Participants who have demonstrated intolerance to 125 mg of palbociclib are ineligible for the phase I portion
Previous treatment with palbociclib
Patients who have previously received palbociclib or other CDK4/6 inhibitors are not eligible
Previous exposure to a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib)
Prior treatment with palbociclib
Subjects must be receiving endocrine therapy consisting of 1) letrozole +/- palbociclib; or 2) exemestane +/ everolimus; or 3) fulvestrant +/- palbociclib; or 4) anastrozole; or 5) tamoxifen; pre-menopausal women must also be receiving a gonadotrophin releasing hormone (LHRH) agonist with endocrine therapy options 1 through 4; option 5 can be used without LHRH agonists for pre-menopausal women
Only for subjects enrolled in Arm 2 - Neratinib and palbociclib: any prior neuropathy should be back to baseline or grade 1.
Only for subjects enrolled in Arm 2 - Neratinib and palbociclib: patients who are taking medications with moderate or potent inhibitors or inducers of CYP450 3A4 should be off for 5 half-lives prior to starting palbociclib.
Scenario 2: the patient must have received an aromatase inhibitor or tamoxifen plus palbociclib as standard of care or received a CDK4/6 inhibitor (palbociclib or ribociclib or abemaciclib) as part of a clinical trial, and demonstrated evidence of disease progression; if the patient was enrolled in a randomized clinical trial involving ribociclib or abemaciclib or palbociclib (such as the MONALEESA or PALOMA series of trials), then it must be known after study discontinuation and unblinding that the patient received the investigational drug and not placebo; documentation of progression and duration of response on aromatase inhibitor or tamoxifen plus CDK 4/6 inhibitor should be provided whenever possible; no prior fulvestrant allowed
Known or possible hypersensitivity to palbociclib, fulvestrant, goserelin (if applicable) or to any of their excipients
Known or possible hypersensitivity to palbociclib (CTCAE version [V] 4.03)
Known or possible hypersensitivity to fulvestrant, or palbociclib or any of their excipients.
Known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib/placebo excipients or to endocrine treatments.
Female subjects of childbearing potential should be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year\r\n* Cohort 1 (accrual to 6 patients) is for patients who had ongoing stable disease (SD) on letrozole + palbociclib, enrolled on prior version of eligibility criteria to receive pembrolizumab after obtaining stable disease on letrozole + palbociclib; these patients must have been on treatment with letrozole and palbociclib for 6 months with SD per RECIST 1.1; received up to 3 lies of previous therapy including endocrine and/or chemotherapy in advanced setting prior to initiation of letrozole and palbociclib; no grade 3 toxicities except alopecia
No known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib excipients or to endocrine treatments.
Participants who have discontinued prior palbociclib for toxicity, or have needed more than one dose or schedule reduction for toxicity from prior palbociclib therapy; if a participant required a single dose reduction during prior palbociclib therapy and tolerated it well, for example prior dosing at 100 mg qd 3 weeks on 1 week off schedule, than that dose may be selected for this trial
Previous treatment with palbociclib, abemaciclib, ribociclib or other investigational CDK4/6 inhibitors
Palbociclib can be started at week 4, if indicated
Must be candidates to receive endocrine therapy and palbociclib or ribociclib as first-line treatment for their advanced disease. Patients will be considered eligible for study enrollment if they have started on treatment with a standard dose and schedule of palbociclib or ribociclib and endocrine therapy (aromatase inhibitor or fulvestrant) as long as they have not started palbociclib or ribociclib treatment for longer than 4 weeks from time of study enrollment, have sufficient tissue to perform the proposed tissue analysis and must meet all other eligibility criteria. Endocrine therapy can be initiated up to 4 weeks prior to starting palbociclib or ribociclib.