Alternative Dosing Schedule of Palbociclib in Metastatic Hormone Receptor Positive Breast Cancer

Study Overview
=================
Brief 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.

Official Title
-----------------
A Phase II Clinical Trial Assessing the Safety of an Alternative Dosing Schedule of Palbociclib in Metastatic Hormone Receptor Positive Breast Cancer

Conditions
-----------------
Breast Cancer, Breast Carcinoma, Cancer of Breast, Malignant Tumor of Breast

Intervention / Treatment
-----------------
* Drug: Palbociclib
* Drug: Letrozole
* Drug: Fulvestrant
* Procedure: Optional research biopsy
* Drug: Goserelin
* Procedure: Research blood draw
* Procedure: Circulating tumor cell blood draw
* Procedure: Tumor biopsy (optional)


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib + letrozole or + fulvestrant<br>Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle). Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle. Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter. 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- or peri-menopausal women only. Optional research biopsy at baseline and progression Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression | Drug: Palbociclib<br>* Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule<br>* Other names: Ibrance;Drug: Letrozole<br>* 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.<br>* Other names: Femara;Drug: Fulvestrant<br>* 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.<br>* Other names: Faslodex;Procedure: Optional research biopsy<br>* Patients may consent to paired tumor biopsies at baseline and time of progression.<br>Drug: Goserelin<br>* 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.<br>* Other names: Zoladex;Procedure: Research blood draw<br>* -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<br>Procedure: Circulating tumor cell blood draw<br>* -Baseline, cycle 2 day 1, post 2 or 3 months of therapy (to coincide with first tumor imaging), and progression<br>Procedure: Tumor biopsy (optional)<br>* -Baseline and progression<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Grade 3 or Higher Neutropenia | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. Grade 3 neutropenia: <1000-500/mm^3; <1.0-0.5 x 10e9/L Grade 4 neutropenia: <500/mm^3; <0.5 x 10e9/L | Through the first 29 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Grade 3 or Higher Neutropenia | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. Grade 3 neutropenia: <1000-500/mm^3; <1.0-0.5 x 10e9/L Grade 4 neutropenia: <500/mm^3; <0.5 x 10e9/L | Through 30 day follow-up (estimated to be 25 months) | 
| Rate of Palbociclib Dose Reduction | -Percentage of participants who have a palbociclib dose reduction during treatment | Through the completion of treatment (estimated to be 24 months) | 
| Rate of Palbociclib Dose Interruption | -Percentage of participants who have a palbociclib dose interruption during treatment | Through the completion of treatment (estimated to be 24 months) | 
| Rate of Palbociclib Discontinuation | -Percentage of participants who discontinue palbociclib | Through the completion of treatment (estimated to be 24 months) | 
| Adverse Event Profile of Palbociclib | -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. | Through the 30 day follow-up (estimated to be 25 months) | 
| Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | 1 year | 
| Overall Response Rate (Complete Response + Partial Response) | Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters | Time of progression (estimated to be 24 months) | 
| Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease) for at Least 6 Months) | Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Time of progression (estimated to be 24 months) |