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: RACHEL1: Radiation and CHEckpoint bLockade Trial in 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
  • NCT ID: NCT03524170

Conditions

  • Malignant Neoplasm of Breast

Interventions

DrugSynonymsArms
M7824MSB0011359CM7824 + Radiation Therapy

Purpose

The goal of this clinical research study is to find the highest tolerable dose of M7824 (MSB0011359C) that can be given with radiation therapy to patients with estrogen and/or progesterone receptor (HR) positive, HER2-negative breast cancer that is metastatic (has spread). The safety and tolerability of MSB0011359C will also be studied. Researchers also want to learn more about how certain immune cells may change when MSB0011359C in given in combination with radiation therapy. The effect of the study treatment combination will also be studied. This is an investigational study. MSB0011359C is not FDA approved or commercially available. It is currently being used for research purposes only. Radiation therapy is part of standard of care for many breast cancer patients. The study doctor can describe how the study drug and radiation therapy are designed to work. Up to 20 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      There are 28 days in every cycle.

      If you are found to be eligible to take part in this study, you will receive 1 of 2 dose
      levels of MSB0011359C, based on when you join the study. The first 3 participants will
      receive the higher of the 2 dose levels. Each new group (of 3) will receive the same dose
      unless intolerable side effects are seen in a certain number of participants. If this occurs,
      the next groups will receive the lower dose level of MSB0011359C. If intolerable side effects
      are seen in a certain number of participants when using the lower dose, the study will be
      stopped.

      You will receive MSB0011359C by vein over about 1 hour every 14 days +/-3 days. You will be
      watched for side effects for 2 hours after each infusion. Radiation therapy will start within
      3 days after the second dose of MSB0011359C. Depending on the site of your disease, you will
      receive radiation 1 time a day for 5 days or 10 days.

      Length of Study:

      You may continue taking the study drug for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the study drug if the disease gets worse, if
      intolerable side effects occur, or if you are unable to follow study directions.

      If you cannot tolerate the study drug, your dose may be lowered or stopped.

      Your participation on the study will be over 90 days after you receive the last dose of
      MSB0011359C.

      Pharmacokinetic (PK) Testing:

      Blood (about 1 teaspoon) will be collected on Day 1 of Cycles 1 and 3, and before study drug
      infusion in Cycles 2 and 6 for pharmacokinetic (PK) testing. They may also be tested at the
      end of study visit. PK testing measures the amount of study drug in the body at different
      time points. The samples will also be tested to learn how the drug has changed inside your
      body. This will help the doctors decide if the daily dose of the study drug needs to be
      increased, decreased, or remain at the current level.

      Study Visits:

      On Day 1 of Each Cycle:

        -  You will have a physical exam.

        -  Blood (about 14 teaspoons) will be drawn for routine tests and to measure your blood
           sugar levels, blood clotting function, the amount of cholesterol in your blood, and your
           thyroid, liver, and kidney functions.

        -  You will have an EKG to check your heart function.

        -  If you can become pregnant, blood (about 1 teaspoon) or urine will be drawn for a
           pregnancy test.

      On Day 56:

        -  You will have a physical exam.

        -  Blood (about 14 teaspoons) will be drawn for routine tests, to measure the amount of
           cholesterol in your blood, and your liver and kidney functions.

        -  If you can become pregnant, blood (about 1 teaspoon) or urine will be drawn for a
           pregnancy test.

        -  You will have a CT scan, a PET/CT scan, and/or an MRI to check the status of the
           disease.

        -  You will have a tumor biopsy of 2 sites if possible (the site that received radiation
           and a site that did not) on Day 56 or within 7 days of Day 56 for immune system and
           biomarker testing, including genetic biomarkers.

      End-of-Study Visit (EOT):

      If the disease gets worse, you will have an end of study visit. At this visit you will have
      the following tests:

        -  Blood (about 14 teaspoons) will be drawn for routine tests and to measure your blood
           sugar levels, blood clotting function, the amount of cholesterol in your blood, and to
           test your thyroid, liver, and kidney function.

        -  You will have a core biopsy to find out if the tumor has grown due to problems with your
           immune system.
    

Trial Arms

NameTypeDescriptionInterventions
M7824 + Radiation TherapyExperimental
  • M7824

Eligibility Criteria

        Inclusion Criteria:

          1. 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.

          2. Is Age >/= 18 years at time of study entry

          3. ECOG Performance Status of 0-1

          4. 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 (see Appendix 2 for further details). 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.

          5. 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 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

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

          7. 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.

          8. Adequate hematological function, defined by white blood cell (WBC) count =/> 3 ×
             10^9/L with ANC =/>1.5 × 10^9/L, lymphocyte count=/> 0.5 × 10^9/L, platelet count
             =/>100 × 10^9/L, and Hgb =/>9 g/dL

          9. Adequate hepatic function defined by a total bilirubin level </= 1.5 × the upper limit
             of normal (ULN), an AST, level </= 2.5 × ULN, and an ALT level </= 2.5 × ULN.

         10. International normalized ratio (INR) < 1.5

         11. 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.

         12. 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.

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

        Exclusion Criteria:

          1. 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].

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

          3. 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.

          4. 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.

          5. 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).

          6. 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 HBV (HBV surface antigen positive) or 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).

          7. 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.

          8. 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.

          9. 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.

         10. 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).

         11. Pregnancy and breast feeding
      
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 determined by dose limiting toxicity (DLT)
Time Frame:6 weeks after first administration of M7824.
Safety Issue:
Description: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:Progression-free survival (PFS) 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:Overall survival (OS) defined as the time from treatment until death from any cause.
Measure:Immunologic/molecular response
Time Frame:56 days
Safety Issue:
Description:Immunologic/molecular response 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 anti-PD-L1/TGF-β Trap (M7824) with radiation (in-field) and non-irradiated (abscopal) sites determined by RECIST
Time Frame:56 days
Safety Issue:
Description:

Details

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

Trial Keywords

  • Malignant neoplasm of breast
  • Metastatic HR+/HER2- breast cancer
  • M7824
  • MSB0011359C
  • Radiation therapy
  • XRT
  • External beam radiation therapy

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