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

NCT ID: NCT03285607

Last Updated: 2018-08-16

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-30
• Study Completion Date: 2021-02-28

Brief Summary

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.

Conditions

Breast Cancer; Cancer of Breast

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

MCS110

Intervention Type: BIOLOGICAL

-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor

Doxorubicin

Intervention Type: DRUG

-Standard of care

Cyclophosphamide

Intervention Type: DRUG

-Standard of care

Paclitaxel

Intervention Type: DRUG

-Standard of care

Bone marrow aspirate

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Peripheral blood samples

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Tumor tissue

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

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.

Group Type: EXPERIMENTAL

MCS110

Intervention Type: BIOLOGICAL

-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor

Doxorubicin

Intervention Type: DRUG

-Standard of care

Cyclophosphamide

Intervention Type: DRUG

-Standard of care

Paclitaxel

Intervention Type: DRUG

-Standard of care

Bone marrow aspirate

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Peripheral blood samples

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Tumor tissue

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

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.

Group Type: EXPERIMENTAL

MCS110

Intervention Type: BIOLOGICAL

-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor

Doxorubicin

Intervention Type: DRUG

-Standard of care

Cyclophosphamide

Intervention Type: DRUG

-Standard of care

Paclitaxel

Intervention Type: DRUG

-Standard of care

Bone marrow aspirate

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Peripheral blood samples

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Tumor tissue

Intervention Type: PROCEDURE

-Time of enrollment and at time of surgery

Interventions

MCS110

-MCS110 is an IgG1/κ humanized monoclonal antibody directed against human macrophage colony stimulating factor

Intervention Type: BIOLOGICAL

Doxorubicin

-Standard of care

Intervention Type: DRUG

Cyclophosphamide

-Standard of care

Intervention Type: DRUG

Paclitaxel

-Standard of care

Intervention Type: DRUG

Bone marrow aspirate

-Time of enrollment and at time of surgery

Intervention Type: PROCEDURE

Peripheral blood samples

-Time of enrollment and at time of surgery

Intervention Type: PROCEDURE

Tumor tissue

-Time of enrollment and at time of surgery

Intervention Type: PROCEDURE

Other Intervention Names

Adriamycin®; Cytoxan; CPM; CTX; CYT; Taxol

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Leonel Hernandez-Aya, M.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Related Links

http://www.siteman.wustl.edu

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Other Identifiers

MCS110ZUS02T

Identifier Type: OTHER

Identifier Source: secondary_id

201711073

Identifier Type: -

Identifier Source: org_study_id