Alternative Dosing Schedule of Palbociclib in Metastatic Hormone Receptor Positive Breast Cancer
Condition: Breast Cancer; Breast Carcinoma; Cancer of Breast; Malignant Tumor of Breast
MeSH terms: Breast Neoplasms
Intervention: Palbociclib; Letrozole; Fulvestrant; Optional research biopsy; Goserelin; Research blood draw; Circulating tumor cell blood draw; Tumor biopsy (optional)
Intervention description: Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule; Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle, at a dose of 2.5 mg.; Patients who are receiving fulvestrant will receive it at a dose of 500 mg as two 5 mL intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.; Patients may consent to paired tumor biopsies at baseline and time of progression.; Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- and peri-menopausal women only.; -Blood will be drawn at the following time points for serum, plasma, cfDNA, and germline DNA (only at baseline):
Baseline
C1D15
C2D1
Every 2-3 months thereafter (to coincide with imaging studies)
Time of progression; -Baseline, cycle 2 day 1, post 2 or 3 months of therapy (to coincide with first tumor imaging), and progression; -Baseline and progression
Intervention MeSH terms: Letrozole; Fulvestrant; Palbociclib; Goserelin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The investigators propose to conduct a study to test an alternative dosing schedule of
      palbociclib. With the current three-week on and one week off schedule, a significant number
      of patients develop grade 3 or higher degree of neutropenia and require dose reduction and
      sometimes discontinuation. This potentially compromises the efficacy of the drug. In
      addition, as the half-life of palbociclib is 27 hours, 1 week break with the standard 3 weeks
      on and 1 week off dosing schedule could potentially lead to recovery of Rb phosphorylation
      during the off week. Hence, the investigators propose a 5 days on and 2 days off schedule
      each week without any weeks off drug. Although the cumulative doses each 28-day cycle is
      roughly the same with this schedule compared to conventional dosing, the bone marrow is not
      exposed to the drug continuously for 21 days and rather gets frequent breaks from therapy.
      The investigators hypothesize that the 5 days on and 2 days off schedule is more tolerable
      with less frequent high grade neutropenia and dose interruption/reduction. In addition, this
      schedule also provides for a more continuous drug delivery to the patient since there is not
      a week's break in therapy, which could ultimately prove to be more efficacious.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed metastatic ER+ and/or PR+ and HER2- breast cancer who are
             candidates for palbociclib in combination with either letrozole or fulvestrant per
             treating physician.

          -  Presence of measurable or non-measurable disease by RECIST 1.1 criteria.

          -  One prior systemic therapy in the metastatic setting is allowed, but patients who have
             not had any prior systemic therapies in the metastatic setting are also eligible.

             *Note: patients who were started on endocrine therapy monotherapy as their 1st line or
             2nd line systemic therapy in the metastatic setting for no more than 28 days and
             without clinical progression prior to the initiation of the study drug therapy are
             allowed to enroll on the study as their 1st line or 2nd line therapy, respectively.

          -  At least 18 years of age.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mcl

               -  Platelets ≥ 100,000/mcl

          -  Total bilirubin ≤ institutional upper limit of normal (IULN) or total bilirubin ≤ 3.0
             x IULN with direct bilirubin within normal range in patients with documented Gilbert's
             syndrome

          -  AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN (up to 5 x IULN in patients with liver disease)

          -  Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum
             creatinine levels above institutional normal (calculated by Creatinine Clearance
             Estimate by Cockcroft-Gault Equation)

          -  Pre- or post-menopausal women are allowed. If pre- or peri-menopausal, concurrent
             ovarian suppression for pre- or peri-menopausal women is required.

          -  Women of childbearing potential must agree to use adequate contraception (hormonal or
             barrier method of birth control, abstinence) prior to study entry and for the duration
             of study participation. Should a woman become pregnant or suspect she is pregnant
             while participating in this study, she must inform her treating physician immediately.

          -  Able to swallow and retain oral medication.

          -  Washout of at least 3 weeks from prior chemotherapy or targeted therapy that induces
             myelosuppression and recovery of treatment related adverse events to grade 1 or less,
             with the exception of alopecia, is required prior to the start of palbociclib.

          -  Ability to understand and willingness to sign an Institutional Review Board (IRB)
             approved written informed consent document (or that of legally authorized
             representative, if applicable).

        Exclusion Criteria:

          -  Prior therapy with any CDK inhibitor.

          -  Currently receiving any other investigational agents.

          -  Currently receiving exogenous estrogen replacement (topical vaginal estrogen therapy
             is allowed).

          -  Known brain metastases. Patients with known brain metastases must be excluded from
             this clinical trial because of their poor prognosis which could affect the evaluation
             of all-cycle adverse events.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to palbociclib or other agents used in the study.

          -  Receiving any medications or substances that are potent inhibitors or inducers of
             CYP3A isoenzymes within 7 days prior to registration.

          -  Clinically significant history of liver disease.

          -  A condition that would interfere with enteric absorption.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac
             arrhythmia.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 7 days of study entry.

          -  Known HIV-positivity on combination antiretroviral therapy because of the potential
             for pharmacokinetic interactions with palbociclib. In addition, these patients are at
             increased risk of lethal infections when treated with marrow-suppressive therapy.
             Appropriate studies will be undertaken in patients receiving combination
             antiretroviral therapy when indicated.