Inclusion Criteria:
- Participants must have histologically confirmed invasive breast cancer that is
metastatic or unresectable locally advanced. Histological documentation of
metastatic/recurrent breast cancer is not required if there is unequivocal evidence
for recurrence of the breast cancer.
- Estrogen and/or progesterone receptor positive breast cancer (>10% staining), as
determined by pathology from either primary or metastatic site(s). Central
confirmation is not required.
- HER2 negative, defined as 0-1+ by immunohistochemistry or FISH-negative (HER2 copy
number <6 and HER2/CEP17 ratio < 2.0). Central confirmation is not required.
- Postmenopausal women are eligible. Postmenopausal is defined as any of the following:
- Age ≥60 years
- Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the
postmenopausal range per local normal range.
- Premenopausal women who have been on a GnRH agonist for at least 3 consecutive
months prior to study entry are eligible. Women in this group MUST remain on the
GnRH agonist for the duration of protocol treatment.
- Status-post bilateral oophorectomy-After adequate healing post surgery.
- Women, age ≥18 years of age. Men are excluded.
- Because no dosing or adverse event data are currently available on the use of
palbociclib and bazedoxifene in participants <18 years of age, children are
excluded from this study. In addition, breast cancer is exceedingly rare in
individuals under 18 years of age.
- Participants must have measurable disease by RECIST 1.1. See section 11 for the
definition of measurable disease.
- Bone only disease if there are lytic lesions is also allowed and treatment response
will be evaluated based on the MD Anderson criteria. See section 11.
- Endocrine resistant breast cancer, defined as either:
- Relapsed while on adjuvant endocrine therapy or within 1 year of completion of
adjuvant endocrine therapy
--- -or-
- Progression through at least one line of endocrine therapy for metastatic or
locally advanced breast cancer. There is no limit on the number of prior
endocrine therapies received.
- Patients may have received up to one prior line of chemotherapy for metastatic or
unresectable locally advanced breast cancer.
- Patients may have initiated bisphosphonate therapy prior to start of protocol
therapy. Bisphosphonate therapy may continue during protocol treatment. Such
patients will have bone lesions considered evaluable for progression
- Patients must be at least 2 weeks from prior chemotherapy or radiotherapy, or any
investigational drug product, with adequate recovery of toxicity to baseline, or
grade <1, with the exception of alopecia and hot flashes. There is no washout
period for prior endocrine therapy.
- ECOG Performance Status 0-1 (Appendix A)
- Life expectancy of greater than 3 months
- Willingness to undergo research biopsy under the following circumstances:
- Patients with "easily accessible disease"
- Patients with skin or chest wall disease amenable to a punch biopsy under
local anesthesia are required to undergo a baseline biopsy and a biopsy at
the time of disease progression as part of this protocol.
- Patients with a breast mass or axillary lymph node amenable to an
image-guided core biopsy are also required to undergo a baseline biopsy and
a biopsy at the time of disease progression as part of this protocol.
- Patients with malignant ascites fluid or a malignant pleural effusion of
sufficient volume to be amenable to tap (either in-office or image-guided)
are also required to undergo a baseline tap and a tap at the time of disease
progression as part of this protocol.
- Patients who undergo a research biopsy procedure for the purpose of this
protocol, and in whom inadequate tissue is obtained, are still eligible and
are not required to undergo a repeat biopsy in order to enter the study.
- Patients will be approached during cycle 1 about providing an optional
tissue sample at that time; however, this biopsy will be optional.
- Patients with "accessible disease"
- Patients with sites felt to be accessible to an image-guided or incisional
biopsy in the opinion of the patient's treating oncologist and physician
performing the procedure, and not meeting the criteria for "easily
accessible disease" as described in Section 3.1.14.1, are required to
undergo a baseline biopsy as part of this protocol. Such sites may include,
but are not limited to: liver, lymph nodes, soft tissue, lung, chest wall,
and bone. Cycle 1 biopsy and biopsy at time of disease progression are
optional.
- Biopsies may be done with local anesthesia or intravenous conscious
sedation, according to standard institutional guidelines.
- If a biopsy requires general anesthesia, then it is only allowed if
acquisition of tissue is necessary for clinical reasons (i.e. is clinically
indicated), and excess tissue that would otherwise have been discarded is
then used for research purposes. If a biopsy requires general anesthesia,
then a biopsy of that site for research purposes only, without a coexisting
clinical indication is not allowed on this protocol.
- Patients who undergo a research biopsy procedure for the purpose of this
protocol, and in whom inadequate tissue is obtained, are still eligible and
are not required to undergo a repeat biopsy in order to enter the study.
- Some patients may have had a clinically indicated biopsy upon recent disease
progression. No additional pre-treatment biopsy is required if that specimen
can be used for the correlative studies described in this protocol.
- Patients will be approached at the time of progression about providing an
optional tissue sample at that time; however, the time of progression biopsy
will be optional.
- Other patients
- Patients who do not have biopsy-accessible disease are not required to
undergo a biopsy as part of study participation.
- In addition, patients who are being treated with therapeutic doses of
anticoagulant(s), are not required to undergo a biopsy as part of study
participation. If it is felt clinically appropriate despite anticoagulation
(i.e. a skin punch biopsy, etc) by the treating physician, a biopsy is
allowed, it is simply not required.
- The sites of metastatic disease and reason that the disease is not
biopsy-accessible should be documented in the medical record and case report
form(s).
- Patients who do not undergo baseline biopsy must have their study
participation approved by the overall PI before start of protocol therapy.
Only patients who have biopsy inaccessible disease may enter the study
without the requirement for baseline biopsy.
- Participants must have normal organ and marrow function as defined below:
- Absolute neutrophil count ≥1,500/mcL
- Platelets ≥100,000/mcL
- Hgb ≥9 mg/dL (which may be post transfusion)
- Total bilirubin ≤1.5 X institutional upper limit of normal (patients with
---- documented Gilbert's disease are allowed total bilirubin up to 3X ULN)
- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit if no liver metastases;
and ≤ 5 X institutional upper limit if liver metastases are present.
- Creatinine ≤ 2X institutional upper limit of normal
- Baseline QTc ≤ 480 ms
- Ability to take oral medications.
- The effects of palbociclib and bazedoxifene on the developing human fetus are unknown.
If, for any reason, a woman should become pregnant or suspect that she is pregnant
while participating in this study, she should inform her treating physician
immediately.
- Women who are made postmenopausal through use of GNRH agonists, and men are required
to use adequate contraception for the duration of protocol treatment and for 6 months
after the last dose of palbociclib and bazedoxifene. Adequate contraception is defined
as one highly effective non-hormonal form of contraception or two effective forms of
non-hormonal contraception by the patient and/or partner.
- Highly Effective Non-Hormonal Contraception Methods of birth control which result in a
low failure rate (i.e., less than 1% per year) when used consistently and correctly
are considered highly-effective forms of contraception. The following non-hormonal
methods of contraception are acceptable:
- True 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].
- Male sterilization (with appropriate post-vasectomy documentation of the absence
of sperm in the ejaculate). For female patients, the vasectomized male partner
should be the sole partner.
--- OR
- Effective Non-Hormonal Contraception
Alternatively two of the following effective forms of contraception may be used instead:
- Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS).
Consideration should be given to the type of device being used, as there is higher
failure rates quoted for certain types, e.g., steel or copper wire.
- Condom with spermicidal foam/gel/film/cream/suppository.
- Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository. The use of barrier contraceptives should always be
supplemented with the use of spermicide.
- The following should be noted:
- Failure rates indicate that, when used alone, the diaphragm and ondom are not highly
effective forms of contraception. Therefore, the use of additional spermicides does
confer additional theoretical contraceptive protection.
- However, spermicides alone are ineffective at preventing pregnancy when the whole
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception
and should not be used alone.
- It should be noted that two forms of effective contraception are required. A
double barrier method is acceptable, which is defined as condom and occlusive cap
(diaphragm or cervical/ vault caps) with spermicidal foam/gel/film/cream
/suppository. Premenopausal women who have been on a GnRH agonist for at least 3
consecutive months prior to study entry are eligible. Women in this group MUST
remain on the GnRH agonist for the duration of protocol treatment. Such patients
should be counseled that GnRH agonists alone may not be adequate contraception
and that adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation
should be employed.
- Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
- Prior treatment with a CDK4/6 inhibitor and/or bazedoxifene.
- Participants may not be receiving any other investigational agents.
- Concurrent treatment with commercial agents or other agents with the intent to treat
the participant's malignancy, including endocrine therapy, chemotherapy, and/or
targeted therapy, with the exception of bisphosphonates and GnRH agonists, as detailed
in sections 3.1.4 and 3.1.9.
- Untreated or progressive brain metastases. Patients with treated brain metastases not
requiring chronic corticosteroids for symptom control are eligible.
- Pending visceral crisis, in the opinion of the treating investigator.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to palbociclib and /or bazedoxifene.
- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A isoenzymes are ineligible. Lists including medications and
substances known or with the potential to interact with the CYP3A isoenzymes are
provided in Appendix D. 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.
- Current use of drugs that are known to prolong the QT interval (See Appendix C)
- Subjects with organ allograft requiring immunosuppression.
- Uncontrolled intercurrent 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. Ability to comply with study requirements is to be assessed by
each investigator at the time of screening for study participation.
- Pregnant women are excluded from this study because effects of palbociclib and
bazedoxifene on a developing fetus is unknown. Breastfeeding should be discontinued
prior to entry onto the study.
- Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: ductal
carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous
cell carcinoma of the skin.
- Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are
ineligible because of the potential for pharmacokinetic interactions or significant
immunosuppression with Palbociclib.
