This is a multicenter, open-label, non-comparative, three-arm, phase IIa trial of Ipatasertib
(GDC-0068) in combination with non-taxane chemotherapy agents for taxane-pretreated
unresectable locally advanced or metastatic triple-negative breast cancer patients
Women age ≥ 18 years with triple-negative unresectable locally advanced or MBC that is not
amenable to resection with curative intent.
Patients must have received at least one, but not more than two, prior chemotherapeutic
regimens for treatment of unresectable locally advanced and/or metastatic disease (at least
one regimen must have contained a taxane).
The number of patients to be included is 54 patients. The primary objective is to evaluate
the safety and tolerability of ipatasertib (GDC-0068) in combination with capecitabine,
eribulin, or carboplatin plus gemcitabine in patients with unresectable locally advanced or
metastatic triple-negative breast cancer
Inclusion Criteria:
1. Signed Informed Consent Form (ICF) prior to participation in any study-related
activities.
2. Female patients ≥ 18 years at the time of signing ICF.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. Life expectancy of ≥ 12 weeks.
5. Histologically confirmed Triple Negative Breast Cancer (TNBC) per American Society of
Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria based on
local testing on the most recent analyzed biopsy. Triple-negative is defined as <1%
expression for estrogen receptor (ER) and progesterone receptor (PgR) and negative for
Human Epidermal Growth Factor Receptor 2 (HER2) (0-1+ by immunohistochemistry (IHC) or
2+ and negative by in situ hybridization [ISH) test].
6. Unresectable locally advanced or metastatic disease documented by computerized
tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to
resection with curative intent.
7. Measurable or evaluable disease as per RECIST v.1.1. Patients with only bone lesions
are also eligible.
8. Refractory to or relapsed after one or two prior standard of care chemotherapy
regimens for unresectable locally advanced or metastatic breast cancer (MBC). Earlier
adjuvant or neoadjuvant therapy for more limited disease will be considered as one of
the required prior regimens if the development of unresectable locally advanced or
metastatic disease occurred within a 12-month period of time after completion of
chemotherapy.
Note: Exclusive tumor marker elevation will not be considered sufficient for diagnosis
of disease progression.
9. Prior therapy must have included a taxane in any combination or order and either in
the early, locally advanced, or metastatic setting. Note: Exclusive prior taxane-based
therapy as adjuvant or neoadjuvant treatment is also allowed if the patient had a
disease-free interval of less than 12 months after completing this treatment.
10. Eligible for one of the chemotherapy options (eribulin, capecitabine, carboplatin plus
gemcitabine) as per local investigator assessment and slots availability. Patients
treated with (neo)adjuvant platinum salts or capecitabine and who have relapsed more
than one year after the last dose of either treatment may be allowed to be included in
the treatment arm based on ipatasertib (GDC-0068) in combination with carboplatin plus
gemcitabine and capecitabine, respectively.
11. Previous treatment with androgen receptor antagonists, poly ADP-ribose Polymerase
(PARP) inhibitors, and immunotherapy is allowed. Those patients who have previously
received a PARP inhibitor will not be included in the carboplatin and gemcitabine arm
unless PARP inhibitors were used in the early breast cancer setting and the period
between the end of PARP inhibitor-based regimen and onset of metastatic disease is at
least of 12 months.
12. Resolution of all acute toxic effects of prior anti-cancer therapy to grade inferior
or equal to 1 as determined by the NCI-CTCAE v.5.0 (except for alopecia or other
toxicities not considered a safety risk for the patient at investigator's discretion).
13. Willingness and ability to provide a tumor biopsy from a metastatic site or the
primary breast tumor at the time of the inclusion in order to perform exploratory
studies. If not feasible, patient eligibility should be evaluated by a Sponsor's
qualified designee. Note: Subjects for whom tumor biopsies cannot be obtained (e.g.,
inaccessible tumor or subject safety concern) may submit an archived metastatic tumor
specimen only upon agreement from the Sponsor.
14. Patients agree to give blood samples (liquid biopsy) at the time of inclusion, after
two cycles of study treatment, and upon progression or study termination.
15. Adequate hematologic and organ function within 14 days before the first study
treatment on Day 1 of Cycle 1, defined by the following:
1. Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil
count (ANC) > 1.5 x 109/L, platelet count > 100.0 x109/L, and hemoglobin > 9.0
g/dL.
2. Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5 times the upper limit of normal
(× ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartate transaminase
(AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases
≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN in the case of liver
and/or bone metastases ≤ 5 × ULN).
3. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on
Cockcroft-Gault glomerular filtration rate estimation.
4. Coagulation: Partial Thromboplastin Time (PTT) (or activated Partial
Thromboplastin Time [aPTT]) and International Normalized Ratio (INR) ≤ 1.5 × ULN
(except for patients receiving anticoagulation therapy).
Note: Patients receiving heparin treatment should have a PTT (or aPTT) ≤ 2.5 × 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 one to four days apart. Patients should be on a stable anticoagulant
regimen.
16. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse), or to use a highly effective non-hormonal form of
contraception, or two effective forms of contraception, as defined in the protocol
during the treatment period and for at least 28 days after the last dose of
ipatasertib (GDC-0068), three months after the last dose of eribulin, and six months
after the last dose of carboplatin and gemcitabine or capecitabine, whichever occurs
later, and agreement to refrain from donating eggs during this same period. Women of
childbearing potential must have a negative serum pregnancy test before study
treatment initiation.
Exclusion Criteria:
1. Inability to comply with study and follow-up procedures.
2. Previous treatment with PI3K, mTOR, or AKT inhibitors.
3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms,
cerebral edema, and/or progressive growth. Patients with a history of CNS metastases
or cord compression are eligible if they have been definitively treated (e.g.,
radiotherapy, stereotactic surgery), are clinically stable, and off anticonvulsants
and steroids for at least two weeks before first dose of study treatment.
4. Radiotherapy or limited-field palliative radiotherapy within seven days prior to study
enrolment, or patients who have not recovered from radiotherapy-related toxicities to
baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been previously
irradiated.
5. Major surgery (defined as requiring general anesthesia) or significant traumatic
injury within 28 days of start of study drug, or patients who have not recovered from
the side effects of any major surgery.
6. Grade ≥ 2 peripheral neuropathy.
7. Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.
8. History of type I or type II diabetes mellitus either requiring insulin or with a
baseline fasting glucose > 150 mg/dL (8.3 mmol/L) or high hemoglobin A1c (HbA1c) as
defined as > 7%. Patients who are on a stable dose of oral diabetes medication during
at least weeks prior to initiation of study treatment are eligible for enrolment.
9. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,
cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic
infections (pneumocystis pneumonia or cytomegalovirus pneumonia).
10. History of malabsorption syndrome or other condition that would interfere with enteral
absorption or results in the inability or unwillingness to swallow pills.
11. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative
colitis) or active bowel inflammation (e.g., diverticulitis).
12. Known hypersensitivity reaction to any investigational or therapeutic compound or
their incorporated substances.
13. Patients have a concurrent malignancy or malignancy within five years of study
enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin
carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk
of recurrence, discussion with the Medical Monitor is required.
14. Current known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV).
Patients with past HBV infection or resolved HBV infection (defined as having a
negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B core
antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients
positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is
negative for HCV RNA.
15. Active uncontrolled infection at the time of enrollment.
16. Congenital long QT syndrome or screening QT interval corrected using Fridericia's
formula (QTcF) > 480 milliseconds.
17. Patients have an active cardiac disease or a history of cardiac dysfunction including
any of the following:
1. Unstable angina pectoris or documented myocardial infarction within six months
prior to study entry.
2. Symptomatic pericarditis.
3. Documented congestive heart failure (New York Heart Association functional
classification III- IV).
4. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated
acquisition (MUGA) scan or echocardiogram (ECHO).
18. Patients have any of the following cardiac conduction abnormalities:
1. Ventricular arrhythmias except for benign premature ventricular contractions.
2. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication.
3. Conduction abnormality requiring a pacemaker.
4. Other cardiac arrhythmia not controlled with medication.
19. Patients have any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment contraindicate patient participation in the
clinical study.
20. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or five
drug-elimination half-lives, whichever is longer, prior to initiation of study
treatment.
21. Pregnant, breastfeeding, or intending to become pregnant during the study or within 28
days after the last dose of ipatasertib (GDC-0068), three months after the last dose
of eribulin, and six months after the last dose of carboplatin and gemcitabine or
capecitabine, whichever occurs later.
22. Treatment with approved or investigational cancer therapy within 14 days prior to
initiation of study drug.
23. Concurrent participation in other interventional clinical trial.
