PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) of ipatasertib plus
carboplatin/paclitaxel (arm A), ipatasertib plus carboplatin (arm B), and ipatasertib,
atezolizumab, and capecitabine (arm C) 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.
VI. To study the profiles of peripheral blood mononuclear cells and its association with
response to therapy.
VII. To study genomic immune biomarkers and its association with response.
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 3 arms depending on available slots.
ARM 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.
ARM 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.
ARM C: Patients receive ipatasertib PO QD on days 1-21, capecitabine PO twice daily (BID) on
days 1-7 and 15-21, and atezolizumab IV over 30-60 minutes on 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 0-2 lines of chemotherapy
and/or biological targeted therapy in the metastatic setting
- Measurable (Arm C only) or non-measurable (allowed for Arm A or B) 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 3 toxicities from previous treatment, not recovered to =< grade 2 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
- Prior exposure to capecitabine for treatment of metastatic TNBC not allowed for Arm C;
prior treatment of capecitabine as adjuvant therapy allowed if the last dose of
therapy completed >= 12 months prior to initiation of the current study for Arm C
- Prior treatment with immune check point inhibitors for Arm C
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Prior treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives
(whichever is longer) prior to initiation of study treatment for Arm C
- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or
anticipation of need for systemic immunosuppressive medication during study treatment,
with the following exceptions for Arm C:
- Patients who received acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for the study after Medical
Monitor confirmation has been obtained
- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
for the study
- Active autoimmune disorders requiring steroid dose higher than prednisone 10 mg daily
for Arm C
- Active disease or receiving treatment for hepatitis B or C or human immunodeficiency
virus (HIV) infection for Arm C
- Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment (start of
treatment), during treatment, or within 5 months following the last dose of
atezolizumab for Arm C
- Known allergy or hypersensitivity to any component of carboplatin and/or paclitaxel or
nab-paclitaxel, or capecitabine (5-FU) formulation (for patients planned for the
respective arms)
- Known dihydropyrimidine dehydrogenase (DPD) deficiency in patients selected to receive
capecitabine for Arm C
- Known severe allergic reactions to cisplatin or other platinum-containing compounds or
mannitol (for patients planned for platinum-containing arms)
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation
- 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)
- Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia
- Known untreated or unstable brain metastasis or leptomeningeal metastasis from
metastatic breast cancer
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently)
- Patients with indwelling catheters (e.g., PleurX) are allowed
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
mg/dL, or corrected calcium > ULN)
- Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome,
or multiple sclerosis with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
within the previous 12 months
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan
- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Active tuberculosis
- Known 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)
- Prior allogeneic stem cell or solid organ transplantation
- 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, 5 months after the last dose of
atezolizumab, 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 and cerebrovascular accident within 3 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, 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 affec
