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

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ClinicalTrials.gov Identifier: NCT03007979
Recruitment Status : Recruiting
First Posted : January 2, 2017
Last Update Posted : May 18, 2018
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Breast Carcinoma Cancer of Breast Malignant Tumor of Breast 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) Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial Assessing the Safety of an Alternative Dosing Schedule of Palbociclib in Metastatic Hormone Receptor Positive Breast Cancer
Actual Study Start Date : June 15, 2017
Estimated Primary Completion Date : July 31, 2019
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
Experimental: 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
Drug: Palbociclib
Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule
Other Name: Ibrance

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.
Other Name: Femara

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.
Other Name: Faslodex

Procedure: Optional research biopsy
Patients may consent to paired tumor biopsies at baseline and time of progression.

Drug: 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.
Other Name: Zoladex

Procedure: 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

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

Procedure: Tumor biopsy (optional)
-Baseline and progression




Primary Outcome Measures :
  1. Rate of grade 3 or higher neutropenia [ Time Frame: Through the first 29 days of treatment ]
    • 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


Secondary Outcome Measures :
  1. Rate of grade 3 or higher neutropenia [ Time Frame: Through 30 day follow-up (estimated to be 25 months) ]
    • 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

  2. Rate of palbociclib dose reduction [ Time Frame: Through the completion of treatment (estimated to be 24 months) ]
    -Percentage of participants who have a palbociclib dose reduction during treatment

  3. Rate of palbociclib dose interruption [ Time Frame: Through the completion of treatment (estimated to be 24 months) ]
    -Percentage of participants who have a palbociclib dose interruption during treatment

  4. Rate of palbociclib discontinuation [ Time Frame: Through the completion of treatment (estimated to be 24 months) ]
    -Percentage of participants who discontinue palbociclib

  5. Adverse event profile of palbociclib [ Time Frame: Through the 30 day follow-up (estimated to be 25 months) ]
    -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.

  6. Progression-free survival (PFS) [ Time Frame: 1 year ]
    • 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).

  7. Overall response rate (complete response + partial response) [ Time Frame: Time of progression (estimated to be 24 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

  8. Clinical benefit rate (complete response + partial response + stable disease) for at least 6 months) [ Time Frame: Time of progression (estimated to be 24 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03007979


Contacts
Contact: Cynthia X Ma, M.D., Ph.D. 314-362-9383 cynthiaxma@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Cynthia X Ma, M.D., Ph.D.    314-362-9383    cynthiaxma@wustl.edu   
Principal Investigator: Cynthia X Ma, M.D., Ph.D.         
Sub-Investigator: Foluso O Ademuyiwa, M.D.         
Sub-Investigator: Ron Bose, M.D., Ph.D.         
Sub-Investigator: Mathew Cherian, M.D.         
Sub-Investigator: Ashley Frith, M.D.         
Sub-Investigator: Leonel Hernandez Aya, M.D.         
Sub-Investigator: Peter Oppelt, M.D.         
Sub-Investigator: Haeseong Park, M.D.         
Sub-Investigator: Caron Rigden, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sub-Investigator: Katherine Weilbaecher, M.D.         
Sub-Investigator: Rebecca Aft, M.D., Ph.D.         
Sub-Investigator: Lindsay Peterson, M.D.         
United States, Nebraska
University of Nebraska Recruiting
Lincoln, Nebraska, United States, 68588
Contact: Jairam Krishnamurthy, M.D.    402-559-1800    jairam.krishnamurthy@unmc.edu   
Principal Investigator: Jairam Krishnamurthy, M.D.         
Sub-Investigator: Kenneth Cowan, M.D.         
Sub-Investigator: Elizabeth Reed, M.D.         
Sub-Investigator: Pavankumar Tandra, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Cynthia X Ma, M.D., Ph.D. Washington University School of Medicine

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03007979     History of Changes
Other Study ID Numbers: 201612098
First Posted: January 2, 2017    Key Record Dates
Last Update Posted: May 18, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Breast Diseases
Breast Neoplasms
Neoplasms
Neoplasms by Site
Skin Diseases
Hormones
Estradiol
Letrozole
Fulvestrant
Palbociclib
Goserelin
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogens
Protein Kinase Inhibitors