Window of Opportunity Trial of Dasatinib in Operable Triple Negative Breast Cancers With nEGFR

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02720185
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 5
• Locations: 2
• Arm: 1
• Actual Duration (Months): 57.2
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Primary Objective:

To determine if dasatinib, an inhibitor of the Src family kinases, can prevent the nuclear translocation of the epidermal growth factor receptor (EGFR) in Stage I-III, nuclear EGFR positive, triple negative breast cancers (TNBC).

Secondary Objectives:

1. To examine the safety and tolerability of dasatinib in patients with operable TNBC

2. To explore potential intracellular mechanisms which impact dasatinib effect on cellular localization of EGFR in operable TNBC.

3. To examine the pathologic complete response (pCR) rates to standard neoadjuvant chemotherapy in nEGFR+ TNBC

4. To examine breast cancer recurrence rates and patterns of metastatic recurrent in nEGFR+ TNBC

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms; Triple Negative Breast Neoplasms	Drug: Dasatinib; Procedure: Conventional Surgery; Other: Laboratory Biomarker Analysis	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Window of Opportunity Study of Dasatinib in Operable Triple Negative Breast Cancers With Nuclear Epidermal Growth Factor Receptor (nEGFR)
• Actual Study Start Date: May 3, 2017
• Actual Primary Completion Date: Jul 2, 2020
• Actual Study Completion Date: Feb 8, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dasatinib 100mg Dasatinib 100mg for 7-10 days until day prior to surgery	Drug: Dasatinib; 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group); Other Names: 732517 863127-77-9 BMS-354825 Sprycel ; Procedure: Conventional Surgery; Undergo surgery; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Plasma Membrane Epidermal Growth Factor Receptor (EGFR) Expression, Measured by VECTRA Imaging [7-10 days]

   An increase of at least 25% from baseline to post-dasatinib treatment will be considered significant. VECTRA is an automated pathology imaging system used to detect biomarkers in samples.

Secondary Outcome Measures

1. Number of Treatment-emergent Adverse Events [Safety and Tolerability] up to 4 Weeks [Up to 4 weeks]

   Safety and tolerability of dasatinib in participants with operable Triple negative breast cancer (TNBC) will be based on NCI Adverse Events (AE) Version 4.0 and will be assessed by frequency tables. AEs were collected on day 1 of treatment and a minimum of 14 days after the last dose. AEs reported here were ranked as either possibly related, probably related, or definitely related to the study intervention. All AEs (including not related and unlikely related) are summarized in the AE section.

2. Number of Participants With Pathologic Complete Response (pCR) [Up to 4 weeks]

   Examine pCR rates to standard neoadjuvant chemotherapy in nuclear Epidermal Growth Factor Receptor (nEGFR) + TNBC. pCR will be defined as ypT0 ypNO (absence of cancer in breast tissue and lymph nodes) an assessed by the investigator.

3. Number of Participants With No Evidence of Disease (NED) at Long-term Follow up [up to 24 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria for nEGFR testing:

• Patients must have histologically or cytologically confirmed Stage I-III triple negative breast cancer

• estrogen receptor (ER) and progesterone receptor (PR) must be <1% by standard assay methods

• human epidermal growth factor receptor-2 (HER2) must be either 0, 1+ by immunohistochemistry (if 2+, in situ hybridization method used to define HER2) OR have HER2: 17 centromere signal of <2.0 using a standard in situ hybridization method

• No prior therapy for current breast cancer

• Meet criteria for neoadjuvant chemotherapy or primary breast surgery, as determined by primary oncologist and surgeon

Inclusion Criteria for study therapy:

• nEGFR positive

• Eastern Cooperative Oncology Group (ECOG) performance status ≤1

• Patients must have normal organ and marrow function as defined below:

• leukocytes ≥3,000/mcL

• absolute neutrophil count ≥1,500/mcL

• platelets ≥150,000/mcL

• total bilirubin <1.25x institutional upper limit of normal

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

• creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

• 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 and for 30 days after the final dose. Should a woman become pregnant or suspect she is pregnant while she or her partner is 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:

• Patients who are receiving any other investigational agents

• Patients not able to swallow oral medications or with gastrointestinal conditions that may impact absorption of dasatinib.

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dasatinib.

• Patients receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, medications should be reviewed by the UW Pharmacy Research Center for any contraindicated medications. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

• H2 antagonists and proton pump inhibitors are not allowed

• Anticoagulants (ie. Coumadin, heparin, anti-Xa inhibitors) and anti-platelet agents (ie. aspirin) are not allowed. NSAIDS and acetaminophen are allowed on study.

• Medications known to prolong QTC are not allowed (See Appendix B)

• No history of prolonged QTC or cardiomyopathy unless normal QTC and ejection fraction confirmed within 1 month prior to study entry.

• 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 dasatinib is a pregnancy category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dasatinib, breastfeeding should be discontinued if the mother is treated with dasatinib and not resumed until at least 2 weeks after the final dose.

• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dasatinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

• Contraindication to repeat breast biopsy (neoadjuvant chemotherapy group)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois Hospital and Health Systems (Outpatient Care Center)	Chicago	Illinois	United States	60612
2	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• University of Wisconsin, Madison
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kari B Wisinski, MD, University of Wisconsin, Madison

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 29, 2019

More Information

Additional Information:

• UW Carbone Cancer Center Home Page

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT02720185
• Other Study ID Numbers: UW15114; 1R01CA193004-01A1; NCI-2016-00237; 2015-1578; A534260; SMPH\MEDICINE\HEM-ONC; Protocol Version 8/29/2019
• First Posted: Mar 25, 2016
• Last Update Posted: Jun 3, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Neoplasms; Triple Negative Breast Neoplasms; Breast Neoplasms; Dasatinib

Study Results

Participant Flow

Recruitment Details	Eligible patients were entered on study at the University of Wisconsin Carbone Cancer Center. Participants were enrolled from May 2017 to June 2020.

Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
Period Title: Overall Study
STARTED	5
COMPLETED	4
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
Overall Participants	5
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 80%
>=65 years	1 20%
Age, Customized (Count of Participants)
30-39 years	2 40%
40-49 years	1 20%
50-59 years	1 20%
60-69 years	0 0%
70-79 years	1 20%
Sex: Female, Male (Count of Participants)
Female	5 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 20%
Not Hispanic or Latino	4 80%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Plasma Membrane Epidermal Growth Factor Receptor (EGFR) Expression, Measured by VECTRA Imaging
Description	An increase of at least 25% from baseline to post-dasatinib treatment will be considered significant. VECTRA is an automated pathology imaging system used to detect biomarkers in samples.
Time Frame	7-10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
Measure Participants	5
Baseline	0.54
After Treatment	0.40

2. Secondary Outcome

Title	Number of Treatment-emergent Adverse Events [Safety and Tolerability] up to 4 Weeks
Description	Safety and tolerability of dasatinib in participants with operable Triple negative breast cancer (TNBC) will be based on NCI Adverse Events (AE) Version 4.0 and will be assessed by frequency tables. AEs were collected on day 1 of treatment and a minimum of 14 days after the last dose. AEs reported here were ranked as either possibly related, probably related, or definitely related to the study intervention. All AEs (including not related and unlikely related) are summarized in the AE section.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
Measure Participants	5
Measure adverse events	14
Fatigue	4
Anemia	2
Creatinine Increase	1
Low E-GFR	1
Nausea	1
Insomnia	1
Body Aches	1
Constipation	1
Headache	1
Dyspepsia	1

3. Secondary Outcome

Title	Number of Participants With Pathologic Complete Response (pCR)
Description	Examine pCR rates to standard neoadjuvant chemotherapy in nuclear Epidermal Growth Factor Receptor (nEGFR) + TNBC. pCR will be defined as ypT0 ypNO (absence of cancer in breast tissue and lymph nodes) an assessed by the investigator.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
Measure Participants	5
Count of Participants [Participants]	1 20%

4. Secondary Outcome

Title	Number of Participants With No Evidence of Disease (NED) at Long-term Follow up
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
Measure Participants	5
NED at 16 months (subsequently lost to follow up)	1 20%
NED at 24 months	4 80%

Adverse Events

Time Frame	up to 4 weeks - see limitations and caveats
Arm/Group Title	Dasatinib 100mg
Arm/Group Description	Dasatinib 100mg for 7-10 days until day prior to surgery Dasatinib: 100mg oral once daily dasatinib taken for 7-10 days up to the day prior to planned surgery or research biopsy (neoadjuvant chemotherapy group) Conventional Surgery: Undergo surgery Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Dasatinib 100mg
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Serious Adverse Events
	Dasatinib 100mg
	Affected / at Risk (%)	# Events
Total	1/5 (20%)
Investigations
Neutrophil Count Decreased	1/5 (20%)	1
Other (Not Including Serious) Adverse Events
	Dasatinib 100mg
	Affected / at Risk (%)	# Events
Total	5/5 (100%)
Blood and lymphatic system disorders
Anemia	1/5 (20%)	2
Febrile neutropenia	1/5 (20%)	1
Gastrointestinal disorders
Nausea	2/5 (40%)	3
Constipation	2/5 (40%)	2
Hemorrhoids	1/5 (20%)	1
Dyspepsia	1/5 (20%)	1
General disorders
Fatigue	4/5 (80%)	7
Body Aches	1/5 (20%)	1
Investigations
Creatinine Increase	1/5 (20%)	1
Low eGFR	1/5 (20%)	1
White Blood Cell Count Decreased	1/5 (20%)	2
Neutrophil count decreased	1/5 (20%)	1
Lymphocyte count decreased	1/5 (20%)	1
AST increased	1/5 (20%)	1
Metabolism and nutrition disorders
Hyponatremia	1/5 (20%)	1
Anorexia	1/5 (20%)	1
Nervous system disorders
Headache	1/5 (20%)	1
Psychiatric disorders
Insomnia	1/5 (20%)	1
Renal and urinary disorders
Proteinuria	1/5 (20%)	1
Respiratory, thoracic and mediastinal disorders
Sore Throat	1/5 (20%)	1

Limitations/Caveats

Statistical analyses were not completed for this study as it was not powered for meaningful results. Study was terminated early due to pandemic related enrollment issues, participants moved on to other therapies compromising intervention-relevant long term AE follow up.

More Information

Certain Agreements

All Principal Investigators ARE 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.