Ruxolitinib in Patients With Breast Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01562873
• Collaborator: (none)
• Enrollment: 21
• Locations: 2
• Arms: 2
• Duration (Months): 48
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Ruxolitinib	Phase 2

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Ruxolitinib (INCB018424) in Patients With PSTAT3+ Breast Cancer
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ruxolitinib-Cohort A 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).	Drug: Ruxolitinib; Other Names: INCB018424 Jakafi
Experimental: Ruxolitinib-Cohort B 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).	Drug: Ruxolitinib; Other Names: INCB018424 Jakafi

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [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).]

   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.

Secondary Outcome Measures

1. Clinical Benefit Rate [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.

2. Overall Survival [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).]

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

3. Progression-Free Survival [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).]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01562873
• Other Study ID Numbers: 12-024
• First Posted: Mar 26, 2012
• Last Update Posted: Feb 23, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute: pSTAT3+
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	Patients enrolled from October 2012 through June 2014.
Pre-assignment Detail	Patients must have had sufficient archival specimen for central pStat3 testing to be eligible.

Arm/Group Title	Ruxolitinib-Cohort A	Ruxolitinib-Cohort B
Arm/Group Description	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).
Period Title: Overall Study
STARTED	21	0
COMPLETED	0	0
NOT COMPLETED	21	0

Baseline Characteristics

Arm/Group Title	Ruxolitinib-Cohort A
Arm/Group Description	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).
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51
Gender (Count of Participants)
Female	21 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%
pStat3 Positive Status (participants) [Number]
moderate to high positive	21 100%
low positive	0 0%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	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.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised all enrolled patients.

Arm/Group Title	Ruxolitinib-Cohort A
Arm/Group Description	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).
Measure Participants	21
Number (90% Confidence Interval) [proportion of patients]	0.0

2. Secondary Outcome

Title	Clinical Benefit Rate
Description	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.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised all enrolled patients.

Arm/Group Title	Ruxolitinib-Cohort A
Arm/Group Description	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).
Measure Participants	21
Number (90% Confidence Interval) [proportion of patients]	0.0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised all enrolled patients.

Arm/Group Title	Ruxolitinib-Cohort A
Arm/Group Description	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).
Measure Participants	21
Median (95% Confidence Interval) [months]	4.5

4. Secondary Outcome

Title	Progression-Free Survival
Description	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.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised all enrolled patients.

Arm/Group Title	Ruxolitinib-Cohort A
Arm/Group Description	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).
Measure Participants	21
Median (95% Confidence Interval) [months]	1.2

Adverse Events

Time Frame	Assessed each cycle throughout the 12 cycles of treatment and at time of off-treatment.
Adverse Event Reporting Description	Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. Other AEs were defined as events with treatment attribution of possible, probable or definite and grades 1 or 2 per CTCAEv4.
Arm/Group Title	Ruxolitinib-Cohort A
Arm/Group Description	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).
All Cause Mortality
	Ruxolitinib-Cohort A
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ruxolitinib-Cohort A
	Affected / at Risk (%)	# Events
Total	6/21 (28.6%)
Blood and lymphatic system disorders
Anemia	2/21 (9.5%)
Investigations
Aspartate aminotransferase increased	2/21 (9.5%)
GGT increased	1/21 (4.8%)
Neutrophil count decreased	2/21 (9.5%)
Other (Not Including Serious) Adverse Events
	Ruxolitinib-Cohort A
	Affected / at Risk (%)	# Events
Total	14/21 (66.7%)
Blood and lymphatic system disorders
BL101	1/5 (20%)
Gastrointestinal disorders
GI108	1/5 (20%)
GI123	1/5 (20%)
GI179	1/5 (20%)
GI216	2/5 (40%)
General disorders
CN101	1/5 (20%)
CN105	1/5 (20%)
CN108	3/5 (60%)
CN109	1/5 (20%)
Infections and infestations
IN999	1/5 (20%)
Investigations
IV129	1/5 (20%)
IV137	1/5 (20%)
Musculoskeletal and connective tissue disorders
MU112	1/5 (20%)
MU999	1/5 (20%)
Nervous system disorders
NE145	1/5 (20%)
Respiratory, thoracic and mediastinal disorders
PU113	1/5 (20%)
PU114	1/5 (20%)
Skin and subcutaneous tissue disorders
DE999	1/5 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.