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Study Of Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer

Primary Purpose

Inflammatory Breast Cancer (IBC)

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ruxolitinib
Paclitaxel
Doxorubicin
Cyclophosphamide
Sponsored by
Dana-Farber Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Inflammatory Breast Cancer (IBC) focused on measuring Inflammatory Breast Cancer, Breast Cancer, Triple Negative Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participants must have histologically confirmed invasive breast cancer. All histologic subtypes are eligible.
  • Patients must have known ER, PR, and HER2 status defined as triple-negative breast cancer (TNBC), defined as:

    --ER and PR <10% by immunohistochemistry, and HER2-negative ( as per ASCO/CAP guidelines, defined as IHC 0 or 1+, or FISH ratio <2.0 or HER2 copy number <6.0).

  • Patients must have the clinical diagnosis of inflammatory breast cancer, involving an intact breast.
  • Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ruxolitinib in participants <18 years of age, children are excluded from this study.
  • ECOG performance status 0 or 1.
  • Participants must have normal organ and marrow function as defined below:

    • Leukocytes ≥ 3,000/mm3
    • Absolute neutrophil count ≥ 1,500/mm3
    • Platelets ≥ 100,000/mm3
    • Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
    • AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal
    • Creatinine ≤1.5 x institutional upper limit of normal OR creatinine clearance > 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal
  • Patients with evidence of extensive nodal involvement are allowed. Extensive nodal involvement is defined as metastatic disease involving any nodal region outside of the involved breast.
  • Patients with minimal metastatic disease involvement in bone or viscera are allowed. Minimal metastatic disease is defined as: evidence of metastatic involvement as demonstrated by imaging only, not amenable to biopsy confirmation.
  • Both men and women are allowed.
  • The effects of ruxolitinib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry until completion of chemotherapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.
  • LVEF > 50% calculated by echocardiogram (ECHO) or MUGA
  • Patients may have bilateral breast cancer so long as one breast meets criteria for inflammatory breast cancer, and neither breast cancer has received prior therapy

Exclusion Criteria:

  • Participants may not be receiving any other investigational agents.
  • Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib.
  • Participants receiving any medications or substances that are potent inhibitors of CYP3A4, including grapefruit juice are ineligible. Participants receiving fluconazole are also ineligible. (Please refer to Appendix B for the full list of potent inhibitors and washout periods).
  • Chronic corticosteroid use in excess of the equivalent of prednisone 10 mg once daily.
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because paclitaxel, doxorubicin, and cyclophosphamide have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study. These potential risks may also apply to other agents used in this study.
  • Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
  • Known HIV-positive individuals on combination antiretroviral therapy are eligible so long as they meet all other criteria. Known HIV-positive individuals who are not on combination antiretroviral therapy are not eligible because these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • Clinically significant malabsorption syndrome.
  • Patients may not have received paclitaxel, doxorubicin, or cyclophosphamide as anti-neoplastic therapy.
  • Patients with prior radiation to the affected breast.

Sites / Locations

  • Dana-Farber Cancer Institute
  • Mayo Clinic
  • Duke University Medical Center
  • MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Paclitaxel (12weeks)

Ruxolitinib with Paclitaxel (12weeks)

Ruxolitinib and Paclitaxel (12weeks)

Arm Description

Paclitaxel is administered weekly followed by standard Doxorubicin and Dyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively 16 patients will be randomized from the Run-In 7 days of Ruxolitinib The drug will be administered at a pre-determine dosage

Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively 16 patients will be randomized from the Run-In 7 days of Ruxolitinib The drug will be administered at a pre-determine dosage

Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively 32 patients will be randomized from the Run-In 7 days of Ruxolitinib + Paclitaxel The drug will be administered at a pre-determine dosage

Outcomes

Primary Outcome Measures

Assess JAK Inhibition With Ruxolitinib On pStat3+ Expression
Comparison of JAK expression in pretreatment biopsy specimens to post-Ruxolitinib run-in (after 7 days of Ruxolitinib alone or with one dose of weekly paclitaxel) biopsy specimens.

Secondary Outcome Measures

Determine Pathologic Complete Response rate (pCR) after preoperative therapy
pCR defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy.
Correlate effects on pSTAT3+ and STAT3 gene expression with pCR
assess pSTAT level and gene expression on pre-treatment tumor biopsy specimens and correlate expression with pCR
Assess changes in pSTAT3 level and STAT3 gene expression following treatment
assess pSTAT level and gene expression on pre-treatment tumor biopsy
Asses difference in pCR rate following preoperative treatment
pCR defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy.
Determine efficacy defined as Disease-Free Survival (DFS)
Defined as time of surgery until occurrence of recurrence, contralateral cancer, death attributable to any cause, second primary cancer other than breast.
Determine efficacy defined as Time to Treatment Failure (TTF)
Defined as time of treatment initiation until occurrence of recurrence, contralateral cancer, death attributable to any cause, second primary cancer other than breast or occurrence of progressive disease during preoperative therapy or treatment of disease that is not surgically resectable.
Determine efficacy defined as Overall Survival (OS)
Defined as time from surgery until death from any cause or from treatment initiation until death from any cause
Assess Residual Cancer Burden (RCB) differences after preoperative therapy
Difference between combination ruxolitinib with paclitaxel or paclitaxel alone followed by doxorubicin/cyclophosphamide; RCB defined by Symmans et al
Describe changes in IL-6 plasma levels during treatment
IL-6 levels will be recorded in the case report forms.
Describe changes in CRP plasma levels during treatment
CRP levels will be recorded in the case report forms.
Assess distribution of CD44+/CD24- stem cell population in tumor pre- and post-exposure to ruxolotinib
Performed on breast biopsies and residual disease in mastectomy specimens

Full Information

First Posted
August 9, 2016
Last Updated
September 21, 2023
Sponsor
Dana-Farber Cancer Institute
Collaborators
Incyte Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT02876302
Brief Title
Study Of Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer
Official Title
Phase II Study Of Combination Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 26, 2017 (Actual)
Primary Completion Date
December 31, 2022 (Actual)
Study Completion Date
February 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
Incyte Corporation

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This research study is studying Ruxolitinib as possible treatment for Inflammatory Breast Cancer (IBC). The Following drugs will be use in combination with Ruxolinitinib. Paclitaxel (also called Taxol) Doxorubicin also called Adriamycin Cyclophosphamide, also called Cytoxan
Detailed Description
This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (U.S. Food and Drug Administration) has not approved Ruxolitinib for Inflammatory Breast Cancer (IBC), but is has been approved for other uses. Ruxolitinib is a newly discovered drug that has been shown to block a pathway (called the IL6/JAK/Stat pathway) that may be important in cancer, including triple negative inflammatory breast cancer. Ruxolitinib brings proteins groups together, which can result in gene (DNA) changes. These DNA changes may stop cancer cells from growing. Paclitaxel (also called Taxol), Doxorubicin and Cyclophosphamide (also called Adriamycin and Cytoxan, ("AC")) are drugs FDA approved for breast cancer patients. They have been shown to result in death of cancer cells when given as preoperative treatment of women with inflammatory breast cancer (IBC). Laboratory studies have shown that Ruxolitinib may make Paclitaxel more effective. In this research study, the investigators are evaluating Ruxolitinib in combination with Paclitaxel followed by the standard chemotherapy, AC. Researchers will also evaluate how the IL6/JAK/Stat pathway is affected by this combination of drugs by studying biopsies and surgical specimens.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Inflammatory Breast Cancer (IBC)
Keywords
Inflammatory Breast Cancer, Breast Cancer, Triple Negative Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Paclitaxel (12weeks)
Arm Type
Experimental
Arm Description
Paclitaxel is administered weekly followed by standard Doxorubicin and Dyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively 16 patients will be randomized from the Run-In 7 days of Ruxolitinib The drug will be administered at a pre-determine dosage
Arm Title
Ruxolitinib with Paclitaxel (12weeks)
Arm Type
Experimental
Arm Description
Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively 16 patients will be randomized from the Run-In 7 days of Ruxolitinib The drug will be administered at a pre-determine dosage
Arm Title
Ruxolitinib and Paclitaxel (12weeks)
Arm Type
Experimental
Arm Description
Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively 32 patients will be randomized from the Run-In 7 days of Ruxolitinib + Paclitaxel The drug will be administered at a pre-determine dosage
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
Jakafi
Intervention Description
15 or 20 mg, twice daily by mouth. The run-in part of ruxolitinib lasts 7 days; The treatment of ruxolitinib part lasts 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Other Intervention Name(s)
Taxol
Intervention Description
80 mg/m2, IV (in the vein) weekly for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriamycin
Intervention Description
60 mg/m2, IV (in the vein) every 14 days for 4 doses.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
600 mg/m2, IV (in the vein) every 14 days for 4 doses.
Primary Outcome Measure Information:
Title
Assess JAK Inhibition With Ruxolitinib On pStat3+ Expression
Description
Comparison of JAK expression in pretreatment biopsy specimens to post-Ruxolitinib run-in (after 7 days of Ruxolitinib alone or with one dose of weekly paclitaxel) biopsy specimens.
Time Frame
7 days
Secondary Outcome Measure Information:
Title
Determine Pathologic Complete Response rate (pCR) after preoperative therapy
Description
pCR defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy.
Time Frame
28 weeks
Title
Correlate effects on pSTAT3+ and STAT3 gene expression with pCR
Description
assess pSTAT level and gene expression on pre-treatment tumor biopsy specimens and correlate expression with pCR
Time Frame
28 weeks
Title
Assess changes in pSTAT3 level and STAT3 gene expression following treatment
Description
assess pSTAT level and gene expression on pre-treatment tumor biopsy
Time Frame
28 weeks
Title
Asses difference in pCR rate following preoperative treatment
Description
pCR defined as absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy.
Time Frame
28 weeks
Title
Determine efficacy defined as Disease-Free Survival (DFS)
Description
Defined as time of surgery until occurrence of recurrence, contralateral cancer, death attributable to any cause, second primary cancer other than breast.
Time Frame
5 years
Title
Determine efficacy defined as Time to Treatment Failure (TTF)
Description
Defined as time of treatment initiation until occurrence of recurrence, contralateral cancer, death attributable to any cause, second primary cancer other than breast or occurrence of progressive disease during preoperative therapy or treatment of disease that is not surgically resectable.
Time Frame
5 years
Title
Determine efficacy defined as Overall Survival (OS)
Description
Defined as time from surgery until death from any cause or from treatment initiation until death from any cause
Time Frame
5 years
Title
Assess Residual Cancer Burden (RCB) differences after preoperative therapy
Description
Difference between combination ruxolitinib with paclitaxel or paclitaxel alone followed by doxorubicin/cyclophosphamide; RCB defined by Symmans et al
Time Frame
5 years
Title
Describe changes in IL-6 plasma levels during treatment
Description
IL-6 levels will be recorded in the case report forms.
Time Frame
5 years
Title
Describe changes in CRP plasma levels during treatment
Description
CRP levels will be recorded in the case report forms.
Time Frame
5 years
Title
Assess distribution of CD44+/CD24- stem cell population in tumor pre- and post-exposure to ruxolotinib
Description
Performed on breast biopsies and residual disease in mastectomy specimens
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must have histologically confirmed invasive breast cancer. All histologic subtypes are eligible. Patients must have known ER, PR, and HER2 status defined as triple-negative breast cancer (TNBC), defined as: --ER and PR <10% by immunohistochemistry, and HER2-negative ( as per ASCO/CAP guidelines, defined as IHC 0 or 1+, or FISH ratio <2.0 or HER2 copy number <6.0). Patients must have the clinical diagnosis of inflammatory breast cancer, involving an intact breast. Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ruxolitinib in participants <18 years of age, children are excluded from this study. ECOG performance status 0 or 1. Participants must have normal organ and marrow function as defined below: Leukocytes ≥ 3,000/mm3 Absolute neutrophil count ≥ 1,500/mm3 Platelets ≥ 100,000/mm3 Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal Creatinine ≤1.5 x institutional upper limit of normal OR creatinine clearance > 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal Patients with evidence of extensive nodal involvement are allowed. Extensive nodal involvement is defined as metastatic disease involving any nodal region outside of the involved breast. Patients with minimal metastatic disease involvement in bone or viscera are allowed. Minimal metastatic disease is defined as: evidence of metastatic involvement as demonstrated by imaging only, not amenable to biopsy confirmation. Both men and women are allowed. The effects of ruxolitinib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry until completion of chemotherapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document. LVEF > 50% calculated by echocardiogram (ECHO) or MUGA Patients may have bilateral breast cancer so long as one breast meets criteria for inflammatory breast cancer, and neither breast cancer has received prior therapy Exclusion Criteria: Participants may not be receiving any other investigational agents. Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib. Participants receiving any medications or substances that are potent inhibitors of CYP3A4, including grapefruit juice are ineligible. Participants receiving fluconazole are also ineligible. (Please refer to Appendix B for the full list of potent inhibitors and washout periods). Chronic corticosteroid use in excess of the equivalent of prednisone 10 mg once daily. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because paclitaxel, doxorubicin, and cyclophosphamide have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study. These potential risks may also apply to other agents used in this study. Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Known HIV-positive individuals on combination antiretroviral therapy are eligible so long as they meet all other criteria. Known HIV-positive individuals who are not on combination antiretroviral therapy are not eligible because these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. Clinically significant malabsorption syndrome. Patients may not have received paclitaxel, doxorubicin, or cyclophosphamide as anti-neoplastic therapy. Patients with prior radiation to the affected breast.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Filipa Lynce, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Study Of Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer

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