Ruxolitinib W/ Preop Chemo For Triple Negative Inflammatory Brca

Study Overview
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Brief Summary
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This phase I/II research study is evaluating a combination of drugs called paclitaxel and ruxolitinib as a possible treatment for inflammatory breast cancer. 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 breast cancer. Blocking this pathway may stop cancer cells from growing. Ruxolitinib has been approved by the FDA for patients with bone marrow disease, and this is the first study using this drug in combination with paclitaxel for breast cancer. Paclitaxel (also called Taxol) is an FDA drug approved for breast cancer patients. Paclitaxel works by blocking the small microtubules inside cancer cells and preventing cell growth. Information from laboratory experiments suggests that ruxolitinib might also have effects on breast cancer.These studies have shown that ruxolitinib may make paclitaxel more effective.

Detailed Description
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This study has two phases. The objective of Phase I to find the maximum dose (MTD) of Ruxolitinib when combined with standard dose of paclitaxel given weekly for advanced or metastatic breast cancer. Three participants will be entered at a dose ruxolitinib equaling 10 mg orally twice daily with weekly paclitaxel. If no dose-limiting toxicity is seen after 6 weeks of treatment (two cycles), then the dose of ruxolitinib will be escalated using a standard 3+3 design, until 2 participants experience dose limiting toxicity (DLT). The dose below the DLT is designated the MTD and this dose of ruxolitinib will be used in the phase II preoperative study for triple negative IBC. During Cycle 1 the participant will come into clinic every week. At each visit, the participant will have a physical exam and will be asked questions regarding general health and specific questions about any problems that the participant might be having with any medications. About 2-3 additional tablespoons of blood will be taken before the participant's begins ruxolitinib, on Cycle 2 Day 1, Cycle 3 Day 1, and at the end of the study for research blood tests. Because these tests are being performed for research, and their clinical usefulness is unknown, the participant will not receive the results of these tests. The investigator will assess the participant's tumor by CT scans or MRI every 2 cycles. In addition, if the participant has tumors that are visible or can be palpated (felt), then they will be measured by the participant's study doctor in the clinic. If the participant has had a history of cancer in the bones or suspected cancer in the bones, then a bone scan will be performed before the participant can begin ruxolitinib. The bone scan may be repeated every 2 cycles and at the end of the study if the participant study doctor believes it is clinically needed. Otherwise, it does not need to be repeated. Photographs may be taken of the participant's tumor to assess the tumor response to the treatment. The phase II period of the study will treat triple negative inflammatory breast cancer participants with ruxolitinib combined with 12 weeks of weekly paclitaxel followed by standard care Doxorubicin and Cyclophosphamide (AC) chemotherapy, eligible participants will proceed to surgical mastectomy followed by radiation. The phase II study will begin once the phase I study has been completed. During the phase II study, participants will have a research biopsy of the breast followed by one week of ruxolitinib given twice daily. A second research biopsy of the breast is then performed and the participants will then receive combination ruxolitinib (at the MTD dose defined in the phase I study) and standard dose paclitaxel for 12 weeks. Participants will be seen weekly during treatment. One week after completing the combination therapy, participants will receive standard dose doxorubicin and cyclophosphamide (AC) every 2 weeks for 4 cycles. We will evaluate the effect of JAK inhibition by ruxolitinib on the tumor by comparing pSTAT3+ expression of the pre-treatment research biopsy with the pSTAT3+ expression on the second research biopsy performed after one week of ruxolitinib. Participants who have disease regression following 12 weeks of ruxolitinib and paclitaxel followed by AC chemotherapy will undergo mastectomy, and the amount of residual breast cancer will be assessed. We will correlate the degree of residual cancer in the mastectomy with the amount of pSTAT3+ expression seen in the research biopsies. We will be checking standard blood tests, IL-6 and CRP levels throughout the treatment to see if the levels change in response to ruxolitinib treatment. This may be an easier method of determining treatment efficacy. Standard radiation therapy will be given following mastectomy.

Official Title
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Phase II Study of Combination Ruxolitinib (INCB018242) With Preoperative Chemotherapy for Triple Negative Inflammatory Breast Cancer Following Completion of a Phase I Combination Study in Recurrent/Metastatic Breast Cancer

Conditions
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Recurrent Breast Cancer, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I Participants must meet the following criteria on screening examination to be eligible to participate in the study: Participants must have histologically confirmed breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. Patients may not have received > 2 prior chemotherapies for advanced disease. Either measurable or evaluable disease is allowed. 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. Life expectancy of greater than 3 months. ECOG performance status ≤ 2 (see Appendix A). Participants must have normal organ and marrow function as defined below: Leukocytes ≥3,000/mcL Absolute neutrophil count ≥1,500/mcL Platelets ≥100,000/mcL Total bilirubin within normal institutional limits AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal Creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels about institutional normal 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 and for the duration of study participation. 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. Exclusion Criteria: Phase I Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study. Participants may not be receiving any other study agents within 2 weeks of initiating treatment. Participants with untreated or uncontrolled brain metastases are excluded from this clinical trial. Patients with treated and stable (> 4 weeks) brain metastasis are allowed. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib. Participants receiving any medications or substances that are strong inhibitors of CYP3A4 are ineligible. (Please refer to Appendix B for list 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 ruxolitinib is a JAK inhibitor with 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 ruxolitinib, breastfeeding should be discontinued if the mother is treated with ruxolitinib. 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. Clinically significant malabsorption syndrome. Prior chemotherapy or radiation administered within 2 weeks from initiating study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: The multi-arm nature of this study is due to the dose-escalation design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Level 0: Paclitaxel + Ruxolitiniib 10 mg<br>Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 10 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 10 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. | Drug: Ruxolitinib<br> <br> * Other names: (INCB18424);Drug: Paclitaxel<br> <br> * Other names: Taxol;|
| Experimental: Phase I Dose Level 1: Paclitaxel + Ruxolitiniib 15 mg<br>Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 15 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 15 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. | Drug: Ruxolitinib<br> <br> * Other names: (INCB18424);Drug: Paclitaxel<br> <br> * Other names: Taxol;|
| Experimental: Phase I Dose Level 2: Paclitaxel + Ruxolitiniib 20 mg<br>Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 20 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 20 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. | Drug: Ruxolitinib<br> <br> * Other names: (INCB18424);Drug: Paclitaxel<br> <br> * Other names: Taxol;|
| Experimental: Phase I Dose Level 3: Paclitaxel + Ruxolitiniib 25 mg<br>Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 25 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 20 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. | Drug: Ruxolitinib<br> <br> * Other names: (INCB18424);Drug: Paclitaxel<br> <br> * Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ruxolitinib Maximum Tolerated Dose (MTD) [Phase I] | Ruxolitinib MTD in combination with paclitaxel 80 mg/m2 intravenously (IV) weekly is determined by the number of patients who have dose limiting toxicity (DLT). See DLT primary outcome measure for definition If a DLT was observed in 0 of 3 patients in a cohort, then 3 patients were enrolled to the next cohort using a 5mg higher dose of ruxolitinib. If a DLT was observed in 1 of 3 patients in a cohort, then 3 additional patients were added, and then if no further DLTs were observed, 3 patients were enrolled to the next cohort using a 5mg higher dose of ruxolitinib. The MTD is identified as the level BELOW the cohort where DLT occurred in less than one third of patients within the cohort. If no DLT's are observed, the MTD is not reached. | Participants were assessed prior to each dose of paclitaxel with ruxolitinib; The observation period for MTD evaluation was the first 2 cycles of treatment. (Up to 8 weeks). | 
| Number of Participants With Dose Limiting Toxicity (DLT) [Phase I] | DLT: (a) grade >2 non-hematologic, non-hepatic, organ toxicity not due to disease progression or another clearly identified cause except: alopecia of any grade; Grade 3 nausea, vomiting or diarrhea and grade 3 fasting hyperglycemia that resolves to grade<2 within 3 days and 7 days, respectively, with our without optimal medical management; and grade 3 fasting hyperglycemia within 3 days of glucocorticoid use; (b) grade >3 thrombocytopenia lasting more than 24 hours or associated with clinically significant bleeding; (c) grade >3 neutropenia lasting >4 days or accompanied with fever; (d) grade>3 anemia; grade>2 total bilirubin, aspartate and alanine aminotransaminase (AST and ALT), or alkaline phosphatase (ALP) lasting > 72 hours except: with baseline grade 2 as a result of liver metastases then levels (ALP, AST, ALT) >10x upper limit of normal is DLT; (e) delay in ability to administer paclitaxel more than 2 weeks due to toxicity. | Participants were assessed prior to each dose of paclitaxel with ruxolitinib; The observation period for DLT evaluation was the first 2 cycles of treatment. (Up to 8 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response [Phase I] | Best Response on treatment was measured according Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. For target lesions, complete response (CR) is complete disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Progressive disease (PD) is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria. CR and PR required confirmation at 4 weeks (not less than 28 days). | Disease was evaluated radiologically every 2 cycles/6 weeks on treatment. Treatment duration was up to 9 months. | 
| All-Cause Neutropenia | Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All-grade neutropenia, a neutrophil deficiency, is determined using established methods. | Measured while on treatment and up to 30 days after coming off treatment. Up to 10 months | 
| C-Reactive Protein Change From Baseline | C-Reactive Protein biomarkers evaluated using established methods. Change in level after 2 cycles of therapy from baseline was measure. | From day 1 of cycle 1 to day 1 of cycle 3 (up to 8 weeks) | 
| IL-6 Change From Baseline | IL-6 biomarkers evaluated using established methods. Change in levels after 2 cycles of therapy from baseline was measure. | From day 1 of cycle 1 to day 1 of cycle 3 (up to 8 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent Breast Cancer, Advanced Breast Cancer, Metastatic Breast Cancer