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

NCT ID: NCT03007979

Last Updated: 2024-03-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-15
• Study Completion Date: 2023-03-31

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.

Conditions

Breast Cancer; Breast Carcinoma; Cancer of Breast; Malignant Tumor of Breast

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Palbociclib + letrozole or + fulvestrant

• 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

Group Type: EXPERIMENTAL

Palbociclib

Intervention Type: DRUG

Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule

Letrozole

Intervention Type: DRUG

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.

Fulvestrant

Intervention Type: DRUG

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.

Optional research biopsy

Intervention Type: PROCEDURE

Patients may consent to paired tumor biopsies at baseline and time of progression.

Goserelin

Intervention Type: DRUG

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.

Research blood draw

Intervention Type: PROCEDURE

-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

Circulating tumor cell blood draw

Intervention Type: PROCEDURE

-Baseline, cycle 2 day 1, post 2 or 3 months of therapy (to coincide with first tumor imaging), and progression

Tumor biopsy (optional)

Intervention Type: PROCEDURE

-Baseline and progression

Interventions

Palbociclib

Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule

Intervention Type: DRUG

Letrozole

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.

Intervention Type: DRUG

Fulvestrant

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.

Intervention Type: DRUG

Optional research biopsy

Patients may consent to paired tumor biopsies at baseline and time of progression.

Intervention Type: PROCEDURE

Goserelin

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.

Intervention Type: DRUG

Research blood draw

-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

Intervention Type: PROCEDURE

Circulating tumor cell blood draw

-Baseline, cycle 2 day 1, post 2 or 3 months of therapy (to coincide with first tumor imaging), and progression

Intervention Type: PROCEDURE

Tumor biopsy (optional)

-Baseline and progression

Intervention Type: PROCEDURE

Other Intervention Names

Ibrance; Femara; Faslodex; Zoladex

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cynthia X Ma, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska

Lincoln, Nebraska, United States

Countries

United States

References

Krishnamurthy J, Luo J, Suresh R, Ademuyiwa F, Rigden C, Rearden T, Clifton K, Weilbaecher K, Frith A, Roshal A, Tandra PK, Cherian M, Summa T, Haas B, Thomas S, Hernandez-Aya L, Bergqvist M, Peterson L, Ma CX. A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis. NPJ Breast Cancer. 2022 Mar 21;8(1):35. doi: 10.1038/s41523-022-00399-w.

Reference Type: DERIVED

PMID: 35314693 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.siteman.wustl.edu

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Other Identifiers

201612098

Identifier Type: -

Identifier Source: org_study_id