Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer

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.

Inclusion Criteria:

- Patients must provide informed written consent

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Clinical stage IV invasive mammary carcinoma

- 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 =< 1% cells), PR negative
(defined as expression of PR in =< 1% cells), HER2 negative (acceptable methods of
HER2 analysis include IHC [0, 1+], fluorescence in situ hybridization [FISH] with
HER2/centromere on chromosome 17 [CEN17] ratio < 2, and/or chromogenic in situ
hybridization [CISH] with HER2/CEN-17 ratio < 2), as previously documented by
histological analysis

- Androgen receptor positivity, defined as >= 10% of tumor cell nuclei with
immunoreactivity for AR on central review at Vanderbilt

- Measurable or bone-only evaluable disease; measurable disease is defined as at least
one lesion that can be accurately measured in at least one dimension by Response
Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1, with radiologic scans
within 21 days of day 1, cycle 1

- Any number of prior therapies as long as patients have adequate performance status and
meet all other eligibility criteria

- Prior treatment with anti-androgens other than enzalutamide is acceptable

- Phase 1b only: Formalin-fixed paraffin embedded blocks (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

- 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; tissue needs to be located
and available at the time of registration (tissue needs to be submitted within 3 weeks
of study initiation)

- 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:

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 75,000/mm^3

- Hemoglobin (HgB) >= 9 g/dL

- Creatinine =< 1.5 X 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)

- Aspartate aminotransferase (AST) and alanine aminotransferase (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:

- 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:

- HbA1c < 8.5 % or IFCC < 69.4 mmol/mol

- Stable regimen of oral anti-hyperglycemic therapy without insulin usage for at
least 3 weeks prior to first study treatment

- Fasting plasma glucose levels =< 160 mg/dL (8.88 mmol/L) and no hypoglycemia
(blood sugar [BS] < 60) during home monitoring for at least 1 week prior to study
entry

- Patients must be able to swallow and retain oral medication

- 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:

- Age >= 60 years

- 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

- 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 1) induced by this treatment; baseline radiologic
scans must be obtained after completion of radiation

- Patients must complete all screening assessments

Exclusion Criteria:

- Any kind of malabsorption syndrome significantly affecting gastrointestinal function,
including history of Crohn's disease or inflammatory bowel disease

- 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, as well as recovered to baseline from
toxicity induced by previous treatments; 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)

- 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

- Prior treatment with enzalutamide

- 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

- 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

- Pregnant or lactating women

- Insulin-dependent diabetes; patients with type II diabetes must meet the inclusion
criteria outlined above

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection requiring parenteral antibiotics

- Impairment of lung function (chronic obstructive pulmonary disease [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])

- Corrected QT using the Fridericia correction formula (QTcF) >= 480 msec on
screening electrocardiogram (EKG)

- Known history of QT/correct 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 >= Common Terminology Criteria for Adverse Events (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

- Conditions that affect lymphocyte counts, such as human immunodeficiency virus
(HIV) infection or immunosuppressive therapy

- Use of prohibited drugs