Clinical Trials /

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

NCT03285607

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MCS110 Combined With Neoadjuvant Doxorubicin, Cyclophosphamide, and Weekly Paclitaxel in Patients With Hormone-Receptor Positive and HER2- Breast Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 17-x226
  • SECONDARY ID: MCS110ZUS02T
  • NCT ID: NCT03285607

Conditions

  • Breast Cancer
  • Cancer of Breast

Interventions

DrugSynonymsArms
MCS110Dose Level 1:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel
DoxorubicinAdriamycin®Dose Level 1:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel
CyclophosphamideCytoxan, CPM, CTX, CYTDose Level 1:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel
PaclitaxelTaxolDose Level 1:MCS110/Doxorubicin/Cyclophosphamide/Paclitaxel

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1:MCS110/Doxorubicin/Cyclophosphamide/PaclitaxelExperimentalMCS110 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.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
Dose Level 2:MCS110/Doxorubicin/Cyclophosphamide/PaclitaxelExperimentalMCS110 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.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
Dose Expansion:MCS110/Doxorubicin/Cyclophosphamide/PaclitaxelExperimentalMCS110 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.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of regimen
Time Frame:Completion of cycle 1 (28 days) for all patients
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:-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.
Measure:Pathologic complete response-rate (pCR)
Time Frame:At the time of surgery (approximately 20 weeks)
Safety Issue:
Description:-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.
Measure:Residual invasive tumor size (RITS)
Time Frame:At the time of surgery (approximately 20 weeks)
Safety Issue:
Description:-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.
Measure:Number of positive axillary lymph nodes
Time Frame:At the time of surgery (approximately 20 weeks)
Safety Issue:
Description:-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).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

September 14, 2017