4 hours prior to taselisib and 
enzalutamide and 2 to 4 hours post treatment.   
l
 Tumor assessment should be performed approximately every 2 cycles (up to -5 days) while on study treatment and at End-of-treatment visit if not obtained within the past 
6 weeks.  Scans should consist of CT scan of the chest, abdomen, and pelvis and a bone scan at baseline.  Subsequent scans should consist of CT chest, abdomen and pelvis, 
and bone scan if bone metastases were present on the baseline studies.  At the end of treatment, all scans (baseline and through disease progression) should be sent on a CD to 
the Vanderbilt Cancer Imaging Support Laboratory for central review and assessment.  See Section 10.5 for details and address.  
m Archived tumor biopsy specimen:  20 unstained slides of archived biopsy block (unstained slides) or fresh tumor biopsy will be requested at the time of enrollment prior to 
initiation of treatment. 
n Tumor biopsies will only be performed in the phase II portion.  A tumor biopsy from a metastatic site will be obtained from patients prior to day 1, at cycle 2 day 14-21, and 
upon progression of disease.  The third biopsy (at the end of treatment) will not be required for patients who are removed from study for reasons other than disease progression.  
A patient who undergoes a research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, is not obligated to undergo a repeat biopsy.  
o See section 9.1.  Required only for patients at Vanderbilt and only in the phase II portion. This should be performed prior to tumor biopsy, if possible. If MRI sub-study is not 
feasible due to scheduling, MRI weight limits, etc., patients may still continue with the remainder of the study.  
p Subjects on the enzalutamide + taselisib arm should begin enzalutamide on day 1 of cycle 1, and taselisib on day 1 of cycle 2. 
q Pill Diary can be found in the packet of supplemental forms. 
r See Section 6.4.2. 
s Phase II only. Biopsy questionnaire should be filled out by the patient on C3D1. Form can be found in the packet of supplemental forms. 
t The cycle 2 day 8 visit is only needed for patients on the combination of taselisib + enzalutamide.  Patients on enzalutamide only do not need a visit on this day. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
11 
Protocol version:  04/05/2017 
 
STUDY CALENDAR: ENZALUTAMIDE + TASELISIB (CROSSOVER) 
Crossover therapy (taselisib) must begin no later than 21 days after the clinic visit at which progression is determined.  
Evaluation
a 
Treatment period 
Post treatment 
 
 
Daily 
Cycle 1  
(28-days) 
Cycle 2  
(28-days)b  
Additional cyclesb 
 
End-of-
treatment
c  
 
30 day 
follow-upc 
Day 
1 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
   
Every 2 
cycles 
from 
C1D1 
Physical exam/signs and 
symptoms
d 
 
X 
X 
X 
X 
X 
 
X 
 
Vital signs (including oxygen sat) 
 
X 
X 
X 
X 
X 
 
X 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
 
X 
 
Blood 
collection 
Clinical laboratory 
tests
e 
 
X 
X 
X 
X 
X 
 
X 
 
Fasting plasma 
glucosef 
 
X 
X 
X 
 
X 
 
X 
 
Circulating tumor 
DNA 
 
X 
 
 
X 
 
 
X 
 
Tumor assessment CTs, bone scang 
 
 
 
 
 
 
X 
 
 
Tumor biopsy (metastatic site)h  
 
 
 
 
 
 
 
 
 
Enzalutamide administration (oral) X Oral, once-daily administration, starting Day 1 
 
 
 
Taselisib administration (oral) 
X 
Oral, once-daily administration 
 
 
 
Pill Diaryi 
X 
 
 
 
 
Concomitant medicationsj 
 
X 
X 
X 
X 
X 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
 
 
X 
 
a Evaluation assessments should be performed prior to administration of IMP unless otherwise indicated. Results should be reviewed by the Investigator prior to the 
administration of the next dose. All visits should occur within 3 days of scheduled visit unless otherwise noted. 
b Patients may continue with daily dosing of enzalutamide with or without taselisib in the absence of unacceptable toxicities after C2 (or if the toxicity has resolved) and with no 
clinical evidence of disease progression.  
c The 30-day follow-up assessments should be done 30 (±3 days) days after the last dose of enzalutamide and taselisib.  30 day follow-up can be done by phone or by a clinic 
visit.  Any ongoing toxicities should be documented.  Any ongoing serious adverse events will be followed every 3 months until resolution. Any AEs or SAEs considered 
possibly or probably related to IMP that have not stabilized, returned to baseline, or are considered irreversible will continue to be monitored as per the protocol in Section 7.   


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d The physical examination will include measurements of height and weight at screening.  Weight will be measured on day 1 of each cycle and at the End-of-treatment visit. 
Physical examination will include examination of major body systems including neurologic, cardiac, respiratory, gastrointestinal, and skin. Clinically relevant signs and 
symptoms will be reported as AEs. 
e Clinical laboratory tests will include hematology and serum chemistry panel including white blood cell count, differential, hemoglobin, platelet count, sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium, SGOT, SGPT, and total serum bilirubin, albumin, and total protein. Additional tests will be 
performed when clinically appropriate. In case of Grade 3 or higher abnormal liver function results, additional testing will be done weekly until recovery to baseline value.  
Labs do not have to be repeated on cycle 1, day 1 if they were done up to 7 days prior to day 1.  For all other timepoints, labs can be performed up to 3 days prior to each 
timepoint indicated in the study calendar.   
f FPG  (fasting plasma glucose) will be collected at screening , on Days 1 and 15  of C1, on CXD1 of subsequent cycles, and at the End-of-treatment visit. FPG will also be 
monitored if patients experience Grade ≥>1 hyperglycemia during the course of the study per the hyperglycemia management guidelines provided in section 7.2 of the protocol.  
FPG does not have to be repeated on cycle 1, day 1 if it was done up to 7 days prior to day 1.  FPG can be obtained up to 3 days prior to each timepoint indicated in the study 
calendar. The fasting plasma glucose is the same as the serum glucose on the days that the patient is fasting. On the days the patient is getting non-fasting labs, it should be 
serum glucose only.  (see Table 3 under section 7.2.1.5) 
g Tumor assessment should be performed approximately every 2 cycles (up to -5 days) while on study treatment and at End-of-treatment visit if not obtained within the past 
6 weeks.  Scans should consist of CT scan of the chest, abdomen, and pelvis and a bone scan at baseline.  Subsequent scans should consist of CT chest, abdomen and pelvis, 
and bone scan if bone metastases were present on the baseline studies.  At the end of treatment, all scans (baseline and through disease progression) should be sent on a CD to 
the Vanderbilt Cancer Imaging Support Laboratory for central review and assessment.  See Section 10.5 for details and address.  
h Tumor biopsies from a metastatic site will be obtained from patients prior to day 1 (this will be the biopsy obtained at disease progression on the enzalutamide only arm).  
i Pill Diary can be found in the packet of supplemental forms.  
j See Section 6.4.2. 


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BRE 1374 / TBCRC 032 
 
 
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Protocol version:  04/05/2017 
1. STUDY DESIGN/SUMMARY 
This is an open-label phase Ib/II multiple institution trial that evaluates the safety profile and 
efficacy of enzalutamide with or without taselisib in patients with androgen receptor positive triple 
negative metastatic breast cancer (AR+ TN MBC).  The phase 1b portion will allow any ER/PR 
status, provided the patient is HER2 negative.  Patients with AR positivity, defined as > 10% of 
tumor cell nuclei with immunoreactivity for AR, will receive enzalutamide +/- taselisib.  All 
patients in the phase Ib portion will receive both drugs.  Patients in the phase II portion will 
undergo core biopsy of a metastatic lesion (if reasonably safe) at baseline, at day 14-21, and at the 
time of progression.  If a fresh biopsy is deemed not safe, a paraffin block from a prior biopsy or 
surgery must be available for enrollment.  Standard staging radiology scans will be performed at 
baseline and every 2 cycles (up to - 5 days) thereafter.  Upon progression of disease by RECIST, 
patients on the enzalutamide only arm will be allowed to crossover to enzalutamide + taselisib.  
Those on the combination arm will be removed from study. Patients will be screened and enrolled 
from the oncology practice at the Vanderbilt-Ingram Cancer Center, from participating member 
centers of the Translational Breast Cancer Research Consortium, and from other approved sites.    
2. OBJECTIVES 
2.1 Primary Objectives 
Phase Ib 
To determine the safety and tolerability of taselisib given in combination with 
enzalutamide: 
 Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment 
(cycle 1) 
 Determination of the maximally tolerated dose (MTD) of  taselisib given in 
combination with enzalutamide 
 
Phase II 
 To evaluate the efficacy, as measured by clinical benefit rate (CBR), of enzalutamide + 
taselisib in patients with AR+ TN MBC.  CBR is defined as the proportion of patients with 
a best response of CR, PR, or stable disease (SD) > 16 weeks. 
2.2 Secondary Objectives 
 To determine the progression free survival (PFS) of enzalutamide + taselisib in patients 
with AR+ TN MBC. PFS is defined as the time from cycle 1, day 1 until objective tumor 
progression. 
 To assess the pharmacokinetics (PKs) of taselisib and enzalutamide in patients with AR+ 
TN MBC  
2.3 Exploratory Objectives 
 To explore predictors of biomarker response and mechanisms of resistance based on 
exploratory analysis of tumor tissue obtained through biopsies  
a) Levels of PTEN expression by immunohistochemistry (IHC) and qPCR  
b) Presence of mutations in the PIK3CA gene  
c) HER2 (IHC, FISH) and ER/PR levels (IHC) in tumor biopsy from a metastatic site.   


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BRE 1374 / TBCRC 032 
 
 
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Protocol version:  04/05/2017 
d) Levels of MEK activity measured by phosphorylated p-ERK1/2 (IHC) and 
phosphorylated p-S6 (S235/236 and S240/244) at baseline and upon progression of 
disease 
e) Levels of phosphorylated p-AKT (IHC) at baseline and upon progression of disease 
f) Gene expression profiling to assign a triple negative subtype 
g) Whole exome DNA-seq on DNA isolated at baseline and upon progression 
h) Plasma for ctDNA analysis to assess PIK3CA mutation status in response and 
resistance 
 To assess the predictive effects of PIK3CA mutations and PTEN loss on PFSand CBR  
 To evaluate the ability of multi-parametric MRI performed early in therapy to predict both 
biological and clinical response. 
 
3. BACKGROUND 
3.1 PI3K Pathway and Breast Cancer 
Molecular alterations involving this pathway are considered the most frequent in breast cancer, 
encompassing over 30% of invasive tumors. PI3K is aberrantly activated in many human 
neoplasias1,2. Alterations in breast cancer resulting in hyperactivity of the PI3K pathway include 
gain-of-function mutations in PIK3CA (the gene encoding the PI3K catalytic subunit p110α)
3-10, 
mutations in AKT111, amplifications of AKT212, and loss of PTEN
13,14. Mutations in PIK3CA 
cluster in two major ‘hot spots’ located in the helical (E542K and E545K in exon 9) and catalytic 
(H1047R in exon 20) domains
4,15. Expression of these mutant p110α isoforms confers growth 
factor-independent growth and protection from anoikis and chemotherapy
16. Loss of PTEN also 
increases PI3K activity and increased phosphorylation, activation, or membrane translocation of 
signal transducers downstream PI3K including Akt, mTOR, S6 kinase, and 4-EBP-1
17. Both 
genetic and biochemical data suggest that activation of the PI3K/Akt survival pathway contributes 
to breast cancer development and tumorigenesis
18-25.   
 
Over the past decade, the term “triple negative breast cancer” has been used to classify tumors that 
lack expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2.  Triple 
negative breast cancers (TNBC) are generally more aggressive than their ER positive counterparts, 
with higher rates of relapse in the early stage and decreased overall survival in the metastatic 
setting.  TNBC has been particularly difficult to treat given that the biology of the disease has not 
been well understood, thus molecular targets for therapeutic intervention are unknown.   Recently, 
104 TNBC exomes were sequenced and identified TP53 (62%) as the most frequently mutated 
gene, followed by alterations in PI3K pathway that included PIK3CA (10.2%) and PTEN (9.6%) 
mutations 26, suggesting that targeting the PI3K pathway would be clinically relevant in TNBC. 
3.2 Correlative Science Background 
3.2.1 PI3K pathway and triple negative breast cancer 


Ph. Ib/II Taselisib Enzalutamide AR+ 
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Protocol version:  04/05/2017 
Using gene expression (GE) analyses, we recently identified distinct TNBC subtypes displaying 
unique biologies 27.  We identified six TNBC subtypes including two basal-like (BL1 and BL2), 
an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal 
androgen receptor (LAR) subtype 27. Further, GE analysis allowed us to identify TNBC cell lines 
representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically 
targeted in these cell lines as proof-of-concept and to generate pre-clinical data to inform clinical 
trial design. The LAR subtype was characterized by androgen receptor signaling.  
 
LAR cell lines were uniquely sensitive to inhibition of AR signaling achieved through siRNA-
mediated AR knockdown or pharmacological inhibition by bicalutamide (an AR antagonist).  
From our initial analysis it was evident that all LAR cell lines analyzed had an activating PIK3CA 
mutation and were sensitive to PI3K inhibitors. The co-evolution of PIK3CA mutations with AR-
dependency is similar to observations that ER-positive breast cancers frequently contain PIK3CA 
mutations28,29.  To confirm the enrichment of PIK3CA mutations in AR expressing TNBC, we 
isolated DNA from 26 LAR and 26 non-LAR TNBC tumors.  Sanger sequencing was performed 
across exons 5 and 20 of amplified PIK3CA DNA from the same tumors as further validation. 
Seventy percent (18/26) of tumors of the LAR subtype contained activating ‘hotspot’ mutations in 
the PIK3CA gene. 
 
AR+ tumors with a PIK3CA mutation expressed higher levels of activated p-AKT (S473).  While 
PIK3CA mutations were detected in non-LAR TNBC (26.9%), the frequency of PIK3CA 
mutations was nearly double in LAR TNBC (70.0%), suggesting that these tumors may depend on 
PI3K and, as such, will be particularly sensitive to PI3K inhibitors.   To determine the single agent 
effectiveness of cisplatin, bicalutamide and a PI3K inhibitor (GDC-0941), we performed viability 
assays evaluating the efficacy of these drugs across a panel of TNBC cell lines.  Cell lines that 
possessed BRCA1/2 mutations and correlated to basal-like TNBC subtypes were especially 
sensitive to cisplatin (Figure 1A).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. TNBC subtypes display differential sensitivity to cisplain, bicalutamide and GDC-0941. IC50 values for cell 
lines 72 h after treatment with  (A) cisplatin, (B) bicalutamide or (C) GDC-0941.   Black, gray, and white color bars indicate 
TNBC subtype; white box with black dot indicates primary HMEC; pink, red, and blue color bars indicate mutation status for 
BRCA1/2, PIK3CA and PTEN, respectively.  Heatmap below bicalutamide graph indicates levels of AR mRNA (Log2 GE). 


Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
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Protocol version:  04/05/2017 
As anticipated, AR+ TNBC cell lines were sensitive to the AR antagonist bicalutamide and the 
PI3K inhibitor GDC-0941 (Figure 1B and C).  Since GDC-0941 displayed activity in PIK3CA 
mutant cell lines and all AR-expressing cell lines, we then sought to test the hypothesis that 
simultaneous targeting of AR and PI3K would be more effective than either agent alone.  We 
genetically knocked down AR using shRNA in the presence of GDC-0941.  Knockdown of AR 
significantly increased the efficacy of GDC-0941 over a range of doses as viability was reduced 
in the presence of two shRNAs targeting AR (Figure 2).  We advanced the combination of these 
inhibitors to in vivo xenograft studies and examined bicalutamide ± GDC-0941; representative 
results are shown (Figure 2D).  
 
To determine if pharmacological inhibition of AR with bicalutamide is more effective in 
combination with PIK3CA inhibition, we treated AR-expressing TNBC cells with either 
increasing doses of GDC-0941 or in combination with fixed doses of the inhibitor (10, 25, and 50 
µM) with bicalutamide.  While increasing doses of bicalutamide alone decreased viability of each 
cell line, the combination with GDC-0941 was either additive or synergistic over a range of doses 
(1 -1000 nM) as measured by a viability assay (Alamar Blue detection).  Bicalutamide treatment 
alone did not affect protein levels evaluated, however the combination with GDC-0941 decreased 
p-S6 more than GDC-0941 alone and decreased AR levels at 48 h.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.  PI3K inhibition increases the efficacy of genetic and pharmacological targeting of AR in AR+ TNBC. (A, upper) 
Immunoblots display decreased AR expression 72h after lentiviral infection with shRNAs targeting AR compared to control in indicated 
AR+ TNBC cell lines. (A, lower) Relative viability of LAR cell lines infected with nontargeting or shRNAs targeting AR (shAR1 and 
shAR2) after 72 h treatment with GDC-0941.  (B) Relative viability of AR+ cell lines after indicated doses of GDC-0941 alone (blue) or 
in combination (red) with 25 µM bicalutamide (CDX).  Dashed black line depicts the theoretical line of additivity from the combined 
effect of bicalutamide and GDC-0941 alone. (C) Immunoblots show decreased pAKT and pS6 at 24 and 48 after treatment with 1 µM 
GDC-0941 or the combination with 25 µM CDX. (D) CAL-148 xenograft tumors display greater sensitivity to GDC-0941 and the 
combination compared to bicalutamide (CDX) alone. Mice were treated for approximately 3 weeks. Serial tumor volumes (mm
3) were 
measured at the indicated days. Each data point represents the mean tumor volume of 16 tumors. 







Ph. Ib/II Taselisib Enzalutamide AR+ 
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BRE 1374 / TBCRC 032 
 
 
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Protocol version:  04/05/2017 
(1%), lung infection (1%), pneumonia (1%), erythematous rash (1%), generalized rash (1%), 
maculopapular rash (1%) and skin exfoliation (1%) and acute renal failure (1%). 
 
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of taselisib at 
dose levels of 6 and 9 mg daily (19 patients at 6 mg, and 8 patients at 9 mg) daily in combination 
with letrozole (Cohort E).  No DLTs were observed at either dose level.  Adverse events of any 
grade and assessed by the investigator as drug related that occurred in  10% of the 27 safety-
evaluable patients assessed as related to  taselisib were diarrhea (67%), fatigue (30%), nausea 
(30%), rash (30%), decreased appetite (26%), hyperglycemia (26%), stomatitis (26%), dysgeusia 
(22%), mucosal inflammation (19%), asthenia (15%), pruritis (15%), vomiting (15%) and dry 
mouth (11%).  Grade 3 and 4 adverse events assessed by the investigator as  taselisib related 
include diarrhea (11%), mucosal inflammation (7%), increased amylase (4%), hyperglycemia 
(4%), increased aspartate aminotransferase (AST) (4%), stomatitis (3.7%). increased blood 
alkaline phosphate (4%), fatigue (4%), increased gamma-glutamyltransferase in the blood (4%), 
hypokalemia (4%), increased lipase in the blood (4%) and papilloedema (4%). 
 
As of 5 July 2013, a total of 27 patients have been enrolled in the expansion cohort of taselisib at 
dose levels of 6 and 9 mg daily (21 patients at 6 mg and 6 patients at 9 mg) in combination with 
fulvestrant (Cohort F).  No DLTs were observed at either dose level.  One patient has been enrolled 
in the Phase II part of the study with 6 mg taselisib in combination with fulvestrant.  Adverse 
events assessed by the investigator as  taselisib related and of any grade that occurred in  10% of 
the 27 patients and were assessed as related to  taselisib were diarrhea (48%), hyperglycemia 
(33%), nausea (33%), decreased appetite (26%), fatigue (26%), rash (26%), stomatitis (22%), 
asthenia (19%), muscle spasms (15%), vomiting (15%), dysgeusia (11%), gastroesophageal reflux 
disease (11%) and mucosal inflammation (11%).  Grade 3 and 4 adverse events assessed by the 
investigator as related to taselisib included hyperglycemia (15%), diarrhea (7%), dyspnea (4%), 
flank pain (4%), hyponatremia (4%), neutropenia (4%), rash (4%) and vomiting (4%).  A phase 
1b study of taselisib in combination with paclitaxel is ongoing. 
 
Refer to the taselisib Investigator’s Brochure for further information regarding the nonclinical and 
clinical safety evaluation of taselisib. 
 
3.3.2 Enzalutamide 
 
Enzalutamide (Medivation) is approved by the United States Food and Drug Administration 
(FDA) for the treatment of men with metastatic castrate resistant prostate cancer (CRPC) who 
previously received docetaxel.  Enzalutamide is marketed as Xtandi and was formerly known as 
MDV3100.   Enzalutamide is an androgen receptor antagonist which acts by competitively 
inhibiting (1) testosterone binding to androgen receptors, (2) nuclear translocation of androgen 
receptors, and (3) DNA binding and activation by androgen receptors. Enzalutamide is 
administered orally. 
 
Refer to the Enzalutamide Investigator’s Brochure for further information regarding the 
nonclinical evaluation of Enzalutamide. 




Ph. Ib/II Taselisib Enzalutamide AR+ 
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BRE 1374 / TBCRC 032 
 
 
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Protocol version:  04/05/2017 
3.4 Rationale 
 
Therapies for breast cancer should be guided by biologic features of the tumor, such as expression 
of steroid hormone receptors and hormone dependence and/or HER2/neu overexpression. Notable 
examples are the successful use of hormonal therapy (e.g. tamoxifen or aromatase inhibitors) for 
patients with hormone-sensitive (estrogen receptor [ER] and/or progesterone receptor [PR] 
expressing) tumors
32, and the use of trastuzumab (Herceptin™), a monoclonal antibody against 
HER2/neu, for patients with overexpression of the aforementioned protein33. These are excellent 
examples of where appropriate patient selection is instrumental on the success of these therapies. 
An unfortunate problem triple in negative breast cancer is that the key drivers of this disease are 
not well understood, and thus molecular targets for therapeutic intervention have not been 
identified.   
 
We have identified distinct subtypes of triple negative breast cancer to better understand potential 
drivers of disease progression and to help identify potential therapeutic targets.  Considering all of 
our preclinical data, we propose a clinical trial in which patients with metastatic TNBC have their 
tumor tissue initially assessed for androgen receptor (AR) status by standard CLIA-certified AR 
IHC analysis.  For patients who are AR positive, we propose a phase Ib/II study of enzalutamide 
+/- taselisib. We hypothesize that the combination of enzalutamide + taselisib will provide an 
improvement in outcome compared to enzalutamide alone.  This study will elucidate the safety 
and preliminary therapeutic value of this combination. 
4. PARTICIPANT SELECTION 
4.1 Inclusion criteria 
4.1.1 Patients must provide informed written consent. 
4.1.2 Patients must be 18 years of age. 
4.1.3 ECOG performance status 0-1. 
4.1.4 Clinical stage IV invasive mammary carcinoma  
4.1.5 For phase 1b: HER2 negative, as defined for phase II.  Any ER/PR (negative or 
positive) can be enrolled in the phase 1b portion.  For phase II: ER negative 
(defined as expression of ER in < 5% cells), PR negative (defined as expression 
of PR in < 5% cells), HER2 negative [acceptable methods of HER2 analysis 
include IHC (0, 1+), fluorescence in situ hybridization (FISH) with 
HER2/CEN-17 ratio < 2, and/or chromogenic in situ hybridization (CISH) with 
HER2/CEN-17 ratio <2], as previously documented by histological analysis.  
4.1.6 Androgen receptor positivity, defined as > 10% of tumor cell nuclei with 
immunoreactivity for AR on central review at Vanderbilt. 


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4.1.7 Measurable or evaluable disease.  Measurable disease is defined as at least one 
lesion that can be accurately measured in at least one dimension by RECIST 
criteria 1.1, with radiologic scans within 28 days of day 1, cycle 1.  Evaluable 
disease must include bone metastases (pleural effusions and ascites are not 
considered evaluable for this study). 
4.1.8 Any number of prior therapies as long as patients have adequate performance 
status and meet all other eligibility criteria. 
4.1.9 Prior treatment with anti-androgens other than enzalutamide is acceptable. 
4.1.10  Phase 1b only: FFPB or fresh frozen tissue from the original diagnosis or the 
metastatic setting should be located.  Tissue must be submitted with 3 weeks of 
study initiation.  
4.1.11 Phase II only: Biopsy of a metastatic lesion in patients with reasonably 
accessible metastatic lesions (chest wall, skin, subcutaneous tissue, lymph 
nodes, skin, breast, bones, lung, and liver metastases). If a reasonably 
accessible metastatic lesion is not available, the patient may go on study 
provided that archived tissue is available.  However, if a reasonably accessible 
site is available for biopsy, the patient must agree to biopsy.  Any patients not 
undergoing biopsy must be approved for study enrollment by the Protocol 
Chair. Biopsies may be done with local anesthesia or intravenous conscious 
sedation, according to institutional guidelines.  If a biopsy requires general 
anesthesia, then it is only allowed if acquisition of tissue is clinically 
indicated, and excess tissue may be collected for research purposes. Patients 
without sites available for biopsy must have available tissue [archived 
formalin-fixed paraffin embedded blocks (FFPB) or fresh frozen tissue from 
original diagnosis or metastatic setting] for correlative studies per Section 9.2. 


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Tissue needs to be located and available at the time of registration (tissue 
needs to be submitted within 3 weeks of study initiation). 
4.1.12 Patients must have adequate hematologic, hepatic, and renal function. All tests 
must be obtained within 28 days of starting treatment.  Labs are to be repeated 
on C1D1 and must still meet eligibility. These include: 
 ANC >1500/mm3 
 Platelet count > 75,000/mm
3 
 HgB ≥ 9 g/dL 
 Creatinine 1.5X upper limits of normal (ULN) 
 INR ≤2 
 Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a 
total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)  
 AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present) 
 For patients without known Type II diabetes, the following is required at screening: 
o Fasting plasma glucose
 
 160 mg/dL (7.49 mmol/L) and glycosylated 
hemoglobin (HbA1c)
 
 7.5 % or International Federation of Clinical 
Chemistry (IFCC) < 53 mmol/mol 
 For patients with Type II diabetes receiving only oral anti-hyperglycemic therapy 
(patients receiving insulin are not eligible), the following are required at screening:  
o HbA1c  8.5 % or IFCC  69.4 mmol/mol  
o Stable regimen of oral anti-hyperglycemic therapy without insulin usage for 
at least 3 weeks prior to first study treatment 
o Fasting plasma glucose levels  160 mg/dL (8.88 mmol/L) and no 
hypoglycemia (BS<60) during home monitoring for at least 1 week prior to 
study entry 
4.1.13 Patients must be able to swallow and retain oral medication. 
4.1.14 For patients who are not postmenopausal or surgically sterile (absence of 
ovaries and/or uterus), agreement to remain abstinent or to use two adequate 
methods of contraception(e.g., condoms, diaphragm, vasectomy/vasectomized 
partner, tubal ligation), during the treatment period and for at least 30 days after 
the last dose of study treatment or 3 months after discontinuation of  taselisib 
and/or enzalutamide, whichever is longer. Hormone based oral contraceptives 
are not allowed on study.   Postmenopausal is defined as: 
o Age  60 years 
o Age  60 years and amenorrheic for 12 months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle 
stimulating hormone and estradiol in the postmenopausal range 


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Protocol version:  04/05/2017 
4.1.15 Patients may have received radiation therapy to painful bone metastases or areas 
of impending bone fracture as long as radiation therapy is completed ≥ 2 weeks 
prior to day 1 of cycle 1 of treatment. Patients who have received prior 
radiotherapy must have recovered from toxicity (≤ grade 2) induced by this 
treatment.  Baseline radiologic scans must be obtained after completion of 
radiation. 
4.1.16 Patients must complete all screening assessments as outlined in the protocol. 
4.2 Exclusion Criteria 
4.2.1 Any kind of malabsorption syndrome significantly affecting gastrointestinal 
function, including history of Crohn’s disease or inflammatory bowel disease. 
4.2.2 Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, hormonal therapy, biologic therapy) other than the ones 
specified in the protocol. Patients must have discontinued the above cancer 
therapies for 1 week prior to the first dose of study medication.  Any 
investigational drugs should be discontinued 2 weeks prior to the first dose of 
study medication and radiotherapy must have been completed ≥ 2 weeks prior 
to initiation of study drug (Cycle 1, Day 1).  
4.2.3 Prior use of PI3K or Akt inhibitors in the metastatic setting for the treatment of 
cancer.  These include, but are not limited to:  taselisib, GDC-0941, GDC-0980, 
BEZ235, BKM120, LY294002, PIK-75, TGX-221, XL147, XL765, SF1126, 
PX-866, D-87503, D-106669, GSK615, CAL101. Patients who have received 
PI3K/Akt inhibitors previously for <4 weeks will be eligible. 
4.2.4 Prior treatment with enzalutamide.   
4.2.5 Current or previously treated brain metastasis or active leptomeningeal disease; 
head imaging is required during screening in all patients to exclude the presence 
of central nervous system (CNS) metastatic disease.   
4.2.6 History of seizure or any condition that may predispose to seizure; history of 
loss of consciousness or transient ischemic attack within 12 months before day 
1.   
4.2.7 Pregnant or lactating women. 
4.2.8 Insulin-dependent diabetes.  Patients with Type II diabetes must meet the 
inclusion criteria outlined above. 
4.2.9 Uncontrolled intercurrent illness including, but not limited to: 
 Ongoing or active infection requiring parenteral antibiotics 


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 Impairment of lung function (COPD > grade 2, lung conditions requiring oxygen 
therapy) or current dyspnea at rest 
 Symptomatic congestive heart failure (class III or IV of the New York Heart 
Association classification for heart disease)  
 Known Left Ventricular Ejection Fraction (LVEF) < 50%  
 Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 
6 months 
 Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood 
pressure > 100 mm Hg, found on two consecutive measurements separated by a 1 
or 2-week period despite adequate medical support) 
 Clinically significant cardiac arrhythmia (multifocal premature ventricular 
contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or 
requires treatment [National Cancer Institute -Common Terminology Criteria for 
Adverse Events, Version 4.0, grade 3]  
 QTcF ≥ 480 msec on screening EKG  
 Known history of QT/QTc prolongation or Torsades de Pointes (TdP) 
 ST depression or elevation of ≥ 1.5 mm in 2 or more leads 
 Diarrhea of any cause ≥ CTCAE grade 2 
 Active autoimmune disease that is not controlled by nonsteroidal or steroidal 
( 10 mg of prednisone per day) anti-inflammatory drugs or active inflammatory 
disease, including small or large intestine inflammation such as active Crohn’s 
disease or ulcerative colitis, which requires immunosuppressive therapy 
 Psychiatric illness/social situations that would compromise patient safety or limit 
compliance with study requirements including maintenance of a compliance/pill 
diary 
 Known history of chronic liver disease including cirrhosis, current alcohol abuse, 
or infection with hepatitis B virus or hepatitis C virus (active or carrier) or renal 
failure 
 Known history of chronic pancreatitis 


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 Conditions that affect lymphocyte counts, such as HIV infection or 
immunosuppressive therapy   
4.2.10 Use of prohibited drugs, as described in section 6.4. 
4.3 Inclusion of Underrepresented Populations 
Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards 
age or race in the clinical trial outlined. This trial is open to the accrual of men and women. 
 
5. REGISTRATION PROCEDURES 
Patients must be AR positive to register for the study.  Sections 5.1, 5.2, and 5.3 describe how 
AR testing can be done.  Once AR positivity is confirmed, all patients MUST be registered with 
the Vanderbilt-Ingram Cancer Center (VICC) prior to the start of protocol treatment (see Section 
5.4).  Each participating site must also be registered with their own institution according to their 
institutional guidelines prior to start of protocol treatment. 
 
5.1 Pre-Screening 
Patients with TNBC may submit archival tissue to test for AR expression. A separate prescreening 
consent will be available to enable testing of archival tissue for AR expression before initiating 
other screening activities. Patients must sign the separate prescreening consent form if AR status 
is not already known (see section 5.2). Study site personnel must document the informed consent 
process for tissue analysis in the patient’s clinical record.  
 
If archival tissue is not available for AR analysis and the patient is otherwise eligible for the study 
and willing to go on study within 4 weeks, the patient may undergo a biopsy of metastatic site to 
assess AR status after signing the prescreening consent (see Section 5.3).  The prescreening 
consent form allows extra study-related research biopsy specimens to be obtained so that the 
patient would not have to undergo a repeat biopsy at baseline for study purposes.  Patients must 
be informed that analysis of tissue will not guarantee eligibility for this study, as patients found to 
have AR+ disease must meet all other eligibility criteria at the time of enrollment. 
5.2 AR testing for registration 
AR testing can be performed on a prior breast cancer biopsy (primary or local recurrence), 
surgical specimen, or biopsy of a metastatic site.  
 For participants who are known to have androgen receptor-positive triple negative breast 
cancer by local testing in a CLIA certified lab on any one of the above samples (primary, 
local recurrence or metastasis), after discussion with the Protocol Chair, the prescreening 
consent does not need to be signed and he/she can sign the main consent form to proceed 
with eligibility screening.   Patients who are found to be AR negative upon central review 
at Vanderbilt will be considered screen failures.   


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 For participants in whom androgen receptor status is not known upfront and who have 
archival tissue for testing: participants can sign the prescreening AR testing consent form 
to allow for AR testing.   Please send: 
o A tissue block to the address below and indicate on the requisition that AR testing 
needs to be performed for registration.  
OR 
o If a participating institution does not allow release of formalin-fixed paraffin-
m each, on charged 
(plus) slides for AR testing by immunohistochemistry. 
 For participants who are undergoing biopsy of a metastatic site as standard of care or 
specifically for AR testing: participants can sign the prescreening AR testing consent 
form to allow for AR testing from the biopsy, and to obtain the extra biopsies required for 
the study so that the participant would not have to undergo another biopsy if he/she is 
found to AR+ and qualifies for the study.  Tissue must be sent to Vanderbilt-Ingram 
Cancer Center, along with the tissue block registration form for central testing of 
androgen receptor.  See section 9 of the protocol for details on what should be obtained. 
Please note that a patient can only undergo a biopsy specifically for AR testing for 
this study if he/she otherwise meets all eligibility criteria and is able to go on 
study within 4 weeks of obtaining the AR results.  
 The coordinating center must be notified if a sample is being sent for AR testing (see lab 
manual for details). Once the tissue to be tested is received at Vanderbilt, AR testing 
results will be provided to the ordering institution within 7-10 days.  If the patient is 
AR+, the patient will be eligible to sign the treatment consent form and continue 
screening for protocol participation; the steps in section 5.4 should be followed.   
 
Outside sites should ship specimens along with Tissue Registration Form directly to:  
 
For all tissue and blood/plasma: 
 
 
 
5.3 Biopsy of metastatic lesion 
After signing informed consent for the research biopsy, potential participants should have 2-3 
paraffin-embedded diagnostic core biopsy specimens and 2-3 core biopsy specimens suspended 
in RNAlater solution from a metastatic site if reasonably safe submitted prior to randomization. 


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Please see section 9 for further details. If AR status has already been confirmed centrally on a 
prior biopsy, tissue from the metastatic biopsy needs to be available, but not evaluated centrally, 
prior to beginning treatment on study.   
 
Outside sites should ship specimens along with Tissue Registration Form directly to:  
 
For all tissue and blood/plasma: 
 
 
 
5.4 Ship ALL paraffin material, RNAlater tubes or slides as detailed in the lab manual.  
**Specimens should be mailed to arrive at VUMC from Monday 8AM through 
Friday 1PM**Registration 
Once patients are confirmed to AR positive and if they meet all other eligibility criteria, patients 
will be centrally registered with the Vanderbilt-Ingram Cancer Center (VICC) at study entry by 
emailing the Multi-Institutional Team at coordinating.center@vanderbilt.edu .  At the time 
of registration, the following documents must be emailed to the VICC CTSR office 
(coordinating.center@vanderbilt.edu):  
 
 Copy of the patient’s signed and dated Informed Consent including documentation of the 
consent process 
 Patient Enrollment From  
 Eligibility Checklist including source documents to verify eligibility 
Prior to registration a copy of IRB approval at the respective sites will be requested and on file at 
VICC.  
 
CTSR requests 24-48 hours to review all documents and confirm eligibility. 
 
. 
 
In the phase II portion, the VICC Coordinating Center will assign sequence numbers to all 
patients in screening. Only patients deemed eligible will be randomized to a treatment arm. 
Sequence numbers will not be re-used if a patient screen fails.  The Center will randomize 
eligible patients to enzalutamide + taselisib or enzalutamide alone.  Following registration and 
randomization (after AR results are released to the treating institution, see below), eligible 
participants should begin protocol treatment within 2 weeks. Issues that would cause treatment 
delays should be discussed with the Protocol Chair. If a participant does not receive protocol 
therapy following randomization within allowed time period, the participant will become 
ineligible and will be cancelled from the study.  Such patients will have to undergo screening 


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again to participate in the study in the future.  Any requests for eligibility exceptions and/or 
deviations must be approved in writing by the Protocol Chair and the local IRB prior to 
execution. As is generally accepted, standard of care procedures performed prior to consent, but 
within the protocol defined screening window for each assessment can be used for study 
purposes. All research only procedures must be performed after the consent date.  
 
 
 
 
 
 
 
 
 
6. TREATMENT PLAN 
6.1 Overview 
This is an open-label phase Ib/II multi-institution trial that evaluates the safety profile and anti-
tumor activity of enzalutamide +/- taselisib in patients with androgen receptor positive metastatic 
triple negative (ER negative, PR negative, HER2Neu negative by IHC or FISH) breast cancer 
(AR+ TN MBC).   
 
As taselisib has not been evaluated with enzalutamide, we will proceed with a phase Ib portion to 
ensure safety of the combination prior to open enrollment on the study.  
 
6.2 Phase Ib component of the trial 
The phase Ib component is complete.  The primary objective of this portion of the trial was to 
determine the safety profile [dose-limiting toxicities (DLTs) during the first cycle of treatment, 
and maximum tolerated dose (MTD)] of the combination of taselisib and enzalutamide.  The phase 
Ib portion allowed patients who are estrogen and/or progesterone receptor positive or negative, 
provided they are HER2 negative (see eligibility criterion 4.1.5). 
 Enzalutamide + taselisib: the taselisib dose will start at 2 
mg (dose level 1). 
 Dose escalation 
proceeded among cohorts of 3 patients according to a standard 3+3 algorithm beginning at 
the lowest dose level.   
In addition, pharmacokinetic (PK) sampling was collected from patients enrolled into the Phase Ib 
part of the study to allow for comparison within the study and to previous observations when 
taselisib was administered as a single agent in the Phase Ia trials.  All open sites were able to 
participate in the phase Ib component. 
6.2.1 Phase I Agent Dose Escalation 
 
Dose level    
Enzalutamide   
  
Taselisib 
1  
  
  
160 mg PO daily  
  
2 mg PO daily 


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2  
  
  
160 mg PO daily  
  
4 mg PO daily 
3  
  
  
160 mg PO daily  
  
6 mg PO daily 
4  
  
  
160 mg PO daily  
  
8 mg PO daily 
 
 
 
1 cycle = 28 days 
 
All pills were self-administered (by the patients themselves). A pill diary was given to all patients 
enrolled in the study.. The investigator will instruct the patient to take the study drugs exactly as 
specified in the protocol.  Taselisib and enzalutamide were administered on a continuous once 
daily dosing schedule.  To assist in PK assessment, for patients enrolled in the combination arm 
(phase Ib or II) at Vanderbilt only, taselisib was started on day 1, and enzalutamide was added on 
day 9. 
 
6.2.2 Definition of Dose-Limiting Toxicity (DLT) 
 
Any of the following events that occur during Cycle 1 (first 4 weeks) was considered a DLT when 
possibly, probably or definitively classified as drug-related (according to NCI CTCAE v 4.0 
Requirements).  Whenever a patient experienced toxicity that fulfilled the criteria for a DLT, 
treatment with taselisib was held and the toxicity was followed up, Dose reductions as listed in 
Section 7.1 were followed.  No DLTs were noted in the phase Ib. 
 
 
Table 1: DLT criteria and Follow-up Evaluation (CTCAE v 4.0) 
Toxicity 
DLT criteria 
Follow-Up Evaluation 
Hematologic 
 Anemia CTCAE Grade ≥ 3 will 
not be considered a DLT unless 
judged to be a hemolytic process 
secondary to study drug.   
 Febrile neutropenia CTCAE 
Grade ≥ 3 
 ANC CTCAE Grade 3 for > 7 
consecutive days.  G-CSF use is 
permitted during the DLT 
window. 
 ANC CTCAE Grade 4 
 Platelet count CTCAE Grade 3 
for > 7 consecutive days and/or 
with signs of excessive bleeding 
 Platelet count CTCAE Grade 4 
 
If ≥ CTCAE grade 3 neutropenia or 
≥ CTCAE grade 3 thrombocytopenia 
have been demonstrated, these 
parameters must be repeated at least 
once a week until resolution to ≤ 
CTCAE grade 1 neutropenia or ≤ 
CTCAE grade 1 thrombocytopenia 
to allow for initiation of re-treatment, 
and then at least weekly until either 
resolution or until stabilization. 


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Table 1: DLT criteria and Follow-up Evaluation (CTCAE v 4.0) 
Toxicity 
DLT criteria 
Follow-Up Evaluation 
Cardiac disorders 
 Cardiac toxicity CTCAE Grade ≥ 3 
or cardiac event that is 
symptomatic or requires medical 
intervention 
 Clinical signs of cardiac disease, 
such as unstable angina or 
myocardial infarction, or Troponin 
CTCAE Grade 3 (confirmed with a 
repeat Troponin within 24 hrs) 
 ECG QTc interval prolonged 
CTCAE Grade ≥ 3 (after repeat 
confirmation on at least 2 more 
ECGs at the same time point) 
Patients who experience ECG 
abnormalities indicative of an 
ischemic cardiac event should be 
evaluated by cardiology and have 
EGCs repeated at least once a week 
until normalization or stabilization of 
ECG findings. 
If troponin ≥ CTCAE grade 3 has 
been demonstrated, the patient 
should be evaluated by cardiology 
and this parameter must be repeated 
once a week or as clinically indicated 
until resolution to ≤ CTCAE grade 1, 
and then at least weekly until either 
resolution or until stabilization. 
Patients who experience QTc 
prolongation should be followed as 
per Dose Modification section 
guidelines and should be evaluated 
by cardiology. 
Vascular disorders/ 
Hypertension 
Persistent hypertension CTCAE 
Grade ≥ 3 requiring more than one 
drug or more intensive therapy than 
previously 
 
Fatigue  
Fatigue CTCAE Grade 3 for > 7 
consecutive days 
 
Rash and/or 
photosensitivity  
Rash or photosensitivity CTCAE 
Grade 3 for > 7 consecutive days 
despite skin toxicity treatment, 
including oral steroid and 
antihistamines 
Photosensitivity CTCAE Grade ≥ 4  
Rash should be evaluated weekly 
until resolution. 


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Table 1: DLT criteria and Follow-up Evaluation (CTCAE v 4.0) 
Toxicity 
DLT criteria 
Follow-Up Evaluation 
Endocrine: 
Hyperglycemia  
 Hyperglycemia Grade 3 (FPG 
250 – 399 mg/dL; 13.9 - 22.2 
mmol/L) (confirmed with a repeat 
FPG within 24 hrs) for > 7 
consecutive days despite oral 
anti-diabetic treatment 
 Hyperglycemia Grade 4 (FPG ≥ 
400 mg/dL; ≥ 22.3 mmol/L) 
 Hyperglycemia leading to 
diabetic keto-acidosis, 
hospitalization for IV insulin 
infusion, or non-ketotic coma 
 Hyperglycemia occurring during 
corticosteroid administration will 
be only considered DLT if not 
resolved within 2 days after the 
end of corticosteroid treatment. 
 
For details of the follow-up and 
treatment of ≥  grade 3 
hyperglycemia refer to the 
Guidelines for the treatment of study 
drug-induced hyperglycemia 
provided in the Dose Modification 
Section 
GI disorders  
 Diarrhea CTCAE Grade ≥ 3 for ≥ 
48 hrs, despite the use of optimal 
anti-diarrhea therapy  
 Nausea/vomiting CTCAE Grade 
≥ 3 for ≥ 48 hrs, despite the use of 
optimal anti-emetic therapy  
 Pancreatitis CTCAE Grade ≥ 3 
If amylase and/or lipase ≥ CTCAE 
grade 3 (> 2 x ULN) has been 
demonstrated, these parameters must 
be assessed once at 2 to 4 days and 
once again at 7 days (± 1 day) and be 
repeated twice a week until 
resolution to ≤ CTCAE grade 2 to 
allow for initiation of re-treatment, 
and then at least weekly until either 
resolution to ≤ CTCAE grade 1 or 
until stabilization. 
 
A CT scan or other imaging study to 
assess the pancreas, liver, and 
gallbladder must be performed 
within 1 week of the first occurrence 
of any ≥ CTCAE grade 3 of amylase 
or lipase.  Amylase and lipase should 
be followed weekly until resolution 
to < CTCAE grade 1. 
 


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Table 1: DLT criteria and Follow-up Evaluation (CTCAE v 4.0) 
Toxicity 
DLT criteria 
Follow-Up Evaluation 
Hepatic 
 Total bilirubin  CTCAE Grade 2 
for > 7 consecutive days, if less 
normal-grade 1 at baseline 
 Total bilirubin  CTCAE Grade ≥ 
3, if grade 2 at baseline 
 AST or ALT CTCAE Grade ≥ 2 
in conjunction with blood 
bilirubin d CTCAE Grade ≥ 2 of 
any duration  
 AST or ALT CTCAE Grade 3 
for > 7 consecutive days 
 AST or ALT CTCAE Grade 4 
 Serum alkaline phosphatase 
CTCAE Grade 4  
 Serum lipase and/or serum 
amylase (asymptomatic) 
CTCAE Grade 3 for > 7 
consecutive days 
 Serum lipase and/or serum 
amylase (asymptomatic) 
CTCAE Grade 4 
 ALT or AST of 3X ULN and 
concomitant bilirubin of >2 X 
ULN (Hy’s Law) with no other 
explanation other than study 
drug should be permanently 
discontinued from treatment 
with study drug. 
Both 
taselisib and enzalutamide 
should be held. 
If total bilirubin ≥ 2 x ULN or ≥ 
CTCAE grade 3 AST/ALT has been 
demonstrated, these parameters must 
be repeated at least twice a week 
until resolution to ≤ CTCAE grade 1 
(or ≤ grade 2 for AST or ALT, if 
liver metastasis are present) to allow 
for initiation of re-treatment, and 
then at least weekly until either 
resolution or until stabilization. 
Patients with total bilirubin > ULN 
(any duration) should have 
fractionation of bilirubin into 
total/direct or indirect/direct 
components and any additional 
work-up as clinically indicated by 
these results. Follow-up of 
hyperbilirubinemia should proceed 
as per the guidelines above, 
irrespective of the results of 
fractionation. 
For any hepatic toxicity CTCAE 
Grade 4, or CTCAE Grade 3 that 
does not resolve within 7 days to 
CTCAE Grade ≤ 1 (or CTCAE 
Grade ≤ 2 if liver infiltration with 
tumor present), an abdominal CT 
scan should be performed to assess if 
it is related to disease progression. 
Renal 
Serum creatinine CTCAE Grade ≥ 3 
If serum creatinine ≥ 3 x ULN has 
been demonstrated, this parameter 
must be repeated at least twice a 
week until resolution to ≤ CTCAE 
grade 1 to allow for initiation of re-
treatment, and then at least weekly 
until either resolution or until 
stabilization. 
 
Serum creatinine ≥ 2.0 x ULN and 
[+3] proteinuria or  hematuria ≥ 
CTCAE grade 2 has been 
demonstrated, a 24-hour urine 
collection for total protein and total 
creatinine must be done at least 
weekly until either resolution to 
baseline value or until stabilization. 
Whenever a measured CrCl is 
obtained, a serum creatinine should 


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Table 1: DLT criteria and Follow-up Evaluation (CTCAE v 4.0) 
Toxicity 
DLT criteria 
Follow-Up Evaluation 
be obtained within ≤ 72 hours of the 
urine collection. 
 
Other hematologic and 
non-hematologic 
toxicities 
Any other CTCAE ≥ Grade 3 
toxicity except: 
 Lymphocyte count decreased 
(lymphopenia) CTCAE grade ≥ 3 
unless clinical significance 
 Alopecia of any grade 
Patients who experience 
neurotoxicity should be followed as 
per Dose Modification Section 
 
Patients who experience non-
laboratory DLTs must be evaluated 
at least once a week following 
demonstration of the toxicity until 
resolution of the toxicity to allow for 
re-treatment, stabilization of the 
toxicity, or study treatment 
completion. 
Apart from the criteria listed above, if a lower grade AE leads to a 
dose interruption of 
taselisib of more than 7 consecutive days, this 
AE may be considered as a DLT.  Such cases will be considered 
individually.  Patients who withdraw or are withdrawn from the 
study prior to completing the DLT assessment window for any 
reason other than a DLT or miss > 7 days for non-drug related AEs 
will be replaced. 
   
 
The following were instructions for DLTs in the phase Ib.  Patients who meet DLT criteria must 
stop taselisib. Patients who meet DLT criteria for hepatoxicity should hold both taselisib and 
enzalutamide. Patients whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value must be followed as outlined in the table 
above, at least once a week for 4 weeks, and subsequently at 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. Patients that require a dose delay of > 28 days 
due to a cause unrelated to study participation will have the opportunity to continue study if 
deemed appropriate to do so by the Protocol Chair of the study. If patients experience a DLT 
considered related to taselisib, the patient may remain on enzalutamide on-study after resolution 
of the DLT at the discretion of the treating physician after receiving counseling about alternate 
treatment options. If patients experience a DLT considered related to enzalutamide, they have the 
option of remaining on single agent GDC0032 on-study at the discretion of the treating physician 
after receiving counseling about alternative treatment options. After resolution of the DLT, 
patients may be able to restart taselisib or enzalutamide at a lower dose at the discretion of the 
treating physician. However, such cases will be considered a DLT for the purposes of defining the 
MTD. All patients who continue taking taselisib and/or enzalutamide as a single agent will not be 
evaluable.  
 
Patients who withdraw or are withdrawn from the study prior to completing the DLT assessment 
window for any reason other than a DLT or miss > 7 days for non-drug related AEs will be 
replaced. This includes patients whose disease progresses within 30 days of starting the study.  
Patients requiring dose reduction of enzalutamide or taselisib for reasons other than a DLT in cycle 
1 of the phase Ib portion will not be included in the DLT evaluation. After the MTD is reached, 


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patients in the phase Ib on lower dose levels can dose escalate to the MTD at the discretion of the 
treating physician and after discussion with the Protocol Chair. 
6.2.3 Definition of Maximum Tolerated Dose (MTD) 
The MTD was defined as the highest dose of taselisib tested in which a DLT is experienced by 0-
1 out of 6 patients among the dose levels. The dose of enzalutamide remained constant. The first 
cohort of patients (3 patients) in each arm started at dose level 1, and each patient was observed 
for 4 weeks on the specified dose and instructions were followed as below:  
• If no patient in the first cohort of 3 experiences a DLT, dose escalation will proceed and 
patients will be accrued at the next dose level. If 1 of these patients experiences a DLT, the 
cohort will be expanded to 6 patients.  If <33% of these patients experiences a DLT (e.g., 
1 of 6 patients), dose escalation may proceed.   
• If a DLT is observed in > 33% of the patients in a given cohort (e.g. > 2 of 6 patients), the 
MTD will have been exceeded and the lower dose level will be evaluated.   
An exception to the above rule would be in the case in which the two DLTs observed out 
of 6 patients are both hematologic in nature and potentially reflect poor bone marrow 
reserve in this heterogeneous patient population and not the true MTD for the combination. 
In this instance, up to 3 additional patients may be enrolled to expand the total cohort size 
to 9 patients to assess for further DLT. In this situation, if a third DLT is observed, the 
MTD will have been exceeded and the lower dose level will be evaluated. 
• If the 2 mg dose does not exceed the MTD, then dose escalation will proceed to the 4 mg 
dose. If the 4 mg dose does not exceed the MTD, then dose escalation will proceed to the 
6 mg dose, and if the 6 mg dose does not exceed the MTD, then dose escalation will 
proceed to the 8 mg dose. If <33% of patients experience a DLT in the 8 mg cohort, then 
this dose level will be the maximum administered dose (MAD). 
No new cohort of patients will be treated until the previous cohort has been fully evaluated for 
toxicity.  Patients requiring dose reduction for reasons other than a DLT in cycle 1 of the phase Ib 
portion will not be included in the DLT evaluation.  If the frequency of Grade 3 or 4 toxicities or 
other unacceptable lower grade chronic toxicities in the phase 1b portion suggests that the MTD 
has been exceeded at that dose level, any remaining accrual at that dose level will be halted and a 
lower dose of taselisib may be examined. 
If taselisib dosing is not well tolerated, a less frequent dosing schedule may be evaluated at the 
same or lower dose of taselisib in that arm. Consistent with the dose escalation rules above, the 
lowest dose level will be 2 mg, and the highest dose level will be 8 mg.   
6.3 Phase II component of the trial 
Based on the phase Ib and data from other studies of taselisib, the recommended dose of taselisib 
for phase II is 4 mg.  Note that dose reduction within patients (individually) is allowed. Dose 
reduction will be required for a given patient in case of grade 3 or 4 toxicities.  
The primary efficacy endpoint is clinical benefit rate (CBR) of enzalutamide + taselisib in patients 
with androgen receptor positive triple negative metastatic breast cancer. Secondary objectives are 
to determine the ORR and progression free survival (PFS). CBR is defined as the proportion of 
patients achieving a complete response (CR) plus partial response (PR) plus stable disease (SD) 


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for at least 16 weeks. To assess objective responses, we will estimate the overall tumor burden at 
baseline to which subsequent measurements [performed every 2 cycles using the Solid Tumor 
Response Criteria (RECIST) v1.1] will be compared.   
 
Section 6.3.1 and 6.3.2 discuss administration of taselisib and enzalutamide. Patients on the 
combination arm can take both drugs at the same time. Patients on the enzalutamide only arm 
should take enzalutamide only as directed below. 
6.3.1 Taselisib  
Taselisib tablets are administered once daily until disease progression or intolerable toxicity.  
Taselisib administration will begin on C2D1 for patients enrolled on the combination arm (with 
enzalutamide alone beginning on C1D1).   Each dose should be taken with a minimum of 3−4 
ounces (90−120 mL) of water with or without food in the morning (before noon). If a dose is 
missed (not taken by noon), the patient will resume dosing with the next scheduled dose. Missed 
or vomited doses will not be made up. The occurrence and frequency of any vomiting during a 
treatment cycle must be noted as an adverse event.  Patients should swallow the capsules as a 
whole and not chew or crush them.  
 
A sufficient number of taselisib tablets should be provided to the patient to last until the next cycle.  
Patients will be instructed to bring their bottles of study drug and their medication diary with them 
to each study visit.  
6.3.2 Enzalutamide 
The daily dose of enzalutamide is 160 mg/day given in 4 capsules (40 mg each) by mouth. 
Enzalutamide capsules are administered once daily until disease progression or intolerable 
toxicity. The first ten subjects on the enzalutamide + taselisib arm at Vanderbilt will have blood 
draws for PKs as outlined in the study calendar.  
 
Patients should be instructed to take the dose of enzalutamide at the same time in the morning 
(before noon) every day, with or without food. Enzalutamide should be taken with a glass of water. 
Patients should swallow the capsules as a whole and not chew, crush, or open them.  
If the patient forgets to take her/his dose and it is past noon, then the dose should be withheld that 
day and enzalutamide should be restarted the following day. Missed or vomited doses will not be 
made up.  The occurrence and frequency of any vomiting during a treatment cycle must be noted 
as an adverse event. 
 
A sufficient number of enzalutamide capsules should be provided to the patient to last until the 
next visit or, at the investigator’s discretion, to last until the next cycle. Patients will be instructed 
to bring their bottles of study drug and their medication diary with them to each study visit. 
6.4 Concomitant Treatment and Supportive Care Guidelines 
6.4.1 Concomitant Therapy and Drug-drug Interactions 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a patient between the 7 days preceding day 1 of treatment and the treatment completion visit. 
 


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All concomitant medications should be documented. Patients who experience toxicities may be 
treated symptomatically as clinically indicated. Patients treated with anti-convulsant medications 
(see below for restrictions) should have levels monitored regularly. 
 
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19.  
Taselisib is a substrate of CYP3A4, and results of a clinical study with a potent CYP3A4 
inhibitor (itraconazole) suggest that there is a moderate potential for a drug-drug interaction 
between taselisib and any medication that strongly inhibits CYP3A4.  Therefore, the concomitant 
use of strong CYP3A4 inhibitors should be avoided.  The effects of strong/moderate CYP3A4 
inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.  Co-
administration of enzalutamide may decrease the plasma exposure of enzalutamide and should be 
avoided.  If use of one of these drugs is necessary, the risks and benefits should be discussed 
with the Protocol Chair and documented prior to its concomitant use with taselisib and 
enzalutamide: 
• Strong/moderate CYP3A4 inhibitors or inducers (which should be avoided): atazanavir, 
bosentan,  carbamazepine, ciprofloxacin, clarithromycin, cyclosporine,  efavirenz, erythromycin, 
etravirine, fluconazole, hyperforin (St. Johns Wort), indinavir, itraconazole, ketoconazole, 
modafinil, nafcillin, nefazodone, nelfinavir, oxcarbazepine, phenobarbital, phenytoin, 
posaconazole, quinidine, rifabutin, rifampin, rifapentine, ritonavir, saquinavir, sirolimus, 
tacrolimus, telithromycin, troleandomycin, verapamil, and voriconazole.  
• CYP2C8 inhibitors or inducers: gemfibrozol should be avoided. 
• Strong P-glycoprotein inhibitors, including cyclosporine, amiodarone and quinidine should be 
avoided  
• In-vitro protein binding studies have shown that enzalutamide can displace coumarin 
anticoagulants from binding sites.  Patients already on coumarin anticoagulants should have 
closely monitored Prothrombin times while taking enzalutamide.   
• Grapefruit juice or grapefruit supplements should be avoided. 
 
See the following websites for updated lists of CYP inhibitors, inducers, and substrates: 
• http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm#potency 
• 
6.4.2 Excluded Therapy 
Use of the following therapies is prohibited for≤ 14 days prior to Cycle 1 Day 1 dosing and 
during the study.  
 
• Any experimental concomitant therapy intended for the treatment of cancer , including 
chemotherapy, radiotherapy, immunotherapy, biologic therapy, herbal therapy, or hormonal 
therapy.  Bisphosphonate and denosumab therapy for bone metastases is allowed. 
• Quinidine or other anti-arrhythmic agents are prohibited 
6.5 Assessments during Treatment 
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted. Please see 
the Study Calendar at the beginning of this protocol for the schedule of treatment period 
assessments.  


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6.6 Cross-over post-progression 
Patients who are randomized to enzalutamide alone can crossover to receive enzalutamide + 
taselisib upon disease progression.  Patients who are randomized to enzalutamide alone and who 
discontinue enzalutamide for toxicity cannot crossover to receive single agent taselisib.  However, 
patients on the enzalutamide + taselisib arm can continue to receive single agent taselisib if they 
discontinue enzalutamide due to toxicity. Patients who cross over to receive taselisib in 
combination with enzalutamide will follow the assessments and procedures as outlined in the study 
calendar. The duration of each cycle will continue to be 28 days and the cycle numbers will "reset" 
to 1 and will be followed by the “X” suffix (e.g., Cycles 1X, 2X, etc.). Crossover therapy (taselisib) 
must begin no later than 21 days after the clinic visit at which progression is determined, but can 
begin as early as C1XD1. 
 
Patients must have labs and procedures performed as outlined in the cross-over study calendar and 
must meet the values as described in the Inclusion Criteria, prior to receiving taselisib based on 
assessments and procedures performed within 28 days prior to Day 1 of Cycle 1X.  Labs and 
procedures not included in the cross-over study calendar do not have to be repeated.  Patients must 
also agree to a tumor biopsy, as outlined in the eligibility criteria, prior to initiating taselisib. 
Patients will receive crossover treatment until progression, intolerable toxicity, or elective 
withdrawal from the study. Patients who crossover will be evaluated with radiologic assessments 
every 2 cycles until disease progression. 
 
6.7 Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue until 
one of criteria in Section 6.9 applies. 
6.8 Duration of Follow-Up  
Participants will be followed for 30 days after the final dose of study drug. The 30 day follow-up 
can be done by phone or through a clinic visit. Patients who at the treatment completion visit have 
an ongoing serious adverse event or an adverse event leading to treatment discontinuation will be 
followed every 3 months until the event resolves, the investigator assesses the event as stable, or 
the patient is lost to follow-up. Participants will also be followed annually for disease progression 
by phone, and if necessary, by chart review.  If the patient is no longer coming to the institution 
for care, then the patient may be called as needed for follow-up. 
6.9   Criteria for Removal from Study  
Patients will be removed from study when any of the criteria listed below apply. All patients who 
initiate protocol treatment will be included in the overall evaluation of response (intent-to-treat 
analysis). All reasons for discontinuation of therapy should be documented clearly in the medical 
record.  
 
If a subject discontinues or withdraws from the study, every attempt will be made to get a 
tissue/tumor biopsy at the end of treatment, along with blood if the subject is able and willing to 
do so. 
 


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   Patients may be withdrawn from the study if they experience any of the following: 
• Disease progression, per investigator assessment 
• Intolerable toxicity to taselisib or enzalutamide.  Patients experiencing toxicity to taselisib or 
enzalutamide can continue on study with single agent enzalutamide or taselisib, respectively, 
at the discretion of the treating physician.  Patients will be followed for disease progression 
and should continue radiologic assessments every 2 cycles as per the study.  
 
     Other reasons for patient discontinuation may include, but are not limited to, the following: 
• Non-compliance with the study protocol, including, but not limited to not attending the 
majority of scheduled visits. The Protocol Chair will determine when non-compliance should 
lead to removal from study. Note: The patients will still be included in the overall evaluation 
of response (intent-to-treat analysis). 
• Patient personal decision. The reason for discontinuation from the study must be 
documented. The patients will be included in the overall evaluation of response (intent-to-
treat analysis) if any protocol therapy was administered prior to withdrawal. 
• If the patient becomes pregnant 
• Patient is lost to follow-up 
• Study is terminated for any reason 
 
The investigator has the right to discontinue a patient from the study for any medical condition 
that the investigator determines may jeopardize the patient’s safety if he or she continues in the 
study; for reasons of noncompliance (e.g., missed doses, visits); or if the investigator determines 
it is in the best interest of the patient.  The Protocol Chair should be notified in such cases. 
7. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
7.1 Dose Modifications/ Delays 
 
Table 2 below lists dose level reductions for taselisib and enzalutamide.  Please see section 7.2 to 
7.4 for thresholds to reduce doses. 
 
 
 
 
 
Table 2: Dose Modifications 
Taselisib dose level reductions 
Starting dose 
First reduction 
Second reduction 
 
4 mg daily 
2 mg daily 
Discontinue 
 
Enzalutamide dose level reductions 
Starting dose 
First reduction 
Second reduction 
Third reduction 
160 mg daily 
120 mg daily 
80 mg daily 
Discontinue 









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Table 3: Dosage Modification Criteria and Guidelines for Management of TASELISIB Related Toxicities  
Toxicity  
NCI-
CTCAE (v 4.0) 
Actions 
Diarrhea   
Grade 1 
• Manage with anti-diarrhealsa. 
• No dose reduction necessary. 
• For persistent Grade 1 diarrhea occurring after Cycle 2, recommend 
evaluation for infectious causes via stool cultureb.  For non-infectious 
diarrhea, consider colonoscopy to evaluate for colitis.   
Grade 2 
• Hold taselisib and initially manage with per institutional standard of care until 
Grade  1.  These include antidiarrheals a. 
• Obtain stool culture for infectious workup b Infections (e.g. Clostridium 
difficile, enteric bacteria, CMV) should be treated with the appropriate 
antibiotic.  
• For persistent Grade 2 non-infectious diarrhea lasting longer than 48 hours 
despite treatment with antidiarrheals, treat with oral corticosteroids (20-40 mg 
prednisone QD starting dose with taper) or budesonide 9mg PO QD.  
• If Grade 2 diarrhea occurred after Cycle 2, was a recurrent episode, or 
improved with corticosteroid treatment, resume taselisib treatment at one 
dose level lower upon improvement to Grade  1 and after completion of 
corticosteroid treatment. 
• If Grade 2 diarrhea occurred before Cycle 2, did not require 
corticosteroid treatment, and was an initial episode, resume taselisib 
treatment at the same dose upon improvement to Grade  1. 
• For Grade 2 colitis, resume taselisib treatment at one dose level lower 
upon improvement to Grade  1 and after completion of corticosteroid 
treatment.  
• If Grade 2 diarrhea does not improve after 48 hours of corticosteroid 
treatment, a colonoscopy is recommended to evaluate for other causes of 
diarrhea (e.g., CMV colitis) 
Grade 3 
First Occurrence: 
 Hold taselisib and initially manage with antidiarrheals.
 
 Obtain stool culture for infectious workup.  
 For Grade 3 diarrhea or colitis, treat with systemic corticosteroids 
(prednisone 60-80 mg QD equivalent or solumedrol 16-20 mg IV q 8 h to 
start).  Can increase steroid dosage if diarrhea does not improve. 
 Concurrent infections (e.g., Clostridium difficile, enteric bacteria, CMV) 
should be treated with the appropriate antibiotic.  
 For patients that do not improve upon 48 hours of corticosteroid 
treatment, a colonoscopy is recommended to evaluate for other causes of 
diarrhea (e.g. CMV colitis) 
If diarrhea or colitis improves to Grade ≤1 and upon completion of any steroid 
taper or antibiotic treatment, resume  taselisib treatment at one dose level lower. 
Second Occurrence: 
• Discontinue  taselisib 
Grade 4 
• Discontinue taselisib. 
Rash 


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Special 
considerations 
• Permanently discontinue for any rash with concurrent signs/symptoms strongly 
suggestive of a severe Type 1 hypersensitivity or anaphylactic/anaphylactoid 
reaction, fever, or with painful desquamation or mucosal involvement suggestive 
of Stevens-Johnson Syndrome/ toxic epidermal necrolysis, or with other life-
threatening complications 
Grade 1 
• Continue dosing at current dose and monitor for change in severity (consider 
contacting patient between study visits).  Consider prescribing topical steroids
c. 
Grade 2  
• Monitor closely for change in severity and hypersensitivity-related systemic 
symptoms (contact patient weekly between study visits) 
• Consider prescribing topical steroidsc  
• Consider dermatological consultation 
• Consider one or more of the following: 
              - Hold dose until resolution to ≤ Grade 1, then resume at next lower dose level 
              - Dose reduction 
              - Initiation of oral steroid treatment unless contraindicatedd; monitor blood sugar  
                 carefully if initiating steroids while continuing  
taselisib  
Grade 3: first event 
• Hold dose and monitor closely for changes in severity and for hypersensitivity-
related systemic symptoms 
• Recommend topical steroids
c 
• Recommend initiating oral steroids unless contraindicated
d 
• Upon resolution to ≤ Grade 1, reduce to next lower dose level 
• Consider dermatological consultation 
• Consider obtaining photographs of rash if permitted by local regulations 
Grade 3: first 
recurrence after 
dose reduction 
• Hold dose and monitor closely for changes in severity and for hypersensitivity-
related systemic symptoms 
• Recommend initiating oral steroids unless contraindicatedd 
• Discuss with Protocol Chair if would like to consider restarting at next lower 
level upon resolution to ≤ Grade 1, or permanently discontinue 
• Recommend dermatological consultation, if not already performed 
• Consider obtaining photographs of rash if permitted by local regulations 
Recurrent Grade 3 
or Grade 4 
• Manage as described above.  
• Discontinue taselisib permanently. 
Hyperglycemia  
For all grades 
• Instruct patient to follow dietary guidelines provided by the American Diabetes 
Association  
• For ≥ grade 2, initiate, continue or intensify medication with appropriate anti-
diabetic treatment (Note: some oral anti-diabetic drugs are  CYP3A inducers or 
inhibitors and should be used with caution) 
• Metformin is the first antihyperglycemic medication of choice because of the 
lower risk of hypoglycemia with this agent.  Because metformin in some patients 
may also cause diarrhea and not be well tolerated, other antihyperglycemic 
medications such as sulfonylureas (e.g., glimepiride, glipizide) can be used.  Extra 
caution should be used with other drugs such as sulfonylureas because of the 
increased risk for hypoglycemia with these agents.  Consultation with an 
endocrinologist can be helpful in managing hyperglycemia.   
• If Grade worsens start following recommendations for the worsened grade 
Grade  1 
• Maintain dose level, check FPG every week for 2 weeks, then continue checking 
every 2 weeks until resolved  


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Grade 2 
• Maintain dose, re-check FPG within 24 hours, if no worse than Grade 2, initiate 
or increase the dose of an anti-hyperglycemic (e.g. metformin) 
• If FPG does not resolve to ≤ Grade 1 within 14 days after initiation/ intensifying 
anti-diabetic treatment: consider endocrine evaluation, consider increasing anti-
hyperglycemic therapy further. 
• Dosing with taselisib may either be held or continued per investigator evaluation. 
Asymptomatic 
Grade 3 
 
 
 
 
 Initiate/increase anti-diabetic treatment, re-check FPG within 24 hours, and if no 
worse than Grade 3: 
• Hold  taselisib until hyperglycemia resolves to Grade < 2.  Anti-hyperglycemics 
may be initiated or intensified.  Consider endocrine evaluation.  After this,  
taselisib may be restarted at the same dose or a lower dose at the discretion of the 
treating physician. If another grade 3 hyperglycemia event occurs, the above steps 
should be followed, but the dose of taselisib must be decreased by one dose level.  
Symptomatic  
Grade 3 or  
Grade 4 
If a fasting patient experiences a symptomatic Grade 3 hyperglycemia event 
(e.g., blurred vision, frequent urination, excessive thirst) or any Grade 4 hyperglycemia 
event: 
 Taselisib dosing should be suspended until the hyperglycemia resolves to 
Grade 
 2.   
 The patient should be managed as per standard care, including implementation 
of additional glucose monitoring and initiation and/or increase of 
anti-hyperglycemic therapy.  The patient will be discontinued from the study if 
such therapy fails to control their hyperglycemia.  Dosing with  taselisib may 
otherwise resume at a lower dose level and after discussion with the Protocol 
Chair. 
Hematologic  
Grade 3 
• Hold taselisib until resolution to ≤ grade 1. 
• If resolved in ≤ 7 days, resume taselisib at the current dose level.  
• If resolved in > 7 days, resume taselisib at one lower dose level. 
Grade 4 
• Discontinue taselisib permanently. 
Pneumonitis  
Grade 1 
• CT scans with lung windows and pulmonary function testing including: 
spirometry, DL
CO, and room air O
2 saturation at rest. Repeat at least every 8 
weeks until return to within normal limits. 
• Administer 100% of taselisib dose.  No specific therapy required. 
Grade 2 
• CT scan with lung windows. Pulmonary function testing including: spirometry, 
DLCO, and room air O
2 saturation at rest. Repeat at least every 8 weeks until return 
to within normal limits. Consider a bronchoscopy with biopsy and / or BAL 
• Consider corticosteroids if symptoms are troublesome and infectious etiology 
ruled out. 
• Reduce taselisib dose by 1 dose level until recovery to < Grade 1. Study treatment 
may also be interrupted if symptoms are troublesome. Patients will discontinue 
study treatment if they fail to recover to < Grade 1 within 28 days. 
• Hold taselisib as long as corticosteroids are being given. 


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Grade 3 
• CT scan with lung windows and pulmonary function testing including: spirometry, 
DLCO, and room air O
2 saturation at rest. Repeat at least every 6 weeks until return 
to within normal limits. Bronchoscopy with biopsy and / or BAL is recommended. 
• Oral corticosteroids if infection is ruled out. Taper as medically indicated. 
• Hold taselisib as long as corticosteroids are being given. 
• Hold treatment with taselisib until recovery to < Grade 1. May restart study 
treatment within 28 days at a reduced dose (by one level) if evidence of clinical 
benefit.  Discontinue taselisib if recovery to Grade < 1 is not evident within 28 
days. 
Grade 4 
• CT scan with lung windows and required pulmonary function testing, including: 
spirometry, DL
CO, and room air O
2 saturation at rest. Repeat at least every 6 weeks 
until return to within normal limits. Bronchoscopy with biopsy and / or BAL is 
recommended if possible. 
• Consider corticosteroids if infective origin is ruled out. Taper as medically 
indicated. 
• Discontinue treatment with taselisib. 
Other clinically significant toxicities  
Grade 3 
• Hold taselisib until resolution to ≤ grade 1 and then restart at one dose level lower. 
Grade 4 
• Discontinue taselisib permanently. 
a:  Suggested antidiarrheals include the following:  1) loperamide (initial:  4 mg, followed by 2 mg after 
each lose stool, up to 16 mg/day); 2) diphenoxylate and atropine (diphenoxylate 5 mg, four times daily 
[QID], until control achieved (maximum:  20 mg/day), then reduce dose as needed; some patients may 
be controlled on doses of 5 mg/day; 3) tincture of opium (6 mg of undiluted opium tincture (10 
mg/mL) QID. 
b:  Non-infectious diarrhea can be diagnosed by stool culture with work-up for various enteric 
bacteria and C. difficile.  Fecal calprotectin is a possible marker for bowel inflammation.  
Blood-based CMV PCR test can also be used to detect CMV infection. 
c: Suggested topical steroids include hydrocortisone 2.5% to face bid, triamcinolone 0.1% or  
     fluocinonide 0.1% cream to body bid. 
d: Suggested oral steroids include methylprednisolone dose pack or prednisone 60 mg daily followed by 
      a taper (e.g., 60 mg X 2 days, 40 mg X 2 days, 20 mg X 2 days, etc.
 
7.3 Enzalutamide 
The most common adverse reactions (≥ 10%) in patients treated with enzalutamide are 
asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper 
respiratory infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, 
headache, hypertension, and dizziness/vertigo.   
7.3.1 Hot flashes 
Hot flashes are common with treatment with enzalutamide. If ≥ grade 3 hot flashes occur, 
enzalutamide may be reduced to the next lower dose level, at the discretion of the treating 
physician. Pharmacologic intervention with low-dose SSRI (or an alternative oral therapy that has 
been demonstrated to have beneficial effect for treatment of hot flashes greater than that reported 
for placebo e.g. clonidine, buproprion) may be administered.  If ≥ grade 3 hot flashes persist at the 
lower dose level and pharmacologic intervention with the above treatments has been unsuccessful, 
a second dose reduction may be instituted.  If ≥ Grade 3 hot flashes persist at lowest treatment 


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dose (50mg), patient will be taken off study, and adverse effect will be reported as intolerable 
toxicity. If ≤ grade 2 hot flashes persist at lowest treatment dose (50mg), patient may be taken off 
study at discretion of treating physician. This toxicity will be reported, but it will not constitute 
unacceptable toxicity for purposes of adverse event reporting. 
7.3.2 Other toxicities 
Asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal 
pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower 
respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, 
anxiety, and hypertension have all occurred on studies of enzalutamide. 
 
Though not expected, if ≥ grade 3 diarrhea occurs that is not controlled with anti-diarrheal agents 
(e.g. loperamide), enzalutamide should be withheld until resolution to ≤ grade 1, then reinstituted 
at the next lower dose level.   
If toxicities are ≤ grade 2, manage symptomatically if possible and retreat without dose reduction. 
If toxicities are ≥ grade 3, except for anemia, treatment should be withheld until resolution to ≤ 
grade 1 or baseline if baseline was greater than grade 1, then reinstituted, if medically appropriate, 
at the next lower dose level. 
For any grade 3 or 4 toxicity not mentioned above, treatment should be withheld until the patient 
recovers completely or to grade 1 toxicity. The treatment should then be resumed at the next dose 
level.  For grade 1 or 2 toxicities, no dose reduction should be made. 
A maximum of two weeks will be permitted for resolution of grade 3 or 4 toxicities. If toxicity has 
not resolved by the end of two weeks, patient will be taken off study. 
7.4 Special Considerations 
 For toxicities which are considered by the treating investigator unlikely to develop into 
serious or life–threatening events (e.g. alopecia, altered taste etc.), treatment may be 
continued at the same dose without reduction or interruption. 
 The treating investigator may reduce a subject’s dose for a toxicity of any 
grade/duration where s/he believes it to be in the best interests of the subject. 
 Any consideration to modification of the above dose modification guidelines should be 
discussed with the Protocol Chair for approval or disapproval in advance. 
 Study participants should be given instructions to minimize sun exposure (i.e. use SPF 
> 30 sunblock, wear hats and long-sleeve clothing) due to the possibility of 
photosensitivity.  
 As referenced above, pneumonitis has rarely been reported in clinical trials with  
taselisib. All patients should be routinely asked about the occurrence of adverse events 
which could include new or changed pulmonary symptoms (consistent with lung 
abnormalities). CT scans and pulmonary function tests should be done, as clinically 
indicated, or if there are symptoms that indicate that the patient has developed 
pneumonitis. In case of a documented pneumonitis, the guidelines (including dose 


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modifications) in the table above should be followed. Consultation with a 
pulmonologist is highly recommended for any pneumonitis case during the study.  
8. DRUG FORMULATION/STORAGE/SUPPLY 
8.1 Taselisib 
 
Taselisib is an investigational agent and will be supplied free-of-charge from Genentech.  
8.1.1 Taselisib Formulation and Storage 
Drug Product taselisib (GDC-0032) is intended for oral administration. The  taselisib tablet is a 
white, film-coated, immediate-release formulation of 2 mg strength, consisting of  taselisib API, 
lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
and Opadry 2 white film coating.   
Taselisib tablets should be stored at 59°F−86°F (15°C−30°C) and should be protected from light. 
 
For additional details, see the taselisib Investigator’s Brochure. 
8.2 Enzalutamide  
 
Enzalutamide will be provided free of charge by the study. 
8.2.1 Enzalutamide Formulation and Storage 
The drug is supplied as 40 mg capsules by Medivation and Astellas. The drug substance is 
formulated in the surfactant caprylocaproyl polyoxylglycerides, or Labrasol. The product will be 
supplied as white to off-white gelatin capsules containing 40 mg of enzalutamide. 
 
Enzalutamide is to be handled and stored safely and properly in accordance with the study drug 
label. 
8.2 Drug Accountability 
Accountability for the drug at all study sites is the responsibility of the site Principal Investigator 
and designated Pharmacy representative. The investigator will ensure that the investigational drug 
is used only in accordance with this protocol. Drug accountability records indicating the drug’s 
delivery date to the site, inventory at the site, use by each patient, and return to Genentech or 
Medivation will be maintained by the clinical site. Of note, only unopened medication packages 
(i.e. not dispensed to patients) will be returned to Genentech or Medivation if not used. Drugs 
returned by patients will be destroyed according to each institution’s policy. Accountability 
records will include dates, quantities, lot numbers, expiration dates, and patient numbers. 
 
 
9. CORRELATIVE/SPEIAL STUDIES 


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9.1 Advanced imaging correlative (Vanderbilt only) 
Patients enrolling at Vanderbilt will be screened for participation in an advanced imaging 
correlative study, to be conducted through collaboration with investigators at the Vanderbilt 
University Institute for Imaging Science (VUIIS).  The advanced imaging correlative will consist 
of multiparametric magnetic resonance imaging (MRI) to be performed at the VUIIS facility at 
three timepoints, chosen to coincide with the timing of required core biopsies: baseline, at day 14-
21 following treatment initiation, and at the end of treatment. 
 
Multiparametric MRI examinations will be designed and made available for four body sites – 
breast/axilla, lower neck/supraclavicular region, liver, and pelvic bone marrow – and patients will 
be eligible to participate in the advanced imaging correlative if their required core biopsies are 
obtained from one of these four body sites. Participation will be mandatory for patients accruing 
at Vanderbilt who meet the criteria outlined below, including presence of measurable disease 
(defined as at least one lesion measuring at least 10 mm in long axis diameter) at the body site of 
interest. If participation in the MRI sub-study is not possible due to scheduling issues, MRI weight 
limits, eligibility, or safety concerns over implanted medical devices, subjects may still continue 
with the rest of the study. 
9.1.1 Background and rationale 
Oncologic imaging is in the midst of a paradigm shift in which a number of advanced quantitative 
techniques reporting on tissue function and composition at the molecular level are now being 
advanced as candidate biomarkers for cancer detection, characterization, and treatment response 
assessment. This advanced imaging correlative deploys several promising MRI techniques within 
a single multiparametric MRI examination. The overall hypothesis for the advanced imaging 
correlative is that these techniques, either individually or in combination, can provide clinically 
useful information beyond that provided by standard-of-care imaging in the context of metastatic 
TNBC.  The components of the multiparametric MRI examination, and hypotheses related to these 
components, are outlined briefly below: 
 
 Dynamic contrast enhancement MRI (DCE-MRI) is a method for characterizing tissue 
vascularity.  The technique involves rapid acquisition of serial MR images before, during, 
and after injection of an intravenous contrast agent; these images are then analyzed with 
mathematical models to estimate quantitative values for pharmacokinetic and tissue 
properties.   We hypothesize that early changes in these derived DCE-MRI parameters 
(i.e., from baseline to day 14-21) will predict treatment response.  We will also test 
whether baseline DCE-MRI parameters by themselves predict patient response to 
treatment, whether baseline DCE-MRI parameters can discriminate between AR+ and 
AR- subtypes of TNBC, and whether DCE-MRI parameters at the time of progression are 
significantly different from DCE-MRI parameters at baseline and early during therapy.  
Finally, we will evaluate the correlation between DCE-MRI parameters and 
phosphorylated p-ERK1/2, p-S6, and p-AKT S-473 levels at serial core biopsies. 
 
 Diffusion-weighted MRI (DW-MRI) is a method for quantifying tissue cellularity.  The 
technique reports on the ability of water molecules to move randomly, or diffuse, within 
tissue; more cellular tissues tend to have more barriers to water movement and, therefore, 










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 Patients who have any type of bioimplant activated by mechanical, electronic, or magnetic 
means (e.g., cochlear implants, pacemakers, neurostimulators, biostimulators, electronic 
infusion pumps, etc), because such devices may be displaced or malfunction. 
 Patients who have any type of ferromagnetic bioimplant that could potentially be displaced. 
 Patients who have cerebral aneurysm clips. 
 Patients who may have shrapnel imbedded in their bodies (such as from war wounds), metal 
workers and machinists (potential for metallic fragments in or near the eyes). 
 Patients who have exhibited past allergic or other adverse reactions in response to intravenous 
injection of Magnevist
® (gadopentetate dimeglumine) or other gadolinium-containing contrast 
agents. 
 Patients who exhibit noticeable anxiety and/or claustrophobia or who exhibit severe vertigo 
when they are moved into the magnet bore. 
 Patients incapable of giving informed written consent, for the following reasons: 
 Inability to adhere to the experimental protocols for any reason 
 Inability to communicate with the research team 
 Limited ability to give informed consent due to mental disability, altered mental 
status, confusion, or psychiatric disorders 
 Prisoners or other individuals deemed to be susceptible to coercion 
 
9.1.3 MRI Imaging procedures 
Patients will undergo multiparametric MRI at baseline, at day 14-21, and at the end of treatment.  
The multiparametric MRI examinations should be scheduled to coincide with the planned core 
biopsies as much as is reasonably practical.  At any given timepoint, however, every effort 
should be made to complete the MRI examination before the core biopsy, because hemorrhage 
from the core biopsy may interfere with the MRI measurements. 
 
The general scan order and anticipated scan durations are summarized below: 
1. Scout images, transmitter tuning, shimming, slice prescription – 5 min 
2. T1 map – 2.5 min 
3. Diffusion-weighted MRI (DW-MRI) – 5 min 
4. Chemical exchange saturation transfer (CEST-MRI) – 10 min 
5. Pre-contrast T1-weighted anatomic MRI – 2 min 
6. Dynamic contrast-enhanced MRI (DCE-MRI) – 8 min 
*Intravenous injection of the FDA-approved contrast agent (CA) Magnevist
® 
(gadopentetate dimeglumine, 0.1 mmol/kg) 60 sec after the start of the scan. Infusion 
time is 5-10 sec, depending on patient weight. CA will be followed by saline flush. 
7. Post-contrast T1- and T2-weighted anatomic MRI – 10 min 
 
 
9.2 Tissue Samples (All participating sites) 
9.2.1 AR testing 
Please see Section 5 for AR testing and requirements for tissue for AR testing.   
 


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9.2.2 Archival tissue 
Once a patient is confirmed to be AR positive, meets all eligibility requirements, and is 
registering for the study, formalin-fixed paraffin embedded tissue blocks from the patient’s 
primary tumor or metastatic lesion collected for diagnostic and therapeutic purposes is requested. 
Blocks will be returned within 8 weeks (or earlier if requested); tissue taken from these blocks 
will not be returned.    
 
In case the participating institutions are not allowed to release clinical paraffin embedded blocks, 
ideally we will need the following cut in this order:  
 
1. H&E slide 
2. 5 peels cut at 10 µm each in a single DNAse-free/RNAse-free tube 
3. H&E slide 
4. 3 peels cut at 10 µm each in a single DNAse-free/RNAse-free tube 
5. H&E slide 
6. 10 unstained slides cut at  5 µm each on charged slides 
7. H&E slide 
 
If remaining tissue is insufficient for the complete request, please send: 
1. H&E slide 
2. 3 peels cut at 10 µm each in a single DNAse-free/RNAse-free tube 
3. H&E slide 
4. 2 peels cut at 10 µm each in a single DNAse-free/RNAse-free tube 
5. H&E slide 
 
If remaining tissue is limited, please send: 
1. H&E slide 
2.  2 peels cut at 10 µm placed in a single DNAse-free/RNAse-free tube 
3.  H&E slide 
 
After removing all stray tissue from the area, the microtome blade and surrounding area should 
be wiped with 70% ETOH before starting to section the block and between patients to prevent 
contamination with extraneous tissue. 
 
All formalin-fixed paraffin embedded tissue and/or slides should be sent with a cold pack 
to avoid melting that could damage tissue analysis. 
 
 
9.2.3 Fresh biopsy of metastatic site 
Once a patient is confirmed to be AR positive, meets all other eligibility, and registers for the 
study, collection of tissue from a metastatic site, if reasonably safe, is also a requirement for 
entry to this study.  A biopsy can also be used for AR testing for the study (see Section 5). 
Pre-trial and day 14-21 biopsies should be collected. Research tissue blocks prepared from 


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these metastatic biopsies will not be returned.  All patients must have a biopsy of a metastatic 
site at the end of treatment if the patient is removed for disease progression or is on the 
enzalutamide only arm and crossing over to enzalutamide + taselisib. See section 9.2.4 
below for details on collecting tissue. 
9.2.4 Guidelines for Tissue Acquisition on Biopsies of Metastatic Lesions 
Tissue specimens, when feasible, will be collected from recurrent or metastatic lesions using 
standard institutional procedures. The amount of tissue collected will follow the guidelines listed 
below. If a patient has more than one site of disease, only one site needs to be biopsied, and the 
site is left to the discretion of the patient and the treating physician. If a patient is undergoing 
resection of a lesion for clinical reasons (i.e. wedge resection of a new lung lesion for confirmation 
of diagnosis or re-testing of hormone receptor or HER2 status; or, resection of a chest wall lesion; 
or, resection of a lymph node), then the patient may opt to have a portion of that tissue (roughly 
equivalent to the goal amount of tissue listed in the guidelines above, i.e. the equivalent of two 5-
mm punch biopsies of the skin, or 3-6 18-gauge core biopsies) stored for research at the time of 
the procedure. 
 
Listed below are the goal amounts of tissue for patients who undergo core biopsy or punch biopsy, 
or who have either ascites fluid or pleural fluid accessible for collection. Please note that the below 
are guidelines for the amount of tissue to be obtained at the baseline biopsy, and are not meant to 
replace clinical judgment at the time the procedure is performed. Less than the goal quantity of 
tissue is accepted for each type of biopsy, and will be left to the clinical judgment of the physician 
performing the procedure. 
 Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional 
guidelines for a diagnostic core biopsy of a breast mass  
 Skin/chest wall: A goal of one to two 5-mm punch biops(ies)  
 Lymph node: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge 
needle  
 Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle  
 Lung: A goal of 3 core biopsy specimens will be obtained using an 18-gauge needle.  Due 
to the risk of pneumothorax associated with core needle biopsies of lung nodules, 
peripheral lesions should be carefully selected.    
 Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, 
if a patient has another accessible site of disease (i.e. skin, lymph node, liver), that site 
should be biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 
3-6 core biopsy specimens will be obtained using an 18-gauge needle.  
 Pleural Fluid (known to be due to malignancy): A goal of 500 cc of pleural fluid will be 
obtained with a standard thoracentesis procedure, with or without image guidance, 
according to the clinical judgment of the treating physician and clinician performing the 
procedure. Less than the goal amount is acceptable, and should be based upon the clinical 
judgment of the Investigator and the clinician performing the procedure. If more than the 
goal amount of fluid is obtained, then the entire specimen (with the exception of what is 
needed for clinical purposes, if applicable) will be stored at Vanderbilt.  


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 Ascites fluid: A goal of 500 cc of ascites fluid will be obtained with a standard paracentesis 
procedure, with or without image guidance, according to the clinical judgment of the 
treating physician and clinician performing the procedure. Less than the goal amount is 
acceptable, and should be based upon the clinical judgment of the Investigator and the 
clinician performing the procedure. If more than the goal amount of fluid is obtained, then 
the entire specimen (with the exception of what is needed for clinical purposes, if 
applicable) will be stored at Vanderbilt.  
9.2.5 Instructions on fresh tissue specimen handling 
1) Core biopsy specimens 
*Tissue obtained at Vanderbilt will be handled differently as it does not need to be shipped.  
Please see the Vanderbilt lab manual for handing if obtaining a biopsy at Vanderbilt* 
 First core biopsy should be suspended in 10% buffered formalin. 
 Second core biopsy should be suspended in “RNAlater” solution*  
 Third core biopsy should be suspended in “RNAlater” solution* 
 Fourth core biopsy should be suspended in 10% buffered formalin. 
 Fifth core biopsy should be suspended in “RNAlater” solution* (outside sites) 
 Fifth core biopsy should be placed in cell culture media (Vanderbilt only) 
 Sixth core biopsy should be suspended in 10% buffered formalin 
If only 2 core biopsies are obtained, one should be placed in “RNAlater solution”* and the other 
should be suspended in 10% buffered formalin. 
*RNAlater kits will be provided.  1 core should be placed in one 1.5ml specimen tube. All 
samples should be shipped immediately, according to the lab manual. 
 
2) Resected lesion (chest wall, lymph node, etc).  
 For specimens greater than 5mm, the specimen should be bisected and one half placed in 
RNA later and the other in 10% buffered formalin 
3) Fine needle aspiration (FNA) 
For patients in whom a core biopsy is not possible and who thus undergo fine needle aspiration 
(FNA), 3 passes should be collected.  
 First pass should be evacuated and rinsed directly into 10% buffered formalin 
 Second pass should be evacuated and rinsed directly into 5-10 volumes “RNAlater” 
solution 
 Last pass should be evacuated and rinsed directly into 10% buffered formalin 


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9.3 Blood/plasma collection (All Participating Sites) 
Streck Cell-Free DNA BCT kits will be provided for circulating tumor DNA.  One vial of whole 
blood should be collected in a Cell-Free DNA BCT tube (Streck tube).  Fill the tube completely.  
Remove the tube from the adapter and immediately mix by gentle inversion 8 to 10 times.  
Collection times are: cycle 1/day 8, cycle 2/day 15, and end-of-treatment (also cycle 1/day 1 for 
those crossing over to enzalutamide + taselisib - see study calendar).  
 
Tube should be packed according to the lab manual and sent immediately (within 24 hours) to 
VICC at the address below with a tissue/blood registration form.  Do not freeze specimens 
collected in Streck tube. 
9.4 Tissue specimen and blood/plasma labeling and documentation  
Label each collection containers with Patient ID sequence number/code letter, site and location 
of biopsy, date and time. 
If sample comes in contact with contaminate, make note in information section of paperwork. 
Enter time core biopsy was collected on paperwork. 
If not retrieved on site by VICC CTSR personnel, outside sites should ship specimens along with 
Tissue Registration Form directly to:  
 
 
2 
 
The specimens will be logged in as a consented specimen and available for molecular pathology 
studies.  
Ship ALL samples with a cold pack.  If specimens are obtained on a Friday or holiday weekend, 
they should be refrigerated (not frozen) and sent out the following week. 
**Specimens should be mailed to arrive at VUMC from Monday 8AM through Friday 
1PM** 
9.5 Pharmacokinetic Sampling 
Pharmocokinetic sampling will occur in the phase Ib portion and in 10 patients in the phase II 
portion (phase II at Vanderbilt only).  PKs for patients in the phase Ib portion: will be obtained 
on cycle 1, day 8 at: 0-4 hours prior to dose of taselisib and 1, 3,  and 6 hours post administration 
taselisib;  on cycle 2, day 15 at:  0-4 hours prior to dose of taselisib and enzalutamide and 1, 3,  
and 6 hours post administration taselisib and enzalutamide; on cycle 4, day 1, plasma sample 
should be obtained 0-4 hours before taselisib and enzalutamide administration, and 3 hours post-
administration of both drugs.  


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The first ten subjects on the enzalutamide + taselisib arm at Vanderbilt should initiate taselisib 
on day 1 and enzalutamide on day 9 to facilitate PKs, which will be done on the first 10 
Vanderbilt patients on the combination arm only. PKs in phase II (Vanderbilt only) should be 
obtained on patients receiving both enzalutamide and taselisib on C1D8, C2D15, and C4D1 at 0-
4 hours prior to taselisib and enzalutamide and 2 to 4 hours post treatment.  Please see the lab 
manual for details of collection and for information about shipping the samples.   
9.6 Specimen Banking 
Any leftover study tissue or blood samples may be stored for future research studies.  The subjects 
will consent to the future use of samples in the consent form for the study.  The study PI and 
collaborators have approval by the TBCRC, which has custodial oversight of all biospecimens 
collected as part of a TBCRC trial, to address the research questions described in the protocol 
document.  All future use as part of residual or repository specimens collected in this trial for 
purposes not prospectively defined will require review and approval by the TBCRC according to 
its established policies, whether the specimens are stored in a central site or at a local institution 
or in a virtual repository. 
9.7 Biopsy Questionnaire 
A questionnaire will be given to each participant to complete at cycle 2, day 1.  This questionnaire 
is designed to assess the impact of the multiple biopsies on the patient’s quality of life and overall 
experience with the study. 
 






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Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Guidelines have defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans). 
Intravenous contrast should be used if appropriate.  
 
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, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 
Tumor markers:  tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in complete response.  
 
PET scans: PET scans are not able to be used for RECIST measurements.  Similarly, the CT 
portion of PET/CT scans cannot be used for RECIST measurements. 
 
Bone scan: Bone scan can be used to evaluate for disease progression by the presence of new 
lesions.  
 
Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain). When effusions are known to 
be a potential adverse effect of treatment (e.g. with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment can be considered if the measurable tumor has met 
criteria for response or stable disease in order to differentiate between response (or stable 
disease) and progressive disease. 











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lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
10.3.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. The patient’s 
best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions.  
 
 Time point response 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non CR/Non 
PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non PD or 
not all 
evaluated 
No 
PR 
SD 
Non PD or 
not all 
evaluated 
No 
SD 
Not  
all 
evaluated 
Non PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
CR= complete response, PR= partial response, PD= progressive disease, SD= stable disease, 
NE= not evaluable. 
*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. 
10.4 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 


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time measurement criteria are first met for CR until the first date that 
recurrent 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. 
10.5 Central tumor measurements 
At the end of treatment, all scans (baseline and through disease progression, along with crossover 
scans) should be sent on a CD to the Vanderbilt Cancer Imaging Support Laboratory for central 
review and assessment. These do not need to be overnighted. Please include patient’s study ID 
number the CD/disc. 
 
 
u 
 


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11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (CTCAE v4.0) that is available at http://ctep.cancer.gov/reporting//ctc.html.  
 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
 
Adverse events experienced by participants will be collected and reported from initiation of 
study medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event related to a study procedure and/or study 
medication beyond 30 days will continue to be contacted by a member of the study team until the 
event is resolved, stabilized, or determined to be irreversible by the participating investigator.  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study as per local requirements. 
11.2 Definitions 
11.2.1 Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered an 
investigational product.  AEs do not necessarily have a causal relationship with the treatment.  
An adverse event (AE) can, therefore, be any unfavorable and unintended sign (including an 
abnormal finding), symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational product. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
11.2.2 Serious adverse event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
 
 results in death 
 is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 


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 is a congenital anomaly or birth defect 
 is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but,  based upon appropriate medical 
and scientific judgment, may jeopardize the patient or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above).  Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 respite care 
11.2.3 Expectedness  
 Expected:  Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an adverse 
event is considered expected when it appears in the current adverse event list, the 
Investigator’s Brochure, the package insert or is included in the informed consent 
document as a potential risk. 
 Unexpected:  An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed 
consent document as a potential risk 
 
11.2.4 Attribution  
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
 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. 


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11.3 Reporting Procedures 
11.3.1 General 
All adverse events will be captured on a centralized electronic case report form called ON-line 
Clinical Oncology Research Environment = Oncore 
(http://www.vicc.org/ct/research/oncore.php). Oncore is a highly secure, web based, cancer 
specific, and customizable system that provides fully integrative clinical data management and 
study administration capabilities developed in an ongoing collaborative effort with NCI 
designated Comprehensive Cancer Centers. It fully integrates study administration functionality 
including protocol tracking, patient registration, NCI reporting, review committee tracking, and 
SAE tracking, with clinical data management functionality including electronic case report forms 
(eCRF) design, clinical data capture, protocol and regulatory compliance monitoring.  Specified 
members at each participating site will submit all regulatory documents to the Coordinating 
Center Data Manager, who will upload it in Oncore. 
11.3.2 Serious Adverse Events 
All serious adverse events, regardless of causality to study drug, occurring after the patient’s first 
dose of study treatment will be reported to the Principal Investigator and/or the Study 
Coordinator at each institution, and also to the Coordinating Center.  Serious adverse events that 
occur during screening do not require reporting unless they are due to a screening procedure (eg 
biopsy).  
 
All serious adverse events must be reported to the Coordinating Center within 1 business day 
after the treating institution becomes aware of the event. Events should be reported using the 
Vanderbilt Serious Adverse Event Form as well as Form FDA 3500A (Mandatory Reporting 
Form for investigational agents). The FDA form can be found online at 
http://www.fda.gov/safety/medwatch/howtoreport/default.htm and the Vanderbilt SAE form is 
part of the packet of supplemental forms.   
 
Both forms must be fully completed and emailed, faxed, or scanned to: 
 
 
u 
 
Follow-up information must also be reported within 1 business day of receipt of the information 
by the investigator. 
 
The Coordinating Center will disseminate information regarding unexpected serious adverse 
events to the participating sites within 5 days of review of the information by the Protocol Chair 
(or her designee in the event of extended absence) only in the case that the event(s) is believed to 
be related (i.e., possibly, probably, or definitely) to the study medication. The Coordinating 
Center will be responsible for reporting of events to the FDA and supporters, as appropriate 
(outlined below).  




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11.3.3 IND Safety Reports Unrelated to This Trial 
IND safety reports not occurring on this trial but involving the study intervention (outside SAEs) 
received from outside sources will be reviewed by the Protocol Chair and will be forwarded to 
participating sites for submission to their Institutional Review Boards per their guidelines.   
 
11.3.4 Institutional Review Board 
All adverse events and serious adverse events will be reported to the participating institution’s 
IRB per current institutional standards. If an adverse event requires modification of the informed 
consent, these modifications will be provided to the IRB with the report of the adverse event. If 
an adverse event requires modification to the study protocol, these modifications will be 
provided to the IRB as soon as is possible. 
11.3.5 Food and Drug Administration (FDA) 
Vanderbilt will report to the FDA any adverse event that is serious, unexpected and reasonably 
related (i.e., possible, probable, definite) to the study treatment.  
 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but no later than 15 calendar days after initial receipt of the 
information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-301-796-9845) 
using Form FDA 3500A (Mandatory Reporting Form for investigational agents). 
11.3.6 Genentech 
All SAEs must be reported to the Coordinating Center (Vanderbilt) within 24 hours. Vanderbilt 
will report all SAEs regardless of causal relationship to study treatment using the MedWatch 
form (using the online form available at 
http://www.fda.gov/safety/medwatch/howtoreport/default.htm) to Genentech as defined in the 
Safety and Data Exchange Agreement (SDEA).  If the SAE is linked to taselesib only, the form 
will only be submitted to Genentech. 
11.3.7 Medivation/Astellas 
All SAEs must be reported to the Coordinating Center (Vanderbilt) within 24 hours. Vanderbilt 
will report all SAEs related to enzalutamide to Astellas using the Medwatch form (using the 
online form available athttp://www.fda.gov/safety/medwatch/howtoreport/default.htm). The 
Investigator will submit a copy of this MedWatch  form to Astellas by either e-mail or fax, 
within the same timeframe. If submission of this SAE to FDA or Astellas or is not possible 
within 24 hours, the Investigator’s local drug safety contact (IRB, etc.) should be informed by 
phone.  If the SAE is linked to enzalutamide only, the form will only be submitted to Astellas. 
 


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The SAE documentation, including the Medwatch 3500A Form and available source records 
should be emailed or faxed to: 
 
 
 
The following minimum information is required: 
 Study number/IIT regulatory identifier 
 Subject number, sex and age 
 The date of report 
 A description of the SAE (event, seriousness of the event) 
 Causal relationship to the study drug 
 
Follow-up information for the event should be sent within promptly (within 7 days) as necessary. 
 
12. DATA SAFETY AND MONITORING 
12.1 Data Management and Reporting 
Participating institutions will be collaborating with Vanderbilt in patient accrual. Data will be 
collected using a centralized electronic case report form called ON-line Clinical Oncology 
Research Environment = Oncor
). Oncore is a 
highly secure, web based, cancer specific, and customizable system that provides fully 
integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with NCI designated Comprehensive Cancer Centers.  It fully 
integrates study administration functionality including protocol tracking, patient registration, 
NCI reporting, review committee tracking, and SAE tracking, with clinical data management 
functionality including electronic case report forms (eCRF) design, clinical data capture, 
protocol and regulatory compliance monitoring.  Also the system is capable in storing basic 
protocol information (e.g., IRB approval dates, dates for annual renewals, etc) and clinical trials 
research data.  Oncore allows the investigator to define specific protocol requirements and 
generate data collection forms.  Creation of the data collection form is done with a single button 
click after the parameters of an individual protocol have been specified. Oncore permits 
specification of study protocols, management of patient enrollment, clinical data entry and 
viewing, and the generation of patient or study-specific reports based on time stamping.  OnCore 
is embedded with a comprehensive domain repository of standard reference codes and forms to 
promote standardization. The sources for the repository include CDUS, CTC, CDEs from NCI, 
ICD, MedDRA and various best practices from contributing NCI-designated Comprehensive 
Cancer Centers. OnCore provides several reporting features specifically addressing NCI 
Summary 3 and Summary 4 and other reporting requirements. Data may also be exported in a 
format suitable for import into other database, spreadsheets or analysis systems (such as SPSS). 
This system will be used to manage all VICCC clinical trials data. OnCore is maintained and 
supported in the VICC Clinical and Research Informatics Resource.  
 


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Specified members at each participating site will submit all pertinent regulatory documents to the 
Coordinating Center Data Manager, who will store it in a secure location. 
 
The Principal Investigator or designee will inform  Genentech as defined in the Safety and Data 
Exchange Agreement (SDEA) of any serious adverse event, and will inform the IRB in 
accordance with each institution’s IRB policy.  The investigator is responsible for the detection 
and documentation of events meeting the criteria and definition of an AE or SAE, as provided in 
this protocol.  During the study when there is a safety evaluation, the treating investigator or site 
staff will be responsible for detecting, documenting, and report AEs and SAEs, as detailed in the 
protocol.  If any problem is identified related to the conduct of this research, the VICC Data 
Safety and Monitoring Committee (DSMC) will be formally asked to review the study and the 
situation that required DSMC intervention. 
12.2 Meetings 
This trial will be monitored by the VICC Breast Cancer Research Team. The Breast Cancer 
Research Team is composed of the Clinical Core Director of the Breast Cancer Program and 
Team Leader, Surgical Oncologists, Radiation Oncologists, Medical Oncologists, Research 
Nurses, the Data Manager, and our Regulatory Specialist. The Breast Cancer Research Team 
meets on a monthly basis to discuss all AEs/SAEs, accrual, compliance, safety issues, adherence 
to protocol, reviews, etc. pertaining to all breast cancer studies. This particular study will be 
thoroughly reviewed during these meetings. These monthly meetings have minutes recorded 
each time and those are also reviewed on a monthly basis by the Breast Cancer Research Team 
Physician Leader. 
 
Subsequent to the Breast Cancer Research Team Monthly Meeting, monthly teleconferences 
between participating site and the Breast Cancer research team at Vanderbilt will be held to 
discuss all issues related to the trial (AEs/SAEs, accrual, compliance, safety issues, adherence to 
protocol, reviews, etc.). 
12.3 Monitoring 
This trial will be monitored continuously by the study’s Protocol Chair and by the Breast Cancer 
Research Team at VUMC. Quarterly safety and monitoring reports are available to the Data and 
Safety Monitoring Committee (DSMC) as determined by the VICC Scientific Review 
Committee (SRC). The DSMC reviews all adverse events reported during the previous month for 
all clinical trials active at the VICC and makes recommendations to address concerns of patient 
safety. The DSMC of the VICC SRC will submit an annual report to the VICC Director on 
activities of the preceding year and will make recommendations to improve data and safety 
monitoring activities as needed. 
 
A Quality Assurance auditor under the direction of the DSMC will audit this clinical trial 
quarterly for compliance with adverse event reporting, regulatory and studies requirements, and 
data accuracy and completion. Audit reports detailing the findings are provided to the DSMC. 
Site visits to ensure compliance will be performed on an ad hoc basis, notably in high accruing 
centers. 
 


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12.4 Data Handling and Record Keeping 
12.4.1 Case Report Forms 
An electronic case report form (eCRF) is required and must be completed for each included 
participant. The completed dataset should not be made available in any form to third parties, 
except for authorized representatives of appropriate Health/Regulatory Authorities, without 
written permission from Vanderbilt. 
12.4.2 Record Retention 
To enable evaluations and/or audits from Health Authorities and Vanderbilt, each site 
investigator agrees to keep records including: The identity of all participants (sufficient 
information to link records; e.g., hospital records), all original signed informed consent forms, 
copies of all source documents, and detailed records of drug disposition. To comply with 
international regulations, the records should be retained by the investigator in compliance with 
regulations.  
 
During data entry, range and missing data checks will be performed on-line. The checks to be 
performed will be documented in the Data Monitoring Plan for the study. A summary report (QC 
Report) of these checks together with any queries resulting from manual review of the eCRF
's 
will be generated for each site and transmitted to the site and the site monitor. Corrections will be 
made by the study site personnel. This will be done on an ongoing basis. 
13. REGULATORY CONSIDERATIONS 
13.1 Informed Consent and Confidentiality 
The investigator (or his/her designee) will explain to each subject the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits involved 
and any discomfort it may entail.  Each subject will be informed that participation in the study is 
voluntary, that s/he may withdraw from the study at any time, and that withdrawal of consent 
will not affect her subsequent medical treatment or relationship with the treating physician(s) or 
institution.  The informed consent will be given by means of a standard written statement, 
written in non-technical language, which will be IRB approved.  The subject should read and 
consider the statement before signing and dating it, and will be given a copy of the document.  
No subject will enter the study or have study-specific procedures done before his/her informed 
consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written informed consent document (or a separate document to be given in conjunction with the 
consent document) will include a subject authorization to release medical information to the  
Investigator Sponsor, Genentech and supporting agencies and/or allow these bodies, a regulatory 
authority, or Institutional Review Board access to subjects’ medical information that includes all 
hospital records relevant to the study, including subjects’ medical history. 
 
The investigator agrees to keep all information provided by this study in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 


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provided (protocols, investigators
' brochures, CRFs and other material) will be stored 
appropriately to ensure their confidentiality.  
 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. Upon the patient’s permission, medical information 
may be given to his or her personal physician or other appropriate medical personnel responsible 
for his or her welfare.  This medical information must be made available to the IRB and DSMC, 
upon request, for source verification of study documentation.  Data generated by this study must 
be available for inspection upon request by representatives of the U.S. FDA, local health 
authorities, Dr. Vandana Abramson and her authorized representative(s), collaborators and 
licensees, and the IRB for each study site, if appropriate. We will make all reasonable efforts to 
keep patient’s protected health information (PHI) private and confidential. We will only utilize 
or relinquish this kind of information according to federal privacy guidelines. There are many 
safeguards in place to prevent the unintentional disclosure of information obtained for or 
produced by this study.  Research data, including the data collected from the medical charts will 
be entered into a password-protected database.  Any publications or public disclosure of data 
relating to the patient’s tumor will be done without any identifying information.   
 
PHI will be collected and stored in the OnCore system.  The coordinating center will have access 
to all research data, which will be kept for at least 2 years after the study is completed. Any 
research data entered in a patient medical record will be stored for an indefinite amount of time. 
There are no plans to destroy data at this time. 
 
Confidentiality and security will be maintained for the tissue collection within this study. All 
tissue samples obtained for this study will be assigned a code and this code used to identify the 
sample. The samples will not be labeled with the patient’s name, address or other information 
that would identify them.  All information will be coded to maintain privacy. Research data, 
including the data collected from the medical charts will be entered into a password-protected 
database.  The database (Breast Cancer Program Database) in which this study data is going to 
be stored has a firewall (in addition to the institutional firewall) with the highest level of 
protection, i.e. the same level of protection as the on-line hospital information system at 
Vanderbilt.  This means that users must log on to a web server that sits between the institutional 
firewall and the firewall to the database, and only this application server is allowed to query the 
database.   Information, including the identifier and password for the authorized users, is 
transmitted via a secure shell protocol using 128k encryption. Only Dr. Vandana Abramson, the 
PI, and the Breast Team Data Manager, approved through our institutional review board will be 
allowed access to patient identifiers. Other levels of authorization may exist for approved users, 
e.g. access to de-identified data. This database will store a de-identified link to the patient data 
and will not otherwise store patient data, even de-identified.  The safety monitoring will be 
performed by the groups deemed appropriate by the Vanderbilt University Medical Center 
Institutional Review Board for reviewing the clinical trials procedure.  Safety monitoring for the 
database is also performed by the Networking and Security Services of the Vanderbilt University 
Medical Center. Audit trails for access to the web server and the databases behind the dual 
firewall system are maintained in accordance with the practices of the Networking and Security 
Services of the Vanderbilt University Medical Center. 


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13.2 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
14. MULTI-CENTER GUIDELINES 
14.1 Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional Review 
Board (IRB) per the current institutional standards of each participating center. 
 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB of each institution prior to implementation.   
 
The Protocol Chair (or her designee) is responsible for the coordination and development of all 
protocol amendments.  Once approved by the Protocol Chair, Vanderbilt will disseminate this 
information to the participating centers. 
14.2 Study Documentation 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not limited 
to the following: local IRB approvals (i.e., protocol, consent form, amendments, patient 
brochures and recruitment material, etc.), each participant’s informed consent, enrollment form, 
eligibility checklist and tissue block registration, summary of unanticipated problems or protocol 
deviations, and documentation of expertise of the investigators. The Coordinating Center will 
provide each participating site with a comprehensive list of the necessary documents. It is the 
responsibility of the participating sites to maintain copies of all documentation submitted to the 
Coordinating Center. 
 
The requirements for data management, submissions, and monitoring are outlined below. The 
participating sites will submit all the research related information (source documents and 
research records – IRB approval documents, patient registration list, CRF info, toxicity 
assessments, tumor measurements/ responses, etc.) to the Coordinating Center Data Manager, 
who will upload it on Oncore at the appropriate time points: prior to study initiation, when 
patients are enrolled, and monthly during study duration. Personnel from the VICC Clinical Trial 
Shared Resource will monitor the trial and may periodically visit the investigative site to assure 


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proper conduct of the trial and proper collection of the data.  The investigators at other sites will 
allow the monitor to review all source documents used in the preparation of the case reports. 
 
14.3 Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be retained by each Principal 
Investigator for 2 years after marketing application approval. If no application is filed, these 
records must be kept 2 years after the study is discontinued and the U.S. FDA and the applicable 
national and local health authorities are notified.  
 
Following closure of the study, each participating center will maintain a copy of all site study 
records in a safe and secure location.  The Coordinating Center will inform the investigator at 
each site at such time that the records may be destroyed. 
14.4 Publication 
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to the TBCRC Central Office and all participating sites and Genentech prior to 
submission for publication or presentation. 
15. STATISTICAL CONSIDERATIONS 
15.1 Study Design/ Endpoints 
This is an open-label phase Ib/II multi-institution trial that evaluates the safety profile/ tolerability 
and efficacy of enzalutamide + taselisib in patients with metastatic triple negative (ER/PR/HER2 
negative) breast cancer who are AR positive.  As taselisib has not been evaluated with 
enzalutamide, we would begin with a phase Ib portion to ensure safety of the combination and to 
determine a recommended dose for phase II of taselisib when given in combination with 
enzalutamide at 160 mg/day. In the Phase II portion, we will randomize patients in a 3:1 ratio to 
enzalutamide + taselisib or enzalutamide only.  AR positivity is defined as > 10% of tumor cell 
nuclei with immunoreactivity for AR.  Upon progression of disease by RECIST, patients on the 
combination arm will be discontinued from the study. Those on the enzalutamide alone arm can 
cross-over to receive enzalutamide + taselisib.   
15.2 Phase Ib Study 
The taselisib dose will start at 2 mg/day (dose level 1) and enzalutamide at 160 mg/day.  Dose 
escalation will proceed among cohorts of 3 patients according to a standard 3+3 algorithm 
beginning at the lowest dose level as described in Section 6.2.   
In the phase Ib component of the trial, the MTD will be defined as the highest dose tested in which 
a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels. The first cohort 
of patients (3 patients) in each arm will be started at dose level 1, and each patient will be observed 
for 4 weeks on the specified dose.  
No new cohort of patients will be treated until the previous cohort has completed one cycle of 
therapy without any DLTs.  


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Once the phase Ib portion is completed, the safety data will be analyzed and the phase II component 
of the study will be completed to assess tolerability and efficacy of the study combination. 
 
 Patients 
in the phase II component of the study will initiate study treatment at the MTD. Note that dose 
reduction within patients (individually) is allowed in the phase II component of the study (see dose 
modification section). Dose reduction will be required for a given patient in case of grade 3 or 4 
toxicities.  The phase Ib study will require approximately 15-24 patients. 
15.3 Phase II Study  
The primary endpoint of the phase II portion is to assess the CBR of enzalutamide + taselisib at 
16 weeks.  This will be studied using a Simon two-stage design.  Because there is sparse data on 
single agent enzalutamide, we also plan to accrue patients to a single agent enzalutimide 
arm.  Patients will be randomized to the dual therapy vs monotherapy arms using a 3:1 
randomization.  The coordinating center (VICC) will randomly assign patients to an arm. No direct 
comparison of the two arms will be conducted.  Rather, the monotherapy arm will serve as an 
informal anchor when interpreting results, and will be especially informative when interpreting 
many of the secondary analyses. 
  
We have designed the enzalutamide + taselisib arm as a Simon optimal two stage.  This design 
allows for early termination for inefficacy.  The antiandrogen bicalutamide, in a prior study with 
a similar patient population, resulted a CBR of approximately 20%
35.  Thus, for this study, we aim 
to show an improvement in CBR from 20% to 40%.  With a Type I error of 10% and a Type II 
error of 10%, we will accrue 17 patients in the first stage.  After the first 17 patients in the phase 
II portion have completed 2 cycles and obtained scans, the data will be analyzed.  If 4 out of the 
17 have a response (CR, PR, or SD), we will expand the study to a total of 37.  If, at the end of the 
trial, there are 11 out of 37 patients with response, we will deem the regimen worthy of further 
study.  If there are 3 or few responses in the first 17 patients, the study will terminate early.  If 10 
or few responses are seen in the total of 37, the regimen will be deemed unworthy of further 
study.  This study has a 55% probability of stopping early under the null hypothesis. Patients 
whose disease progresses within 30 days of starting the study without a DLT will be replaced 
during the phase I portion.    
  
Concurrently, an arm of single agent enzalutimide will be accrued.  For every 3 patients 
randomized to the enzalutamide + taselisib arm, 1 patient will be randomized to the enzalutamide 
only arm. If the dual therapy arm terminates early due to inefficacy, we will also terminate the 
monotherapy arm.  Thus, this arm will have a minimum of 6 and a maximum of 12 patients.  We 
do not plan to do any formal analysis on this group of patients. 
15.4 Sample Size 
Based on preliminary data on these therapies, we expect to require 15 patients for the Phase Ib 
portion of the trial.  However, with 4 dose levels it is possible, though not likely that 24 patients 
will be required.  For the phase II portion of the trial, we will require 17+6=23 to 37+12=49 (23-
59) patients depending on whether the number of responses reach the threshhold at the interim 
analysis. Patients in the phase I portion who are the recommended dose for phase II will be 
included in the evaluable patients for phase II. The total sample size for the study will be 
approximately 73 patients. 


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15.5 Reporting 
Demographic information such as age and race will be tabulated. Descriptive statistics, including 
means, medians, standard deviations, and ranges for continuous parameters, as well as percents 
and frequencies for categorical parameters, will be presented. Investigation for outliers and 
assumptions for statistical analysis, e.g., normality and homoscedasticity will be made. Adverse 
medical events will be tabulated. NCI toxicity Grade 3 and Grade 4 laboratory abnormalities will 
be listed.  
 
All patients who receive any study drugs will be included in the toxicity evaluation. All patients 
who receive study drugs for at least 4 weeks will be included in the efficacy evaluation (modified 
intention to treat).  Deaths, early progression, and other reasons for drop-out of the study prior to 
4 weeks will be reported. 
15.6 Analysis of Secondary Endpoints 
We will calculate the ORR and corresponding 95% confidence intervals at the dose recommended 
for phase II. The overall PFS data for the patients at the dose recommended for phase II will be estimated 
using the Kaplan-Meier method with 95% confidence intervals. 
 
Biopsy analysis will be performed in conjunction with the Pathology and Tissue Informatics Core 
to assess baseline, therapy-induced changes and status upon progression of the following:  
proliferation (Ki67), mitosis (mitotic index), apoptosis (cleaved caspase 3 levels by IHC), genomic 
instability (H2AX by IHC), levels of PTEN by IHC, PI3KCA mutational analysis, HER2 (IHC, 
FISH) and ER/PR levels (IHC).  Levels of MEK [total and phosphorylated ERK1/2 (pERK1/2)] and 
AKT [phosphorylated AKT, S473 (pAKT)] will be measured by IHC.    
 
RNA-seq will be performed on all biopsies to assign a triple negative subtype
36, to determine 
baseline and treatment-induced changes in GE after 5-10 days of therapy and define mutations 
present in the tumors both at baseline and upon progression of the disease.  We expect an enrichment 
of drug resistance-associated mutations/gene amplifications particularly in tumors that regress and 
later recur while on therapy.  Somatic SNPs and structural variants will be validated by whole exome 
sequencing (WES) of genomic DNA from the tumor and matched blood.  We will validate mutations 
by targeted capture approaches that allow high-level coverage (greater than 200X) and analysis of 
clonality. The status of p53, BRCA1/2, PIK3CA, PTEN, INPP4B and other mutations associated 
with TNBC in the tumor tissue is critical for testing our hypothesis.  This genetic information is key 
for determining the prognostic significance of mutations relative to response of agents being tested 
and for understanding mutation selection relative to the underlying genetic milieu of each tumor at 
time of entry into the trial.  We anticipate significant opportunity for discovery of novel mutations 
as well as those arising from selection during resistance to the therapies under investigation.  
Statistics on the correlative endpoints (tissue assays and MRI scan) will be primarily descriptive. 
Therefore, these studies are considered to be exploratory and potentially hypothesis-generating. 
 
Pharmacokinetic samples are being collected in all patients to assess concentrations of GDC-0032 
and enzalutamide and estimate PK parameters, as appropriate. Plasma samples may be used for 
exploratory analysis to evaluate potential taselisib-related metabolites and/or exploratory biomarker 
development. 
 


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15.7 Reporting and Exclusions 
All patients included in the study must be assessed for safety, tolerability, and response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 
4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  
 
All of the patients who met the eligibility criteria and received study drugs for 4 weeks should be 
included in the main analysis of the clinical benefit rate. Patients in response categories 4-9 should 
be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule 
or drug administration does not result in exclusion from the analysis of the response and clinical 
benefit rate. 
 
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Ph. Ib/II Taselisib Enzalutamide AR+ 
Vandana Abramson, MD 
BRE 1374 / TBCRC 032 
 
 
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Protocol version:  04/05/2017