This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.
The U.S. Food and Drug Administration (FDA) has not approved ipatasertib as a treatment for
any disease.
The FDA has approved fulvestrant, the aromatase inhibitors, and palbociclib as treatment
options for this disease.
This research study will evaluate the safety and tolerability of ipatasertib in combination
with an aromatase inhibitor or fulvestrant with or without palbociclib.
Resistance to standard of care treatment for people with your type of cancer is common.
Stopping (inhibiting) an enzyme called Akt in the cancer cells may overcome resistance to the
standard of care treatment. Ipatasertib is a type of inhibitor that is believed to work by
inhibiting Akt. Through the different combinations of ipatasertib and the standard of care
drugs, the chance of cancer cells becoming resistant to the standard of care drugs may
decrease, causing the cancer cells to stop growing and spreading.
Inclusion Criteria:
- Adult women (≥ 18 years of age) with biopsy proven HR+/HER2 negative breast cancer;
HR+ defined as ≥1% positivity for ER, and/or PR (≥1%), as per local assessment. HER2
as per standard CAP guidelines (local assessment).
- Postmenopausal women with locally advanced or metastatic BC. Patients must be
postmenopausal women as defined by one of the following:
- Women >60 years OR
- Women ≤60 years, and any one of following:
- LH and FSH level in the postmenopausal range according to institutional
standards
- s/p post bilateral surgical oophorectomy.
- Premenopausal/perimenopausal women on gonadotropin-releasing hormone agonist
(to be continued during study) and estradiol level in the postmenopausal
range according to institutional standards
- Disease progression on at least one prior therapy for metastatic disease, including
endocrine therapy with/without CDK 4/6 inhibitor (palbociclib or ribociclib or
abemaciclib). Disease recurrence during/within 12 month of (neo)adjuvant endocrine
therapy (with/without CDK 4/6 inhibitor) will count as one prior therapy for this
definition.
- ECOG Performance Status 0 - 2
- Left ventricular ejection fraction (LVEF) ≥ 50%
- Evaluable or measurable disease: at least one lesion that can be accurately measured
in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with
spiral CT or MRI. Bone lesions in the absence of measurable disease as defined above
is also acceptable.
- Discontinuation of prior breast cancer therapies, including endocrine therapy, for 14
days (non-myelosuppressive) or 21 days (myelosuppressive). Wash-out for Fulvestrant
and tamoxifen will be 28 days.
- Prior mTOR inhibitor and/or PI3K inhibitor allowed (all arms)
- Prior aromatase inhibitor is allowed (all arms)
- Adequate bone marrow function: ANC ≥ 1000/mm3, hemoglobin ≥9 g/dl, and platelets ≥
100,000/mm3.
- Adequate hepatic function: Total bilirubin < 1.5mg/dL, AST and ALT < 3X Institutional
ULN (or 5 X Institutional ULN in presence of hepatic mets).
- Adequate renal function: Calculated creatinine clearance ≥ 30 mL/min
- Fasting blood glucose <140 mg/dL, and hemoglobin A1c <7.
- Signed informed consent and agree to comply with study procedures.
Exclusion Criteria:
- Participants with progressive CNS metastatic disease. Patients with stable CNS
metastasis would be eligible, provided mets radiologically stable for atleast one
month, and patient is not actively taking steroids.
- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.
- Prior use of AKT inhibitor (any setting)
- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or 5
drug-elimination half-lives, whichever is longer, prior to initiation of study
treatment. Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference may also provide this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product.
- Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements. Patient has impairment of gastrointestinal (GI) function or GI
disease that may significantly alter the absorption of the study drugs (e.g.,
inflammatory bowel disease, ulcerative diseases, uncontrolled nausea, vomiting,
diarrhea, malabsorption syndrome, or small bowel resection).
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality including any of the following:
- History of angina pectoris, symptomatic pericarditis, coronary artery bypass
graft (CABG) or myocardial infarction within 6 months prior to study entry.
- Documented cardiomyopathy.
- History of cardiac failure, significant/symptomatic bradycardia, Long QT
syndrome, family history of idiopathic sudden death or congenital long QT
syndrome or any of the following:
- Known risk to prolong the QT interval or induce Torsade's de Pointes.
- Uncorrected hypomagnesemia or hypokalemia.
- Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg.
- Bradycardia (heart rate <50 at rest), by ECG or pulse.
- On screening, inability to determine the QTcF interval on the ECG (i.e.:
unreadable or not interpretable) or QTcF >450 screening ECG (based on a mean of 3
ECGs).
- HIV-positive participants on combination antiretroviral therapy are ineligible. These
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.
- 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. Patients must meet the laboratory eligibility
criteria for fasting blood glucose and hemoglobin A1c as outlined in the inclusion
criteria.
- Pregnant women are excluded from this study because the safety of study medications is
not established in pregnant women.
- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
throughout the study and for 8 weeks after study drug discontinuation. Women are
considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g.
age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago.
In the case of bilateral oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment is she considered not
of child bearing potential. Highly effective contraception methods include:
- Total abstinence when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment
- Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception.
- In case of use of oral contraception, women should have been stable on the same pill
for a minimum of 3 months before taking study treatment. Note: While oral
contraceptives are allowed, they should be used in conjunction with a barrier method
of contraception due to unknown effect of drug-drug interaction.
- For Arm A only: patients who have received prior fulvestrant.
- For Arm C only: h/o of intolerable toxicity to CDK 4/6 inhibitor resulting in
treatment discontinuation due to toxicity
