AN OPEN-LABEL, PHASE Ia/Ib/IIa STUDY OF GDC 0810 SINGLE AGENT OR IN COMBINATION WITH PALBOCICLIB AND/OR AN LHRH AGONIST IN WOMEN WITH LOCALLY ADVANCED OR METASTATIC ESTROGEN RECEPTOR POSITIVE BREAST CANCER

Breast cancer is the most common form of cancer in women, accounting for more
than 1,300,000 new cases and nearly 500,000 cancer deaths annually (Jemal,
2011). Approximately 80% of all breast cancers express and are dependent on
the estrogen receptor (ER) for tumor growth and progression. Modulation of
estrogen activity and/or synthesis is the mainstay of therapeutic approach in
postmenopausal women with ER-positive (ER+) breast cancer. However, despite
the effectiveness of available hormonal therapies such as tamoxifen, aromatase
inhibitors and full ER antagonists/degraders, many patients ultimately relapse
or develop resistance to these agents and therefore require further treatment
for optimal disease control. As such, there is a need for the development of
new ER-targeting therapies with increased anti-tumor activity to further delay
disease progression and/or overcome resistance to the currently available
hormonal therapies and ultimately prolong survival in postmenopausal women with
ER+ advanced breast cancer.
Despite becoming refractory to aromatase inhibitors or tamoxifen, growth and
survival of resistant tumor cells remain dependent on ER signaling; therefore,
patients with ER+ breast cancer can still respond to second/third line hormonal
treatment after progression on prior hormonal therapy (Di Leo, 2010; Baselga,
2011). An agent with a dual mechanism of action (ER antagonism plus
degradation) has the potential to target both ligand-dependent and independent
ER signaling and, consequently, improve treatment outcomes in late stage ER+
breast cancer. Furthermore, recent studies have identified mutations in ESR1
affecting the ligand-binding domain (LBD) of the estrogen receptor. Mutant
receptors drive ER-dependent transcription and proliferation in the absence of
estrogen and reduce the efficacy of ER antagonists, suggesting that LBD-mutant
forms of ER are involved in mediating clinical resistance to endocrine therapy
and that more potent ER antagonists may be of substantial therapeutic benefit
(Toy, 2013; Robinson, 2013; Li, 2013).
GDC-0810 is a novel, potent ER-* antagonist and inducer of ER-* degradation
that is being developed for the treatment of postmenopausal women with ER+
advanced breast cancer whose disease has recurred or progressed following
treatment with hormonal therapy. In murine MCF-7 xenograft models, GDC-0810
has demonstrated robust tumor regression in both tamoxifen-sensitive and
tamoxifen-resistant models. Based on its bipartite activity profile, the
nonclinical efficacy in tamoxifen-sensitive and tamoxifen-resistant xenograft
studies, and nonclinical safety profile, GDC-0810 has the potential to be an
important therapeutic drug for the treatment of postmenopausal women with ER+
advanced breast cancer.

Primary Objective
Phase Ia
* To determine the maximum tolerated dose (MTD) and/or recommended Phase II
dose (RP2D)and assess the safety of single agent GDC-0810 in postmenopausal
women with locally advanced or metastatic estrogen-receptor-positive (ER+) and
human epidermal-growth-factor-negative (HER2-) breast cancer

Phase IIa
* To determine the anti-tumor activity of single agent GDC-0810 in

Secondary Objectives:
Phase Ia
* To evaluate the pharmacokinetics of GDC-0810 single agent and its glucuronide
metabolites following single and multiple dose treatments.
Phase IIa
* To evaluate the safety of GDC-0810 single agent when administered at the
RP2Ds in women with locally advanced or metastatic ER+ (HER2-) breast cancer
* To evaluate the effect of GDC-0810 single agent on ventricular repolarization
in postmenopausal women participating in the Phase IIa portion of the study

Exploratory Objectives:
* To perform exploratory evaluation of biomarkers of pharmacodynamic (PD)
response with [18F]-fluoroestradiol (FES) positron emitting tomography (PET) in
Phase Ia and Phase IIa
* To perform exploratory evaluation of ER target genes expression
* To perform exploratory evaluation of mechanisms of resistance to GDC-0810

This is a multi-institution Phase Ia/Ib/IIa open-label, dose-finding, safety,
PK, and proof of concept study of GDC-0810 as a single agent and in combination
with palbociclib and/or LHRH agonist.
The study is divided into three phases: Phase Ia, Phase Ib, and Phase IIa. The
Phase Ib palbociclib combination cohorts will be conducted in the U.S. only and
the LHRH agonists combination cohorts will be conducted in the U.S. and South
Korea. The Phase Ia and IIa part of the study (single agent GDC-0810 cohorts)
will be conducted in Spain, Netherlands South Korea and the U.S.
Enrollment in Study GO29642 has been discontinued; therefore, no patients will
be enrolled in the Phase Ib Cohorts C2, C3, and D2. Any patient currently
enrolled in Phase Ia, Ib Cohort C1, Ib Cohort D1, or IIa experiencing clinical
benefit may continue to receive GDC-0810 as a single agent or combination with
LHRH agonist or palbociclib until disease progression, unmanageable toxicity,
patient withdrawal of consent, GDC-0810 drug supply has been exhausted, or the
Sponsor terminates the study.

Phase Ia
Phase Ia consists of dose escalation in postmenopausal women with locally
advanced or metastatic ER+ (HER2-) breast cancer and enrollment into dose
escalation cohorts has been completed.
Phase Ia consists of dose escalation in postmenopausal women with locally
advanced or metastatic ER+ (HER2-) breast cancer.
During Phase Ia, GDC-0810 single agent was administered orally to
postmenopausal women with locally advanced or metastatic ER+ (HER2-) breast
cancer on a continuous daily dosing regimen with a Day -7 lead-in period for
single dose PK evaluation prior to the start of daily treatment. The incidence
of dose-limiting toxicities (DLTs) will be evaluated from Day -7 through the
first cycle (28 days) of treatment (35 days total). Depending on safety and
tolerability, patients will be assigned sequentially to escalating doses of GDC
0810 using standard 3 + 3 design.
The starting dose will be 100 mg once daily. Dosing will be based on flat
milligram increments without adjustments for body size. It is anticipated that
dose levels will span the anticipated pharmacologically active dose range and
be within the safety margin indicated by nonclinical toxicology studies. The
dosing regimen may be changed if the PK and safety data suggest that a
discontinuous regimen or another dosing frequency (e.g., twice daily [BID]),
with or without a fasting requirement, may be preferable for the Phase IIa
portion of the study.

Phase IIa
Expansion cohorts consisting of a total of 100 postmenopausal women with
locally advanced or metastatic ER- (HER2-) breast cancer previously treated
with an aromatase inhibitor (AI) will be treated at the RP2D to further
characterize the safety, PK, PD, and anti-tumor activity of GDC-0810 as follows:
Cohort A: 30 patients who have confirmed ER+ (ESR1) mutation of the ligand
binding domain (LBD), further divided into 2 subsets:
Cohort A1: 20 patients who had no prior treatment with fulvestrant. FES-PET
will be obtained for PD analysis only in Cohort A1.
Cohort A2: 10 patients where prior treatment with fulvestrant is allowed
Cohort B: 70 patients who have progressed following 1 prior therapy with an
AI in the advanced/metastatic setting, further divided into 2 subsets:
Cohort B1: 50 patients who had no prior treatment with fulvestrant
Cohort B2: 20 patients where prior treatment with fulvestrant is allowed

During the Phase Ib and Phase IIa portion of the study, there will be no PK
week lead in period (i.e., all eligible patients will start continuous daily
dosing treatment on Cycle 1 Day 1).
The effect of GDC-0810 on ventricular repolarization will be evaluated in all
patients enrolled in the Phase IIa portion of the study.
After enrollment is complete in Cohorts A2, B1, and B2 of the Phase IIa portion
of the study, further enrollment in Cohort A1 may be discontinued. Enrollment
in the Phase IIa portion of the study is complete.
All patients will be treated until disease progression, unacceptable toxicity,
or patient withdrawal of consent.

At the MTD and/or RP2D, a total of 100 patients will be enrolled to further
assess the safety, tolerability, and preliminary evidence of anti-tumor
activity and exploratory pharmacodynamic markers of response of GDC-0810 in 3
distinct patient populations (Cohorts A1 and A2 will be combined for analysis
purposes). Future clinical development of GDC-0810 as a single agent will
likely depend on the results observed from these 3 cohorts of patient

The most common side effects (i.e., occurs in more than 10 out of 100 patients
with breast cancer) considered by the study doctor to be related to GDC-0810
were as follows: Diarrhea, Nausea, Fatigue (feeling tired), Hot flashes and
flushing, Constipation, Vomiting, Heartburn, Decreased appetite, Flatulence,
Anemia (low levels of red blood cells that can make you feel tired or
breathless), Abdominal discomfort or pain, Dry mouth, Muscle pains and aches,
High levels of liver enzymes (chemicals made by the liver, which can indicate
damage to the liver if elevated), Disturbance of taste, Vaginal discharge, Low
counts of white blood cells.

Less common side effects (i.e., occurs in 1 * 10 out of 100 patients)
considered by the study doctor to be related to GDC-0810 were as follows:
Abdominal swelling, Swelling of areas such as the arms and legs with fluid
(edema), Sore throat or mouth, Difficulty breathing, Dizziness, Dry skin,
Headache, Low blood pressure, Insomnia (difficulty sleeping), Night sweats,
Deep vein thrombosis (blood clots, usually in the legs that can on occasion
cause serious or life threatening health problems), Dryness in the vaginal
area, Pain in the joints, Back pain, Low levels of phosphate (a chemical in the
blood important for proper functioning of your cells), Chalazion (a red,
painful swelling on the eyelid), Cataract (a problem with the lens of the eye
making it turn cloudy), Rash and itching, High triglycerides (fats in your
blood), High levels of cholesterol in the blood, Soreness and irritation of the
mouth, gums, and lips or other mucous membranes, Pulmonary embolism (blood
clots in the lungs that can cause serious or life threatening health problems),
Swelling of the face, Ringing in the ears, Enlargement of the lining of the
womb (endometrium), Polyps in the uterus (growths in the womb that may be
benign or may be early signs of cancer), Bleeding from the vagina, High blood
sugar, High levels of a chemical called uric acid in the blood. If severe,
this can cause gout (a painful joint problem) or cause damage to the kidneys,
Low levels of magnesium, sodium, chloride and potassium in the blood (important
minerals that if severely low can lead to problems with the heart, kidneys or
health in general), High levels of magnesium in the blood, Weight loss, Damage
to the nerves in the arms, legs, hands, and feet, which may result in numbness,
tingling, or pain, Anxiety and depression, Irritability, Palpitations of the
heart, Bleeding hemorrhoids, Low levels of albumin in the blood (a protein
important for many aspects of general health), Pain in the face, chest,
arms/legs or breast, Discomfort or pain when having sex, Increase in lactate (a
chemical that can indicate damage to tissues if increased), Disturbance of
hormones that control the thyroid, Low platelet counts (small cells that are
important for the clotting of blood), Cough, Runny nose, Need to suddenly pass
water, Acne, Hair loss, Increase levels of alkaline phosphatase, a protein in
the blood that can indicate damage to liver or bone, Soft stool.

As of August 2015, blood clots have been seen in five subjects with breast
cancer who received GDC-0810, including one who suffered a life-threatening
clot in the lungs. This subject was treated with drugs to thin the blood and
was able to continue in the study. Blood clots can potentially be serious or
life-threatening. If you experience discomfort or swelling in the arms or
legs, shortness of breath, difficulty breathing, or pain in the chest, please
inform your study team immediately.
Diarrhea is the most common side effect of GDC-0810 and is generally manageable
and tolerable. In rare cases it can be severe, but your study doctor will
monitor you closely for this.


Other Risks:
Because GDC-0810 blocks the action of female sex hormones, it may also
contribute to loss of muscle and bone and likely lead to hot flashes, vaginal
dryness or discharge, irritation, mood swings, and decreased interest in sex.
Adverse events in animal studies where animals were treated with high doses of
GDC-0810 included diarrhea, vomiting, reduced appetite, dehydration, reduced
body weight, and reduced body temperature. It was also observed that in rats,
some of the animals had ovarian cysts (a closed sac that develops abnormally on
one or both ovaries), changes in the appearance of the vagina (paleness or
thinning), and changes in the appearance of the uterus. The weights of certain
body parts (adrenal gland, pituitary gland, uterus, and ovarian) either
decreased or increased.

There are also risks or discomforts associated with blood draws, biopsies, and
radiation exposure from the imaging studies.

Risk of blood drawing: As with all blood drawing for the purpose of obtaining
samples, there is a risk of bruising, pain, or infection at the site of the
blood draw.

Radiation risks from imaging studies: As part of this study you will have CT/
MRI, and bone scans which involve exposure to radiation. The amount of
radiation exposure you may receive from these standard diagnostic tests is
considered small, and will not adversely affect the treatment of your disease.
In addition, you may also have FES-PET scans, which are considered for research
purposes only. The scan involves injecting a small amount of radioactive
material into your vein. The radioactive material travels through your blood
to reach the tumors. As it wears off, it gives off a small amount of
radiation. All radiation will be gone from the body within a day. The risk is
probably no greater than with routine or conventional x-rays. Other potential
risks are rare, but may include an allergic response.

Contrast dye for imaging scans: Contrast dye is usually administered when you
get a CT or bone scan. Some people may develop hives and itching or other
allergic symptoms from this dye. In addition, if you have low kidney function,
this dye can temporarily or permanently decrease your kidney function.

MRI (Magnetic Resonance imaging) scans: As part of this study you may have an
MRI scan. A MRI scan involves a strong magnetic field so please tell your
doctor if you have a pacemaker (the magnetic field can cause your pacemaker to
malfunction), metal dental work or a metal prosthesis (implant) in your body.
Also MRI scans require you to be in a small space, so please tell your study
doctor if you have claustrophobia (fear of being in a confined space).

Biopsies: The risks and complications associated with collecting tumor samples
include those related to anesthesia and those related to any type of surgery.
Risks related to anesthesia include, but are not limited to stroke, kidney
failure, pneumonia, and blood clots. Risks related to surgery include infection
and bleeding either during or after the biopsy, which may necessitate a blood
transfusion or another surgery. Fluid may collect under the skin, which may
need to be taken out with a needle. Finally, skin scars may result from the
biopsy which may be painful or cosmetically unattractive.