MCS110 Combined With Neoadjuvant Doxorubicin, Cyclophosphamide, and Weekly Paclitaxel in Patients With Hormone-Receptor Positive and HER2- Breast Cancer

August 14, 2018 updated by: Washington University School of Medicine

Phase I Study of MCS110 Combined With Neoadjuvant Dose-Dense Doxorubicin, Cyclophosphamide, and Weekly Paclitaxel in Patients With Hormone-Receptor Positive and HER2- Breast Cancer

In patients with locally advanced hormone receptor positive (HR+)/HER2- breast cancer, neoadjuvant chemotherapy produces a pathologic complete response rate (pCR) of only 9-15%, and late recurrences often occur despite neoadjuvant chemotherapy. Therefore, there is an unmet clinical need to improve the outcomes of these patients. Tumor-associated macrophages (TAM) infiltration leads to poor outcomes in breast cancer patients by promoting angiogenesis, activating epithelial-mesenchymal transition, degrading the extracellular matrix, and suppressing the anti-tumor immune response. Pre-clinical studies, as summarized above, have shown that the breast cancer immune microenvironment may be reprogrammed by targeting colony-stimulating factor-1 (CSF-1) to decrease TAM infiltration and increase CD8+ TIL infiltration, in order to foster antitumor immunity and improve response to therapy.

Here, the investigators propose a phase I dose-escalation study in patients with locally advanced HR+/HER2- breast cancer to determine the feasibility of adding MCS110, a CSF-1 inhibitor, to the standard neoadjuvant chemotherapy regimen of dose-dense doxorubicin, cyclophosphamide followed by paclitaxel. The investigators will also include a dose expansion cohort for preliminary efficacy analysis and correlative studies. The investigators propose that if they can decrease the TAM-induced immunosuppression and TAM-induced chemoresistance observed in breast cancer patients, then the patients' own immune system could find and destroy the dormant and resistant tumor cells, and combined with enhanced chemotherapy efficacy, the investigators will see durable remissions and long term cures.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed ER+ HER2- breast cancer. ER-positivity is to follow local guidelines. If IHC HER2 is 2+, a negative FISH test is required.
  • Clinical stage II or stage III (by AJCC 7th edition) breast cancer eligible for neoadjuvant chemotherapy with complete surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal.
  • Clinically positive axillary lymph nodes.
  • At least 18 years of age.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

  • Normal bone marrow and organ function as defined below:

    • Absolute neutrophil count ≥ 1,500/mcL
    • Platelets ≥ 100,000/mcL
    • Hemoglobin ≥ 9.0 g/dL
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
    • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
    • Creatinine ≤ 1.5 x IULN
    • PT/INR ≤ 1.5 x IULN (for participants on anticoagulation therapy, ≤ 1.5 x baseline value)
    • aPTT ≤ 1.5 x IULN (for participants on anticoagulation therapy, ≤ 1.5 x baseline value)

  • Adequate cardiac function as defined below:

    • LVEF ≥ 50%
    • QTC ≤ 470 msec for females and ≤ 450 msec for males
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 90 days after the last dose of MCS110. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 4 month after completion of MCS110 administration.
  • Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Presence of metastatic disease.
  • Therapy for underlying malignancy within 2 weeks prior to start of study treatment.
  • A history of other malignancy ≤ 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
  • Bilateral or inflammatory breast cancer.
  • Currently receiving any other investigational agents.
  • Receiving immunosuppressive agents or > 10 mg daily prednisone or equivalent of corticosteroids.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to MCS110, doxorubicin, cyclophosphamide, paclitaxel, or other agents used in the study.
  • Known hypersensitivity to monoclonal antibodies.
  • Personal or family history of long QT syndrome.
  • Evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment / central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration.
  • Diagnosis of any type of muscle disease that may result in CK elevation.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Clinically significant cardiovascular disease within 6 months of screening.
  • Presence of any Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater toxicity.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
  • Known history of human immunodeficiency virus or infection with hepatitis requiring antiviral therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SEQUENTIAL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Dose Level 1:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel
  • MCS110 will be administered intravenously over 60 minutes (up to 120 minutes permitted) on a 28-day cycle. The dose of MCS110 given will depend on the dose level to which a given patient is enrolled.

  • The standard neoadjuvant chemotherapy regimen of dose-dense doxorubicin/ cyclophosphamide followed by weekly paclitaxel consists of:

    • doxorubicin 60 mg/m^2 IV Q2W during Weeks 1 through 8 (total of 4 doses)
    • cyclophosphamide 600 mg/m^2 Q2W during Weeks 1 through 8 (total of 4 doses)
    • paclitaxel 80 mg/m^2 IV QW during Weeks 9 through 20 (total of 12 doses)
  • Surgery will be performed approximately 4-6 weeks after the end of the last cycle of treatment (Week 20-22). It is outside the scope of this study as part of each patient's standard of care. Both types of surgery (lumpectomy or mastectomy) are allowed. The decision on surgical approach and timing will be at the discretion of the treating surgeon.
Biological: MCS110
-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor
Drug: Doxorubicin
-Standard of care
Other Names:
  • Adriamycin®
Drug: Cyclophosphamide
-Standard of care
Other Names:
  • Cytoxan
  • CPM
  • CTX
  • CYT
Drug: Paclitaxel
-Standard of care
Other Names:
  • Taxol
Procedure: Bone marrow aspirate
-Time of enrollment and at time of surgery
Procedure: Peripheral blood samples
-Time of enrollment and at time of surgery
Procedure: Tumor tissue
-Time of enrollment and at time of surgery
EXPERIMENTAL: Dose Level 2:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel
  • MCS110 will be administered intravenously over 60 minutes (up to 120 minutes permitted) on a 28-day cycle. The dose of MCS110 given will depend on the dose level to which a given patient is enrolled.

  • The standard neoadjuvant chemotherapy regimen of dose-dense doxorubicin/ cyclophosphamide followed by weekly paclitaxel consists of:

    • doxorubicin 60 mg/m^2 IV Q2W during Weeks 1 through 8 (total of 4 doses)
    • cyclophosphamide 600 mg/m^2 Q2W during Weeks 1 through 8 (total of 4 doses)
    • paclitaxel 80 mg/m^2 IV QW during Weeks 9 through 20 (total of 12 doses)
  • Surgery will be performed approximately 4-6 weeks after the end of the last cycle of treatment (Week 20-22). It is outside the scope of this study as part of each patient's standard of care. Both types of surgery (lumpectomy or mastectomy) are allowed. The decision on surgical approach and timing will be at the discretion of the treating surgeon.
Biological: MCS110
-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor
Drug: Doxorubicin
-Standard of care
Other Names:
  • Adriamycin®
Drug: Cyclophosphamide
-Standard of care
Other Names:
  • Cytoxan
  • CPM
  • CTX
  • CYT
Drug: Paclitaxel
-Standard of care
Other Names:
  • Taxol
Procedure: Bone marrow aspirate
-Time of enrollment and at time of surgery
Procedure: Peripheral blood samples
-Time of enrollment and at time of surgery
Procedure: Tumor tissue
-Time of enrollment and at time of surgery
EXPERIMENTAL: Dose Expansion:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel
  • MCS110 will be administered intravenously over 60 minutes (up to 120 minutes permitted) on a 28-day cycle. The dose of MCS110 given will depend on the dose level to which a given patient is enrolled.

  • The standard neoadjuvant chemotherapy regimen of dose-dense doxorubicin/ cyclophosphamide followed by weekly paclitaxel consists of:

    • doxorubicin 60 mg/m^2 IV Q2W during Weeks 1 through 8 (total of 4 doses)
    • cyclophosphamide 600 mg/m^2 Q2W during Weeks 1 through 8 (total of 4 doses)
    • paclitaxel 80 mg/m^2 IV QW during Weeks 9 through 20 (total of 12 doses)
  • Surgery will be performed approximately 4-6 weeks after the end of the last cycle of treatment (Week 20-22). It is outside the scope of this study as part of each patient's standard of care. Both types of surgery (lumpectomy or mastectomy) are allowed. The decision on surgical approach and timing will be at the discretion of the treating surgeon.
Biological: MCS110
-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor
Drug: Doxorubicin
-Standard of care
Other Names:
  • Adriamycin®
Drug: Cyclophosphamide
-Standard of care
Other Names:
  • Cytoxan
  • CPM
  • CTX
  • CYT
Drug: Paclitaxel
-Standard of care
Other Names:
  • Taxol
Procedure: Bone marrow aspirate
-Time of enrollment and at time of surgery
Procedure: Peripheral blood samples
-Time of enrollment and at time of surgery
Procedure: Tumor tissue
-Time of enrollment and at time of surgery

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose (MTD) of regimen
Time Frame: Completion of cycle 1 (28 days) for all patients
  • The maximum tolerated dose (MTD) is defined as the dose level at which <1 patients of a cohort (of 3 to 6 patients) experience dose-limiting toxicity during the first cycle.
  • A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of CTCAE Grade ≥ 3 assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurs within the first cycle of treatment with the combination treatment and meets any of the criteria outlined.
Completion of cycle 1 (28 days) for all patients

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Safety and tolerability of regimen as measured by grade and number of adverse events experienced per participant
Time Frame: 30 days after completion of treatment (approximately 24 weeks)
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
30 days after completion of treatment (approximately 24 weeks)
Pathologic complete response-rate (pCR)
Time Frame: At the time of surgery (approximately 20 weeks)
-Pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes. All eligible patients who have completed neoadjuvant therapy and have subsequently undergone surgery are included in the analysis of pCR.
At the time of surgery (approximately 20 weeks)
Residual invasive tumor size (RITS)
Time Frame: At the time of surgery (approximately 20 weeks)
-Residual invasive tumor size (RITS) is histopathologically assessed by the largest dimension of the dominant invasive tumor focus from the surgical specimen. In cases in which there was no residual invasive tumor, the RITS will be 0 mm. In cases in which multifocal pathology is present, the largest dimension of the residual invasive tumor focus will be recorded.
At the time of surgery (approximately 20 weeks)
Number of positive axillary lymph nodes
Time Frame: At the time of surgery (approximately 20 weeks)
-Number of positive axillary lymph nodes is defined as number of resected lymph nodes with axillary nodal micrometastases (>0.2-<2 mm) or overt metastases (⩾2 mm).
At the time of surgery (approximately 20 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Novartis Pharmaceuticals

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Leonel Hernandez-Aya, M.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 30, 2018

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 31, 2019

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 28, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 14, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 14, 2017

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 18, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 16, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 14, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 201711073
  • MCS110ZUS02T (OTHER: Novartis Pharmaceuticals)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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