Ruxolitinib in Patients With Breast Cancer

Ruxolitinib is a drug which blocks the Janus tyrosine Kinase (JAK) signaling pathway. It is thought that this pathway might be important in certain types of breast cancer, and that blocking this pathway might lead to anti-cancer effects. This study is testing the effects of ruxolitinib in patients with breast cancer.

Objectives: Primary The primary objective of this two-stage, phase II study is to estimate the objective response rate to ruxolitinib in patients with metastatic or unresectable locally advanced breast cancer which is pStat3+ and which has progressed on at least one line of chemotherapy for advanced disease, and/or has recurred within 12 months of completion of neoadjuvant/adjuvant chemotherapy. Secondary To describe the toxicity profile To evaluate clinical benefit rate (CR + PR + SD >/= 24 weeks) To estimate progression-free and overall survival Exploratory To explore whether baseline hs-CRP level higher than the group median is associated with objective response To explore whether baseline IL-6 level higher than the group median is associated with objective response To describe hs-CRP level over time, and to describe the proportion of patients with a) hs-CRP > 3mg/L at baseline, on treatment, and at time of progression, and b) hs-CRP > 1mg/L at baseline, on treatment, and at time of progression To describe IL-6 level over time, and to describe the proportion of patients with IL-6 level above the upper limit of normal at baseline, on treatment, and at time of progression To describe pStat3 status by IHC in baseline metastatic biopsies To describe pStat3 status by IHC in on-study biopsies To describe pStat3 status by IHC in the time of progression biopsy samples To characterize archival and metastatic biopsy samples using triple immunofluorescence for CD44, CD24, and pStat3 To characterize archival and metastatic biopsy samples using a previously characterized pStat3 gene signature To characterize circulating tumor cells (CTCs) for CD44, CD24, and pStat3 at baseline and time of progression

Patients received Ruxolitinib 25 mg twice daily for up to 12 cycles (cycle duration=28 days) until evidence of disease progression or unacceptable toxicity. Patients enrolled sequentially into two possible cohorts based on pStat3+ expression score by central testing: Cohort A - moderate to high positive status defined as a score of >/=5 by central testing or Cohort B - low positive status defined as a score of 3-4. Each cohort was evaluated with a 2 stage design. Cohort B only opened if 2 objective responses were observed in 1st stage Cohort A patients (n=21).

Patients received Ruxolitinib 25 mg twice daily for up to 12 cycles (cycle duration=28 days) until evidence of disease progression or unacceptable toxicity. Patients enrolled sequentially into two possible cohorts based on pStat3+ expression score by central testing: Cohort A - moderate to high positive status defined as a score of >/=5 by central testing or Cohort B - low positive status defined as a score of 3-4. Each cohort was evaluated with a 2 stage design. Cohort B only opened if 2 objective responses were observed in 1st stage Cohort A patients (n=21).

The objective response rate (ORR) was defined as achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity up to 12 cycles. Treatment duration was a median of 2 cycles range (1-5).

Clinical benefit rate (CBR) was defined as achieving complete response (CR), partial response (PR), or stable disease (SD) for 24 weeks or longer based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. 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. SD needed to be a minimum 24 weeks in duration.

Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity up to 12 cycles. Treatment duration was a median of 2 cycles range (1-5).

Overall survival is defined as the time from study entry to death or date last known alive and estimated using Kaplan-Meier (KM) methods.

In long-term follow-up, patients were followed for survival every 4 months for up to 2 years. Median follow-up in this study cohort was 4.5 months (range 0.6-21.9).

Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or equivocal progression of non-target lesions.

Disease was evaluated radiologically every 8 weeks on treatment through 12 cycles and in long-term follow-up every 4 months for up to 2 years. Median follow-up in this study cohort was 4.5 months (range 0.6-21.9).

Inclusion Criteria: Histologically or cytologically confirmed invasive breast cancer Must have known ER, PR and HER2 status Either, Triple Negative Metastatic Breast Cancer or Inflammatory Breast Cancer with any ER, PR HER2 status Availability of archival tissue specimen suitable for pStat3 testing Life expectancy of greater than 3 months Measurable disease by RECIST At least one prior chemotherapy regimen for treatment of metastatic breast cancer and/or recurrence within 12 months of completion of neoadjuvant/adjuvant chemotherapy or For patients with inflammatory breast cancer but no distant metastases, progression through standard neoadjuvant chemotherapy is required Exclusion Criteria: Pregnant or breastfeeding Active brain metastases History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib Clinically significant malabsorption syndrome Concurrent use of medications/substances that are strong inhibitors of CY3A4 No uncontrolled intercurrent illness