Phase Ib dose-escalation trial of Taselisib (GDC-0032) in combination with anti-HER2 therapies in participants with advanced HER2+ Breast Cancer

This research study is a way of gaining new knowledge about the combination of Taselisib with
other drugs in the treatment of metastatic breast cancer. Taselisib is an investigational
drug which works by blocking a protein called PI3K (phosphoinositide 3-kinase) that helps
cancer cells grow. This drug has been used in laboratory experiments and information from
these studies suggests that this drug may help to prevent or slow the growth of cancer cells.
The main purpose of this study is to find the appropriate dose of Taselisib to be used with
other drugs in further clinical studies. This is an open-label, 3+3 dose-escalation phase Ib
study to identify the Maximum Tolerated Dose(s) (MTD) and to identify the recommended phase 2
dose (RP2D) of Taselisib. This study will be conducted in 4 separate arms. (A-D).

Inclusion Criteria:

- Metastatic, locally advanced , or locally recurrent breast cancer

- Histologically confirmed HER2+ invasive breast cancer

- Measurable or non-measurable disease per RECIST v1.1

- Prior therapy - Prior trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine
(T-DM1) are allowed. Patients who have received prior therapy with Taselisib
(GDC-0032) or BYL-719 are excluded. There is no limit on the number of prior lines of
therapy.

- ECOG performance status 0 or 1

- Normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mm3

- Platelets ≥100,000/mm3

- Total bilirubin < 1.5 X institutional upper limit of normal. For patients with
Gilbert syndrome, the direct bilirubin should be within the institutional normal
range

- AST (SGOT) and ALT (SGPT) < 2.5 X institutional upper limit of normal

- Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min

- Fasting glucose ≤ 120 mg/dL and HbA1c < 7%

- Left ventricular ejection fraction ≥ 50%

- Women of childbearing potential (including those who have had a tubal ligation) must
have a documented negative pregnancy test within 14 days prior to planned initiation
of Taselisib.

- Ability to understand and the willingness to sign a written informed consent document.

- For Part 2: patients must have tissue that is amenable to biopsy and must be willing
to undergo research biopsy. Patients who undergo an attempted research biopsy
procedure for the purpose of this protocol, and in whom inadequate tissue is obtained,
are not required to undergo a repeat biopsy in order to continue on protocol.

Exclusion Criteria:

- Anti-cancer therapy within 2 weeks prior to entering the study or those who have not
recovered from acute adverse events due to agents administered more than 2 weeks
earlier. Palliative radiation to bony metastases ≥2 weeks prior to study entry is
allowed.

- Prior treatment with a PI3 kinase, AKT or mTOR inhibitor in which the patient
experienced a Grade ≥3 drug related adverse event or otherwise would be at increased
risk for additional PI3K related toxicity

- Currently receiving any other investigational agents. Treatment with an
investigational agent within 2 weeks prior to planned initiation of study therapy is
allowed provided that any drug related toxicity has completely resolved

- Major surgical procedure within 4 weeks prior to planned initiation of study therapy

- Significant traumatic injury within 3 weeks prior to planned initiation of study
therapy

- Known untreated brain metastases are excluded. History of treated CNS metastases is
okay, provided the following criteria are met:

- Disease outside the CNS is present.

- No evidence of interim progression between the completion of CNS directed therapy
and the screening radiographic study

- No history of intracranial hemorrhage or spinal cord hemorrhage

- Not requiring anti-convulsants for symptomatic control

- Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and
recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement
for corticosteroid

- History of allergic reactions or hypersensitivity attributed to compounds of similar
chemical or biologic composition to the Taselisib drug formulation or other agents
used in this study.

- Receiving any medications or substances that are inhibitors of CYP3A4.

- Malabsorption syndrome or other condition that would interfere with enteral absorption

- Active small or large intestine inflammation such as Crohn's disease or ulcerative
colitis

- Type 1 or 2 diabetes requiring anti hyperglycemic medication (e.g. metformin,
glipizide, insulin)

- Leptomeningeal disease as the only manifestation of the current malignancy

- Congenital long QT syndrome or QTc > 500 msec

- Active congestive heart failure or ventricular arrhythmia requiring medication

- Uncontrolled ascites requiring weekly large volume paracentesis for 2 consecutive
weeks prior to initiation of study treatment

- Active infection requiring intravenous (IV) antibiotics

- Patients requiring any daily supplemental oxygen

- Uncontrolled hypomagnesemia, hypokalemia or hypocalcemia, defined as values below the
lower limit of normal (LLN) for the institution despite adequate electrolyte
supplementation or management

- Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab
therapy

- Clinically significant history of liver disease, including viral or other hepatitis,
current alcohol abuse, or cirrhosis

- Grade ≥2 peripheral neuropathy

- Any other diseases, active or uncontrolled intercurrent illness including, but not
limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, pulmonary dysfunction, metabolic dysfunction, psychiatric
illness/social situations, physical examination finding, or clinical laboratory
finding that would limit compliance with study requirements.

- Women of childbearing potential (< 1 year amenorrheic) or sexually active males who
are not employing adequate contraception (or practicing complete abstinence).

- Female patients of childbearing potential must commit to using a reliable and
appropriate method of contraception until at least 7 months after the end of last
dose of study treatment.

- Male patients with a partner of childbearing potential must agree to use a
barrier method of contraception (condom) in addition to having their partner use
another contraceptive method during the trial and for 7 months after the last
dose of study treatment.

- Pregnant women and women who are lactating.

- Known human immunodeficiency virus (HIV) infection

- Inability or unwillingness to swallow pills