Ruxolitinib W/ Preop Chemo For Triple Negative Inflammatory Brca

NCT02041429 | Completed Phase 1 Results DMC

• 1 other identifier: 13-494
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent Breast Cancer; Metastatic Breast Cancer

Keywords

Recurrent Breast Cancer; Advanced Breast Cancer; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Best Response [Phase I]

  Disease was evaluated radiologically every 2 cycles/6 weeks on treatment. Treatment duration was up to 9 months.

• All-Cause Neutropenia

  Measured while on treatment and up to 30 days after coming off treatment. Up to 10 months

• C-Reactive Protein Change From Baseline

  From day 1 of cycle 1 to day 1 of cycle 3 (up to 8 weeks)

• IL-6 Change From Baseline

  From day 1 of cycle 1 to day 1 of cycle 3 (up to 8 weeks)

Study Arms (4)

Phase I Dose Level 0: Paclitaxel + Ruxolitiniib 10 mg

EXPERIMENTAL

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; Drug: Paclitaxel

Phase I Dose Level 1: Paclitaxel + Ruxolitiniib 15 mg

EXPERIMENTAL

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; Drug: Paclitaxel

Phase I Dose Level 2: Paclitaxel + Ruxolitiniib 20 mg

EXPERIMENTAL

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; Drug: Paclitaxel

Phase I Dose Level 3: Paclitaxel + Ruxolitiniib 25 mg

EXPERIMENTAL

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; Drug: Paclitaxel

Interventions

Ruxolitinib DRUG

Also known as: (INCB18424)

Phase I Dose Level 0: Paclitaxel + Ruxolitiniib 10 mg; Phase I Dose Level 1: Paclitaxel + Ruxolitiniib 15 mg; Phase I Dose Level 2: Paclitaxel + Ruxolitiniib 20 mg; Phase I Dose Level 3: Paclitaxel + Ruxolitiniib 25 mg

Paclitaxel DRUG

Also known as: Taxol

Phase I Dose Level 0: Paclitaxel + Ruxolitiniib 10 mg; Phase I Dose Level 1: Paclitaxel + Ruxolitiniib 15 mg; Phase I Dose Level 2: Paclitaxel + Ruxolitiniib 20 mg; Phase I Dose Level 3: Paclitaxel + Ruxolitiniib 25 mg

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Incyte Corporation: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Lynce F, Williams JT, Regan MM, Bunnell CA, Freedman RA, Tolaney SM, Chen WY, Mayer EL, Partridge AH, Winer EP, Overmoyer B. Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol. 2021 May;87(5):673-679. doi: 10.1007/s00280-021-04245-x. Epub 2021 Feb 14.

  PMID: 33585999 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

ruxolitinib; Paclitaxel

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Results Point of Contact

• Title: Beth Overmoyer, MD
• Organization: Dana-Farber Cancer Institute

Beth_Overmoyer@DFCI.HARVARD.EDU

617.632.380

Study Officials

• Beth Overmoyer, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The multi-arm nature of this study is due to the dose-escalation design.

Study Record Dates

• First Submitted: January 11, 2014
• First Posted: January 22, 2014
• Study Start: February 1, 2014
• Primary Completion: May 1, 2016
• Study Completion: January 1, 2021
• Last Updated: April 21, 2021
• Results First Posted: April 21, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)