Clinical Trials /

Radiation Therapy and M7824 in Treating Patients With Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer

NCT03524170

Description:

This phase I trial studies the side effects and best dose of anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) when given together with radiation therapy in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. M7824 is a drug that targets specific proteins on immune cells in order to activate immune responses against tumor cells. Giving M7824 together with radiation therapy may work better in treating patients with breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy and M7824 in Treating Patients With Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer
  • Official Title: RACHEL1: A Phase I Radiation and Checkpoint Blockade Trial in Patients With Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2017-0499
  • SECONDARY ID: NCI-2018-00961
  • SECONDARY ID: 2017-0499
  • NCT ID: NCT03524170

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Metastatic Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
Bintrafusp AlfaAnti-PDL1/TGFb Trap MSB0011359C, M7824, MSB0011359CTreatment (M7824, radiation therapy)

Purpose

This phase I trial studies the side effects and best dose of anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) when given together with radiation therapy in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. M7824 is a drug that targets specific proteins on immune cells in order to activate immune responses against tumor cells. Giving M7824 together with radiation therapy may work better in treating patients with breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose (RP2D) of M7824 and radiation therapy in
      patients with metastatic hormone receptor positive (HR+)/HER2 negative (-) breast cancer.

      II. To evaluate the safety and tolerability of M7824 and radiation therapy in patients with
      metastatic HR+/HER2- breast cancer.

      SECONDARY OBJECTIVES:

      I. To assess immunologic/molecular responses, specifically percentage (%) change in
      tumor-infiltrating lymphocytes (TIL) pre and post therapy to M7824 and radiation therapy in
      patients with HR+/HER2- metastatic breast cancer.

      II. To explore progression free survival (PFS) and overall survival (OS) to power future
      definitive trial.

      III. To evaluate the in-field and abscopal effect of treatment with anti-PD-L1/TGF-beta trap
      (M7824) and radiation therapy.

      EXPLORATORY OBJECTIVES:

      I. To characterize the effect of anti-PD-L1/TGF-beta trap (M7824) and radiation therapy on
      immune biomarkers including PD-L1 expression and fibrosis changes in tumor microenvironment
      in tumor tissue obtained from subjects pre- and post-treatment.

      II. To characterize circulating immune cell populations and cytokine profiles in tumor and
      circulation following treatment with M7824.

      III. To conduct ribonucleic acid sequencing (RNAseq), RNA Scope, whole exome sequencing (WES)
      targeted sequencing and tissue IO gene expression.

      OUTLINE:

      Patients receive M7824 intravenously (IV) over 1 hour every 14 days. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity. Beginning within 3 days
      after second dose of M7824, patients undergo radiation therapy once a day (QD) for 5-10 days
      depending on the site of disease in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, participants are followed up for 90 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (M7824, radiation therapy)ExperimentalPatients receive M7824 IV over 1 hour every 14 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Beginning within 3 days after second dose of M7824, patients undergo radiation therapy QD for 5-10 days depending on the site of disease in the absence of disease progression or unacceptable toxicity.
  • Bintrafusp Alfa

Eligibility Criteria

        Inclusion Criteria:

          -  Is willing and able to provide written informed consent for the trial and has signed
             the appropriate written informed consent form, approved by the investigator's
             Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the
             performance of any trial activities.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Highly effective contraception for both male and female subjects if the risk of
             conception exists. Highly effective contraception must be used 30 days prior to first
             trial administration, for the duration of trial treatment, and at least for 4 months
             after stopping trial treatment. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this trial, the treating
             physician should be informed immediately.

          -  Has confirmed HR+ and HER2 negative breast cancer with known metastatic disease. HR
             defined as positive if expression greater than 10% by immunohistochemistry (IHC). HER2
             negative or non-amplified is determined by the current American Society of Clinical
             Oncology-College of American Pathologists (ASCO-CAP) criteria which are as follows:
             HER2 testing by IHC as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be
             performed. HER2 is positive if: i. IHC 3+ based on circumferential membrane staining
             that is a. complete, intense ii. ISH positive based on: a. single-probe average HER2
             copy number >= 6.0 signals/cell. b. Dual-probe HER2/CEP17 ratio >= 2.0 with an average
             HER2 copy number >= 4.0 signals/cell c. Dual-probe HER2/CEP17 ratio >= 2.0 with an
             average HER2 copy number < 4.0 signals/cell d. Dual-probe HER2/CEP17 ratio < 2.0 with
             an average HER2 copy number >= 6.0 signals/cell.

          -  Has at least 2 identified sites of metastatic disease by imaging.

          -  Has received no more than 5 previous lines of chemotherapy and has received at least
             one line of therapy with an endocrine therapy or endocrine therapy combination.

          -  White blood cell (WBC) count >= 3 x 10^9/L.

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.

          -  Lymphocyte count >= 0.5 x 10^9/L.

          -  Platelet count >= 100 x 10^9/L.

          -  Hemoglobin (Hgb) >= 9 g/dL.

          -  Total bilirubin level =< 1.5 x the upper limit of normal (ULN).

          -  Aspartate aminotransferase (AST) level =< 2.5 x ULN.

          -  Alanine aminotransferase (ALT) level =< 2.5 x ULN.

          -  International normalized ratio (INR) < 1.5.

          -  Adequate renal function defined by an estimated creatinine clearance > 30 mL/min
             according to the Cockcroft-Gault formula or be measure for creatinine clearance from
             24 hour urine collection.

          -  Has not had major surgery within 28 days prior to starting study treatment. Central
             venous access surgeries and/or placements would not be considered as major surgery.

          -  Is eligible for palliative radiotherapy as determined by the treating radiation
             oncologist.

        Exclusion Criteria:

          -  Anticancer treatment within 14 days before the start of trial treatment (e.g.,
             cytoreductive therapy, radiotherapy [with the exception of palliative radiotherapy
             delivered in a normal organ-sparing technique], immune therapy, or cytokine therapy).

          -  Major surgery as determined by the investigator within 28 days before the start of
             trial treatment (prior diagnostic biopsy is permitted).

          -  Systemic therapy with immunosuppressive agents within 7 days before the start of
             treatment; or use of any investigational drug within 28 days before the start of trial
             treatment.

          -  Subjects with active central nervous system (CNS) metastases with significant
             neurological compromise or symptoms are excluded. Subjects with a history of treated
             CNS metastases (by surgery or radiation therapy), who show no evolving new
             neurological symptoms are eligible for the study.

          -  Receipt of any organ transplantation, including allogeneic stem-cell transplantation,
             but with the exception of transplants that do not require immunosuppression (e.g.,
             corneal transplant, hair transplant).

          -  Significant acute or chronic infections including, among others: a. Known history of
             testing positive test for human immunodeficiency virus (HIV) or known acquired
             immunodeficiency syndrome. b. Active hepatitis B virus (HBV) (HBV surface antigen
             positive) or hepatitis C virus (HCV) (HCV RNA positive). c. Subjects with known active
             tuberculosis (history of exposure or history of positive tuberculosis test plus
             presence of clinical symptoms, physical or radiographic findings).

          -  Active autoimmune disease that might deteriorate when receiving an immunostimulatory
             agent: a. subjects with type I diabetes, vitiligo, alopecia, psoriasis, hypo- or
             hyperthyroid disease not requiring immunosuppressive treatment are eligible b.
             subjects requiring hormone replacement with corticosteroids are eligible if the
             steroids are administered only for the purpose of hormonal replacement and at doses 10
             mg of prednisone or equivalent per day.

          -  Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral
             vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6
             months prior to enrollment), unstable angina, congestive heart failure (New York Heart
             Association classification class > II), or serious cardiac arrhythmia.

          -  Clinically relevant diseases (for example, inflammatory bowel disease) and /or
             uncontrolled medical conditions, which, in the opinion of the investigator, might
             impair the subject's tolerance or ability to participate in the trial.

          -  Vaccine administration within 4 weeks of M7824 administration. Vaccination with live
             vaccines while on trial is prohibited. Administration of inactivated vaccines is
             allowed (for example, inactivated influenza vaccines).

          -  Pregnancy and breast feeding.

          -  History of conditions associated with bleeding diatheses.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose (RP2D) of M7824 and radiation therapy in patients with metastatic HR+/HER2- breast cancer
Time Frame:6 weeks after first administration of M7824
Safety Issue:
Description:Will be determined by dose limiting toxicity. RP2D defined as the highest dose level with no more than 1 patient with DLT out of 6 patients that are treated.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Start of study drug up to 90 days after study drug stopped
Safety Issue:
Description:PFS is defined as the time from treatment until objective tumor progression or death, whichever occurs first.
Measure:Overall survival (OS)
Time Frame:Start of study drug up to 90 days after study drug stopped
Safety Issue:
Description:OS is defined as the time from treatment until death from any cause.
Measure:Immunologic/molecular response
Time Frame:Up to 56 days
Safety Issue:
Description:Immunologic/molecular response is defined as % change in tumor infiltrating lymphocytes (TIL) pre and post therapy to M7824 and radiation therapy in patients with HR+/HER2- metastatic breast cancer.
Measure:Evaluation of the size of metastasis after treatment with M7824 with radiation (in-field) and non-irradiated (abscopal) sites
Time Frame:Up to 56 days
Safety Issue:
Description:Will be determined by Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

November 19, 2020