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

NCT03007979 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 201612098
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 2

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Rate of Grade 3 or Higher Neutropenia

  Through 30 day follow-up (estimated to be 25 months)

• Rate of Palbociclib Dose Reduction

  Through the completion of treatment (estimated to be 24 months)

• Rate of Palbociclib Dose Interruption

  Through the completion of treatment (estimated to be 24 months)

• Rate of Palbociclib Discontinuation

  Through the completion of treatment (estimated to be 24 months)

• Adverse Event Profile of Palbociclib

  Through the 30 day follow-up (estimated to be 25 months)

Study Arms (1)

Palbociclib + letrozole or + fulvestrant

EXPERIMENTAL

* 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; Drug: Letrozole; Drug: Fulvestrant; Procedure: Optional research biopsy; Drug: Goserelin; Procedure: Research blood draw; Procedure: Circulating tumor cell blood draw; Procedure: Tumor biopsy (optional)

Interventions

Palbociclib DRUG

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

Also known as: Ibrance

Palbociclib + letrozole or + fulvestrant

Letrozole 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.

Also known as: Femara

Palbociclib + letrozole or + fulvestrant

Fulvestrant 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.

Also known as: Faslodex

Palbociclib + letrozole or + fulvestrant

Optional research biopsy PROCEDURE

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

Palbociclib + letrozole or + fulvestrant

Goserelin 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.

Also known as: Zoladex

Palbociclib + letrozole or + fulvestrant

Research blood draw 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

Palbociclib + letrozole or + fulvestrant

Circulating tumor cell blood draw PROCEDURE

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

Palbociclib + letrozole or + fulvestrant

Tumor biopsy (optional) PROCEDURE

-Baseline and progression

Palbociclib + letrozole or + fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Pfizer: collaborator

Study Sites (2)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University of Nebraska

Lincoln, Nebraska, 68588, United States

Location

Related Publications (1)

• 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.

  PMID: 35314693 DERIVED

Related Links

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

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib; Letrozole; Fulvestrant; Goserelin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Results Point of Contact

• Title: Cynthia X. Ma, M.D., Ph.D.
• Organization: Washington University School of Medicine

cynthiaxma@wustl.edu

314-362-9383

Study Officials

• Cynthia X Ma, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2016
• First Posted: January 2, 2017
• Study Start: June 15, 2017
• Primary Completion: March 13, 2020
• Study Completion: March 31, 2023
• Last Updated: March 20, 2024
• Results First Posted: March 15, 2021

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)