Ipatasertib and Carboplatin With or Without Paclitaxel in Treating Patients With Metastatic Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of ipatasertib plus either carboplatin or
carboplatin/paclitaxel in patients with metastatic triple negative breast cancer (TNBC).
(Phase I) II. To obtain initial evidence of activity by examining progression free survival
for each dose regimen. (Phase IB)

SECONDARY OBJECTIVES:

I. To confirm the recommended phase II dose (RPIID) safety in expanded cohort by evaluating
toxicities and confirm tolerability of the combinations.

II. To obtain evidence of activity by examining response rate based on Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1.

III. To evaluate clinical benefit rate (CBR), event-free survival, time-to-treatment failure
and overall survival.

IV. Further describe the cumulative toxicities (Common Terminology Criteria for Adverse
Events [CTCAE] 5.0) of the combinations.

V. To evaluate patient's quality of life (QOL).

EXPLORATORY OBJECTIVES:

I. To evaluate the progression-free survival and overall survival, based on the genomic
alterations including PIK3CA/AKT/PTEN alterations and BRCA status.

II. To study the association of TNBC messenger ribonucleic acid (mRNA) expression profiling
including Vanderbilt molecular subtype and treatment response.

III. To study the association of stool microbiome, calprotectin with diarrhea. IV. To study
peripheral blood circulating tumor deoxyribonucleic acid (DNA). V. To study therapy
resistance by analyzing tumor genomics and transcriptome analysis.

OUTLINE: This is a phase I, dose-escalation trial of ipatasertib, followed by a phase II
trial. Patients are randomized or assigned to 1 of 2 treatment schedules depending on
available slots.

SCHEDULE A: Patients receive ipatasertib orally (PO) once daily (QD) on days 1-28. Patients
also receive carboplatin intravenously (IV) over 30 minutes and paclitaxel IV over 60 minutes
on days 1, 8, and 15 or days 1 and 15. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

SCHEDULE B: Patients receive ipatasertib PO QD on days 1-28. Patients also receive
carboplatin IV over 30 minutes on days 1, 8, and 15 or days 1 and 15. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 36 months.

Inclusion Criteria:

- Signed informed consent form

- Ability to comply with the study protocol, in the investigator's judgment

- Histologically or cytologically confirmed triple negative breast cancer defined by
estrogen receptor (ER) or progesterone receptor (PR) =< 10% by immunohistochemistry
(IHC) and HER2 negative defined by current American Society of Clinical
Oncology/College of American Pathologists (ASCO/CAP) guideline

- Disease progression during or following treatment with up to 2 lines of chemotherapy
and/or biological targeted therapy for metastatic TNBC

- Measurable or non-measurable but evaluable disease per RECIST version (v) 1.1
(previously irradiated lesions can be considered as measurable disease only if
progressive disease has been unequivocally documented at that site since radiation)

- Baseline tissue requirement:

- A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block
(preferred) or at least 20 x 5 um slides containing unstained, freshly cut,
serial sections must be collected along with an associated pathology report prior
to study enrollment

- If only 10-19 slides are available, the patient may still be eligible for the
study, after principal investigator approval has been obtained

- If archival tumor tissue is unavailable or is determined to be unsuitable for
required testing, tumor tissue must be obtained from a biopsy performed at
screening

- A biopsy may also be performed at screening if a patient's archival tissue test
results do not meet eligibility criteria

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

- Life expectancy >= 3 months

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (1,500/uL) without granulocyte
colony-stimulating factor support (obtained within 14 days prior to initiation of
study treatment)

- Platelet count >= 100 x 10^9/L (100,000/uL) without transfusion (obtained within 14
days prior to initiation of study treatment)

- Hemoglobin >= 9 mg/dL (9 mg/dL) (patients may be transfused to meet this criterion)
(obtained within 14 days prior to initiation of study treatment)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN) (obtained within 14 days prior to initiation of study
treatment), with the following exception:

- Patients with documented liver or bone metastases may have AST and ALT =< 5 x ULN

- Alkaline phosphatase (ALP) =< 2 x ULN (obtained within 14 days prior to initiation of
study treatment), with the following exceptions:

- Patients with known liver involvement may have ALP =< 5 x ULN

- Patients with known bone involvement may have ALP =< 7 x upper limit (UL)

- Serum bilirubin =< 1.5 x ULN (obtained within 14 days prior to initiation of study
treatment) with the following exception:

- Patients with known Gilbert disease: serum bilirubin level =< 3 x ULN

- Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min (calculated using
the Cockcroft-Gault formula) (obtained within 14 days prior to initiation of study
treatment)

- Partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT])
and international normalized ratio (INR) =< 1.5 x ULN (except for patients receiving
anticoagulation therapy) (obtained within 14 days prior to initiation of study
treatment)

- Patients receiving heparin treatment should have a PTT (or aPTT) between 1.5 and
2.5 x ULN (or patient value before starting heparin treatment). Patients
receiving coumarin derivatives should have an INR between 2.0 and 3.0 assessed in
two consecutive measurements 1 to 4 days apart

- Fasting total glucose =< 150 mg/dL (obtained within 14 days prior to initiation of
study treatment)

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per
year during the treatment period and for 6 months after the last dose of study
treatment. Women must refrain from donating eggs during this same period.

- A woman is considered to be of childbearing potential if she is post-menarcheal,
has not reached a postmenopausal state (>= 12 continuous months of amenorrhea
with no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus)

- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone- releasing intrauterine devices, and copper
intrauterine devices

- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post
ovulation methods) and withdrawal are not acceptable methods of contraception

- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
a condom, and agreement to refrain from donating sperm, as defined below:

- With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during the treatment period and for 6
months after the last dose of study treatment to avoid exposing the embryo. Men
must refrain from donating sperm during this same period

- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post
ovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria:

- Inability to comply with study and follow-up procedures

- >= grade 2 toxicities from previous treatment, not recovered to =< grade 1 at study
entry

- Prior exposure to PI3K/AKT/mTOR pathway inhibitors including but not limited to
everolimus, ipatasertib, gedatolisib or alpelisib etc

- Prior exposure to carboplatin for treatment of metastatic TNBC not allowed; prior
treatment of carboplatin as neoadjuvant or adjuvant therapy allowed if last dose of
therapy completed >= 12 months prior to initiation of the current study

- Prior exposure to paclitaxel or nab-paclitaxel for treatment of metastatic TNBC not
allowed for carboplatin/paclitaxel arm; prior treatment of paclitaxel or
nab-paclitaxel as neoadjuvant or adjuvant therapy allowed if last dose of therapy
completed >= 12 months prior to initiation of the current study

- Known allergy or hypersensitivity to any component of carboplatin and/or paclitaxel or
nab-paclitaxel formulation

- Known severe allergic reactions to cisplatin or other platinum-containing compounds or
mannitol

- History of malabsorption syndrome or other condition that would interfere with enteral
absorption or results in the inability or unwillingness to swallow pills

- Active infection requiring systemic anti-microbial treatment (including antibiotics,
anti-fungals, and anti-viral agents)

- Known brain metastasis or leptomeningeal metastasis from metastatic breast cancer

- Known human immunodeficiency virus (HIV) infection

- Known clinically significant history of liver disease consistent with Child-Pugh class
B or C, including active viral or other hepatitis (e.g., positive for hepatitis B
surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current
drug or alcohol abuse, or cirrhosis

- Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
(defined as having a negative HBsAg test and a positive hepatitis B core antibody
[HBcAb] test, accompanied by a negative HBV deoxyribonucleic acid [DNA] test) are
eligible

- Patients positive for HCV antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV ribonucleic acid (RNA)

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1 of cycle 1 or anticipation of need for a major surgical procedure
during the course of the study

- Placement of a vascular access device is not considered major surgery

- Pregnant or breastfeeding, or intending to become pregnant during the study or within
28 days after the last dose of ipatasertib and within 6 months after the last dose of
paclitaxel, whichever occurs later

- Women of childbearing potential (who are not postmenopausal with >= 12 months of
non-therapy induced amenorrhea nor surgically sterile) must have a negative serum
pregnancy test result either within 96 hours prior to day 1 of cycle 1 treatment

- New York Heart Association class II, III, or IV heart failure; left ventricular
ejection fraction < 50%; or active ventricular arrhythmia requiring medication

- Current unstable angina or history of myocardial infarction within 6 months prior to
day 1 of cycle 1

- Congenital long QT syndrome or screening QT interval corrected using Fridericia's
formula (QTcF) > 480 milliseconds

- History or presence of an abnormal electrocardiogram (ECG) that is clinically
significant in the investigator's opinion (including complete left bundle branch
block, second- or third-degree heart block, or evidence of prior myocardial
infarction)

- Need for chronic corticosteroid therapy of >= 10 mg of prednisone per day or an
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a
chronic disease

- Treatment with approved or investigational cancer therapy within 14 days prior to day
1 of cycle 1

- Patients with a prior diagnosis of malignancy except non-melanomatous skin cancer
treated >= 5 years ago are eligible, provided that they have not received prior
taxanes or carboplatin as part of their prior treatment regimen, and that they meet
all eligibility criteria

- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
a disease or condition that contraindicates the use of an investigational drug or that
may affect the interpretation of the results or render the patient at high risk from
treatment complications

- Pregnant or breastfeeding, or intending to become pregnant during the study or within
6 month after the last dose of study treatment

- Women of childbearing potential must have a negative serum pregnancy test result
within 96 hours prior to initiation of study treatment

- IPATASERTIB-SPECIFIC CRITERIA

- History of type I or type II diabetes mellitus requiring insulin

- Patients who are on a stable dose of oral diabetes medication >= 2 weeks prior to
initiation of study treatment are eligible for enrollment

- Grade >= 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia

- History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
colitis) or active bowel inflammation (e.g., diverticulitis)

- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic
infections (pneumocystis pneumonia or cytomegalovirus pneumonia)

- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5
drug-elimination half-lives, whichever is longer, prior to initiation of study drug