Clinical Trials /

BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)

NCT04296942

Description:

Background: Breast cancer is the second most common cause of U.S. cancer deaths in women. Immunotherapy drugs use a person s immune system to fight cancer. Researchers want to see if a new combination of immunotherapy drugs can help treat breast cancer that has gone to places in the body outside of the breast (metastasized). Objective: To learn if a new combination of immunotherapy drugs can shrink tumors in people with metastatic breast cancer. Eligibility: Adults 18 and older who have been diagnosed with metastatic breast cancer, such as Triple Negative Breast Cancer (TNBC) or ER-/PR-/HER2+ Breast Cancer (HER2+BC) Design: Participants will be screened with: medical history physical exam disease confirmation (or tumor biopsy) tumor scans (computed tomography, magnetic resonance imaging, and/or bone scan) blood and urine tests electrocardiogram (measures the heart s electrical activity) echocardiogram (creates images of the heart). Participants will be assigned to 1 of 3 groups. The drugs they get will be based on the group they are in. Drugs are given in cycles. Each cycle = 3 weeks. Participants will be seen in clinic every 3 weeks, prior to the start of a new cycle. At each visit, participants will have an clinical exam, have blood drawn and will be asked about any side effects. They will repeat the screening tests during the study. New scans, like a CT scan, will be done every 6 weeks to see if the treatment is working. All participants will get BN-Brachyury. It is 2 different vaccines - a prime and a boost. First the priming vaccines, called MVA-BN-Brachyury help to jump start the immune system. Next the boosting vaccines, called FPV-Brachyury help to keep the immune system going. They are injected under the skin during different cycles. All participants will get M7824 (also known as Bintrafusp alfa ), which is an immunotherapy drug. Some participants will get a commonly used drug is HER2+ breast cancer called adotrastuzumab emtansine (also known as T-DM1DM1 or kadcyla). For both, a needle is inserted into a vein to give the drugs slowly. Some participants will take Entinostat weekly by mouth. It is in tablet form. Participants will keep a pill diary. Participants will continue on their assigned treatment until their cancer grows, they develop side effects or want to stop treatment. About 28 days after treatment ends, participants will have a follow-up visit or a telephone call. Then they will be contacted every 3 months for 1 year, then every 6 months for 1 year. They may have more tumor scans or continue treatment.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)
  • Official Title: A Phase 1b Trial of Sequential Combinations of BN-Brachyury, Entinostat, Ado-trastuzuamb Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)

Clinical Trial IDs

  • ORG STUDY ID: 200056
  • SECONDARY ID: 20-C-0056
  • NCT ID: NCT04296942

Conditions

  • Breast Cancer
  • Triple Negative Breast Cancer
  • HER2+ Breast Cancer
  • Hormone Receptor Negative Breast Cancer
  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Brachyury-TRICOM1/M7824 + BN-Brachyury
Entinostat3/M7824 + BN-Brachyury + T-DM1 + Entinostat
M78241/M7824 + BN-Brachyury
Ado-trastuzumab emtansine2/M7824 + BN-Brachyury + T-DM1

Purpose

Background: Breast cancer is the second most common cause of U.S. cancer deaths in women. Immunotherapy drugs use a person s immune system to fight cancer. Researchers want to see if a new combination of immunotherapy drugs can help treat breast cancer that has gone to places in the body outside of the breast (metastasized). Objective: To learn if a new combination of immunotherapy drugs can shrink tumors in people with metastatic breast cancer. Eligibility: Adults 18 and older who have been diagnosed with metastatic breast cancer, such as Triple Negative Breast Cancer (TNBC) or ER-/PR-/HER2+ Breast Cancer (HER2+BC) Design: Participants will be screened with: medical history physical exam disease confirmation (or tumor biopsy) tumor scans (computed tomography, magnetic resonance imaging, and/or bone scan) blood and urine tests electrocardiogram (measures the heart s electrical activity) echocardiogram (creates images of the heart). Participants will be assigned to 1 of 3 groups. The drugs they get will be based on the group they are in. Drugs are given in cycles. Each cycle = 3 weeks. Participants will be seen in clinic every 3 weeks, prior to the start of a new cycle. At each visit, participants will have an clinical exam, have blood drawn and will be asked about any side effects. They will repeat the screening tests during the study. New scans, like a CT scan, will be done every 6 weeks to see if the treatment is working. All participants will get BN-Brachyury. It is 2 different vaccines - a prime and a boost. First the priming vaccines, called MVA-BN-Brachyury help to jump start the immune system. Next the boosting vaccines, called FPV-Brachyury help to keep the immune system going. They are injected under the skin during different cycles. All participants will get M7824 (also known as Bintrafusp alfa ), which is an immunotherapy drug. Some participants will get a commonly used drug is HER2+ breast cancer called adotrastuzumab emtansine (also known as T-DM1DM1 or kadcyla). For both, a needle is inserted into a vein to give the drugs slowly. Some participants will take Entinostat weekly by mouth. It is in tablet form. Participants will keep a pill diary. Participants will continue on their assigned treatment until their cancer grows, they develop side effects or want to stop treatment. About 28 days after treatment ends, participants will have a follow-up visit or a telephone call. Then they will be contacted every 3 months for 1 year, then every 6 months for 1 year. They may have more tumor scans or continue treatment.

Detailed Description

      Background:

        -  Current greater than or equal to 2nd line treatments for metastatic breast cancer
           provide modest response rates, and modest improvement in progression-free survival but
           no treatments are curative.

        -  Bavarian-Nordic (BN)-Brachyury vaccine is a recombinant poxvirus vaccine against the
           transcription factor brachyury, which plays an important role in the
           epithelial-to-mesenchymal transition in breast cancer. A recently completed phase 1
           study of BN-Brachyury vaccine showed the vaccine was well tolerated and generated an
           immune response.

        -  M7824 is a novel bifunctional fusion protein composed of a monoclonal antibody against
           human PD-L1 fused to the soluble extracellular domain of human TGF-Beta receptor II
           (TGF-BetaRII), which functions as a TGF-Beta trap.

        -  Ado-trastuzumab emtansine (T-DM1 or Kadcyla) is an antibody drug conjugate used in
           second- and third- line treatment of metastatic HER2+ breast cancer (HER2+BC). T-DM1
           activates ADCC, dendritic cell maturation, increases TILs, increased PD-L1 expression,
           and increased immunomodulatory cytokines.

        -  Entinostat is a class 1 histone deacetylase inhibitor (HDACi) which suppresses tumor
           initiating cells, regulatory T-cells and myeloid-derived suppressor cells (MDSCs), as
           well as enhances cytotoxic T-cell mediated lysis, direct natural killer (NK) lysis, NK
           cell activation, increases PD-L1 expression and antibody-dependent cellular cytotoxicity
           (ADCC). In addition, entinostat may also be able to overcome HER2 resistance.

        -  We propose a Phase 1b trial to evaluate the safety and efficacy of the stepwise
           combination of the BN-Brachyury vaccine, M7824, T-DM1 and entinostat in metastatic
           breast cancer.

             -  Arm 1 - Triple Negative Breast Cancer (TNBC); M7824 + BN-Brachyury

             -  Arm 2 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1

             -  Arm 3 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1+ Entinostat

      Objectives:

      Primary Objectives:

        -  Arms 1-3: Overall response rate (ORR; PR+CR)

        -  Arms 1-3: Safety for each of the three combinations of agents explored in the arms

      Eligibility:

      Selected Inclusion Criteria

        -  Histologically confirmed metastatic breast cancer with appropriate IHC testing by a
           certified lab:

             -  For Arm 1: Triple negative breast cancer. Hormone receptor negative is defined by
                estrogen receptor < 10% and progesterone receptor < 10%. HER2 negative breast
                cancer is defined as HER2 per IHC 0 or 1+ or 2+ with negative FISH.

             -  For Arms 2 and 3: Hormone receptor negative, HER2+ breast cancer as defined by
                estrogen receptor < 10% and progesterone receptor < 10%. HER2 positive as per IHC
                3+ or 2+ with positive FISH.

        -  Prior treatment:

             -  For Arm 1: greater than or equal to 1 prior therapy in the metastatic setting.
                Patients with known PD-L1 positive tumors must have received prior treatment with
                atezolizumab + nab-paclitaxel. Patients with ER 1-9% must have received treatment
                with at least two lines of endocrine treatment (SERM, AI, fulvestrant) with one
                prior treatment including a CDK4/6 inhibitor + endocrine therapy for their
                metastatic cancer and should be considered endocrine therapy resistant.

             -  For Arms 2 and 3: greater than or equal to 1 prior treatment in the metastatic
                setting with a taxane (docetaxel or paclitaxel), herceptin and pertuzumab.

        -  Females or males greater than or equal to 18 years old

        -  ECOG 0 or 1

        -  Measurable metastatic disease per RECIST 1.1.

        -  For Arms 2 and 3: At least one biopsiable lesion and willingness to undergo up to three
           research biopsies.

        -  Adequate hematopoietic, hepatic, renal and cardiac (EF greater than or equal to 50%)
           function.

      Selected Exclusion Criteria

        -  Patients who have received chemotherapy, including trastuzumab and pertuzumab in the
           previous 3 weeks; other investigational agents within 4 weeks or a PD-1/PD-L1 antibody
           within 4 weeks prior to study enrollment; radiotherapy less than or equal to 4 weeks of
           study entry.

        -  Symptomatic CNS metastases and leptomeningeal disease are excluded but treated brain
           metastases (no radiotherapy within 6 weeks) or asymptomatic brain metastasis are
           allowed.

        -  History of invasive malignancy less than or equal to 3 years prior to enrollment.

        -  History of congestive heart failure (CHF) as defined as NYHA class 3 or 4 or
           hospitalization for CHF (any NYHA class) within 6 months of trial start.

        -  Concurrent use of chronic systemic steroids except for physiologic systemic steroids for
           replacement defined as 10mg of prednisone or an equivalent dose.

      Design:

      This study contains three separate, single arm phase 1b trials.

        -  Arm 1 will evaluate M7824 and BN-Brachyury in patients with TNBC.

        -  If this doublet is determined to have acceptable toxicity (0-1 DLTs of the first 6
           patients), up to 19 patients will be enrolled on Arm 2 in which BN-Brachyury, M7824 and
           T-DM1 will be evaluated in patients with advanced HR-/HER2+ BC with disease progression
           after treatment with THP or intolerance to THP.

        -  If this triplet is determined to have acceptable toxicity (0-1 DLTs of the first 6
           patients), 19 patients will be enrolled on Arm 3 in which BN-Brachyury, entinostat,
           M7824 and T-DM1 will be evaluated in patients with advanced HR-/HER2+ BC with disease
           progression after treatment with THP or intolerance to THP.

        -  Up to 51 evaluable patients will be recruited for this study, with an accrual ceiling
           set at 55 patients.

      Trial Drugs

        -  BN-Brachyury vaccine every 3 weeks until cycle 9, then every 12 weeks:

             -  Recombinant MVA-BN-Brachyury (R2PD): 4 injections of vaccines with 1 given SC in
                each extremity on Day 1 of Cycles 1 and 2. Each injection is 0.5ml of
                MVA-BN-Brachyury, which consists of 2.0 x 10(8) infectious units (Inf.U).

             -  Recombinant FPV-Brachyury: 1 injection given SC in one extremity on Day 1 of Cycles
                3 and beyond. Each infection is 0.5ml of FPV-Brachyury, which consists of 1.0 x
                10(9) Inf.U.

        -  T-DM1 3.6mg/kg via IV infusion q3 weeks on Day 1 of each cycle.

        -  M7824 2,400mg via IV infusion q3 weeks on Day 1 of each cycle.

        -  Entinostat 5mg by mouth weekly (RP2D) administered by patient on Days 1, 8 and 15 of
           each cycle.
    

Trial Arms

NameTypeDescriptionInterventions
1/M7824 + BN-BrachyuryExperimentalBifunctional fusion molecule involving PD-L1 with TGF-b sequestering agent added to a vaccine for the tumor associated antigen called brachyury.
  • Brachyury-TRICOM
  • M7824
2/M7824 + BN-Brachyury + T-DM1ExperimentalBifunctional fusion molecule involving PD-L1 with TGF-b sequestering agent added to a vaccine for the tumor associated antigen called brachyury. These investigational agents will be added to standard of care treatment called T-DM1.
  • Brachyury-TRICOM
  • M7824
  • Ado-trastuzumab emtansine
3/M7824 + BN-Brachyury + T-DM1 + EntinostatExperimentalBifunctional fusion molecule involving PD-L1 with TGF-b sequestering agent added to a vaccine for the tumor associated antigen called brachyury as well as to an oral HDAC inhibitor called entinostat. These investigational agents will be added to standard of care treatment called T-DM1.
  • Brachyury-TRICOM
  • Entinostat
  • M7824
  • Ado-trastuzumab emtansine

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed metastatic HER2+ breast
             cancer. HER2 positive or amplified breast cancer is defined as IHC 3+ or FISH average
             HER2 copy number greater than or equal to 6 signals per cell or HER2/CEP17 greater
             than or equal to 2.0. HER2 testing must have been performed in a laboratory accredited
             by the College of American Pathology (CAP) or another accrediting entity.

          -  Patients must have hormone receptor negative, HER2+ breast cancer. Hormone receptor
             negative is defined as estrogen receptor < 10% by IHC and progesterone receptor < 10%
             by IHC.

          -  Patients must have measurable disease, per RECIST 1.1.

          -  Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
             up to three biopsies while on trial.

          -  Patients must have received front-line treatment for metastatic disease with a taxane,
             trastuzumab and pertuzumab (THP; docetaxel or paclitaxel allowed) and progressed on
             treatment or were intolerant to treatment. Patients must have received at least one
             prior therapy in the metastatic setting. Prior T-DM1 therapy is allowed.

          -  Female or male greater than or equal to 18 years.

          -  ECOG performance status 0 or 1.

          -  Patients must have adequate bone marrow function as defined below:

               -  absolute neutrophil count greater than or equal to 1,500/mcL (> 1.5X 10(6)/L)

               -  platelets greater than or equal to 100,000/mcL

               -  hemoglobin greater than or equal to 9 mg/dL (transfusion to obtain hemoglobin
                  greater than or equal to 9 mg/dL within 24 hours prior to dosing is allowed)

          -  Patients must have adequate renal function, defined as:

               -  serum creatinine less than or equal to 1.5 X upper limit of normal (ULN) OR

               -  measured or calculated creatinine clearance greater than or equal to 60 mL/min
                  for participant with creatinine levels > 1.5 X institutional ULN (GFR can also be
                  used in place of creatinine or CrCl).

          -  Patients must have adequate hepatic function, defined as AST and ALT levels less than
             or equal to 3 X ULN and total bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert
             s syndrome, where bilirubin less than or equal to 5 mg/dL will be permitted. Gilbert s
             syndrome will be defined as elevated unconjugated bilirubin, with conjugated (direct)
             bilirubin within the normal range and less than 20% of the total. Total bilirubin will
             be permitted up to 5 mg/dL, if patients have historical readings consistent with the
             definition of Gilbert s syndrome prior to entering study. Adequate hepatic function
             for patients with known liver metastases is defined as AST and ALT levels less than or
             equal to 5 X ULN.

          -  Patients must have adequate cardiac function as defined by an ejection fraction
             greater than or equal to 50%.

          -  The effects of BN-Brachyury, entinostat, M7824 and T-DM1 on the developing human fetus
             are unknown. However, the two components of T-DM1 are known to have negative fetal
             effects including oligohydramnios and oligohydramnios sequence (pulmonary hypoplasia,
             skeletal malformations and neonatal death). For this reason, women of child-bearing
             potential must agree to use adequate contraception prior to study entry, for the
             duration of study participation and for 7 months after the last dose of study
             medication. Should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately.

          -  Patients with well-controlled HIV infection are eligible for trial as long as:

               -  On an effective anti-retroviral therapy (ART) 4 weeks and with evidence of viral
                  suppression as defined as HIV viral load 400 copies/mL within the last 3 months;

               -  CD4 greater than or equal to 200 cells/microL within the last 3 months; and

               -  No reported opportunistic infections within 6 months prior to enrollment, except
                  for the following which will be allowed:

                  i. Esophageal candidiasis treated within last 6 months or currently improving
                  with antifungal treatment.

        ii. Oral and/or genital HSV treated within last 6 months or currently improving with
        antiviral treatment.

        iii. Mycobacterium avium infection in last 6 months or that has been treated for at least 1
        month.

          -  Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible for
             trial as long as the HBV viral load is undetectable on suppressive therapy, if
             indicated.

          -  Patients with history of hepatitis C virus (HCV) infection must have been treated and
             cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable or unquantifiable HCV RNA 12 weeks or longer
             after definitive treatment completion.

          -  Patients must be able to understand and willing to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          -  Patients who have received chemotherapy, including herceptin and/or pertuzumab in the
             prior 3 weeks (6 weeks for nitrosoureas or mitomycin); other investigational agents or
             a PD-1/L1 agent within 4 weeks prior to study enrollment.

          -  Patients who have received radiotherapy within 4 weeks prior to study entry.

          -  Patients with active brain metastases or leptomeningeal metastases should be excluded
             from this clinical trial because of their poor prognosis and because they often
             develop progressive neurologic dysfunction that would confound the evaluation of
             neurologic and other adverse events. However, patients with treated brain metastases
             are eligible if there is no magnetic resonance imaging (MRI) evidence of progression
             for 6 weeks after treatment is complete (no radiotherapy within 6 weeks) and within 28
             days prior to the first dose of trial drug or asymptomatic brain metastasis. Patients
             requiring immunosuppressive doses of systemic corticosteroids (> 10mg/day prednisone
             equivalent) for palliation are excluded.

          -  Patients with a history of another invasive malignancy less than or equal to 3 years
             prior to enrollment (patients with non-melanoma skin cancers, carcinoma in situ of the
             breast or cervix are eligible).

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to agents used in study. For example, reaction to prior vaccination with
             vaccinia virus or known hypersensitivity reaction to fully humanized monoclonal
             antibodies (Grade greater than or equal to 3 NCI-CTCAEv5).

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing active
             infection that requires systemic treatment with ongoing antibiotics (eligible if can
             stop antibiotics on day of enrollment), unstable angina pectoris, cardiac arrhythmia,
             or psychiatric illness/social situation that in the opinion of the primary
             investigator would prohibit the patient from complying with study requirements.

          -  Known history of a gastrointestinal illness that in the investigator s opinion would
             prevent the absorption of entinostat, which is an oral agent. (Arm 3 ONLY)

          -  Patients with bone metastases who have initiated denosumab or a bisphosphonate therapy
             within 28 days prior to or after Cycle 1 Day 1. Continuation of prior therapy is
             allowed.

          -  Patients with inherited bleeding disorders, a history of bleeding diathesis such as
             vWF deficiency or recent (within 3 months prior to enrollment) clinically significant
             bleeding events that, in the judgment of the investigator, would interfere with
             patient s ability to carry out the treatment program.

          -  Patients should have no evidence of being immunocompromised as listed below:

               -  Active, known or suspected autoimmune disease. Patients are permitted to enroll
                  if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
                  an autoimmune condition only requiring hormone replacement, psoriasis not
                  requiring systemic treatment or conditions not expected to recur in the absence
                  of an external trigger in the opinion of the primary investigator.

               -  Altered immune function, that in the judgement of the PI that may affect a
                  patient s ability to adequately engage the immune system and respond to the
                  immunotherapy agents being administered, including but not limited to:
                  inflammatory bowel disease; active infectious enteritis; eosinophilic enteritis;
                  lupus erythematous; ankylosing spondylitis; scleroderma; multiple sclerosis.
                  These criteria do not include all disease with an immune-related component, but
                  are not autoimmune in nature or have a primary alteration in the general immune
                  function that may interfere with the vaccine mechanism of action, for example
                  celiac disease.

               -  Immunosuppressive therapy post-organ transplant.

          -  Concurrent use of chronic use of systemic steroids, except for physiologic doses of
             systemic steroids for replacement, defined as 10mg of prednisone per day or
             equivalent, or local (topical, nasal, ophthalmic or inhaled) steroid use or prior
             concomitant use with chemotherapy. Systemic steroids must have been discontinued >2
             weeks prior to trial start. Prior use of corticosteroids in short-term schemes
             (duration shorter than 3 days) for indications such as prophylaxis of reactions to
             intravenous contrast for imaging studies or chemotherapy-related AEs are not
             considered part of this exclusion. Prior use of corticosteroids for brain metastasis
             ending at least 14 days prior to enrollment is not considered part of this exclusion
             criteria.

          -  Pregnant and breastfeeding women are excluded from this study because of the potential
             for teratogenic or abortifacient effects with all of the agents involved in this
             trial.

          -  Clinically significant cardiomyopathy, coronary disease, chronic heart failure (CHF;
             New York Heart Association class III or IV or hospitalization for CHF), or
             cerebrovascular accident within 6 months prior to enrollment.

          -  Patients with a history of myocarditis are excluded due to the potential of
             myocarditis with anti-PD-L1 antibodies.

          -  Patients with pulse oximetry < 92% on room air will be excluded due to the potential
             of pneumonitis with anti-PD-L1 antibodies.

          -  Any other condition, which would, in the opinion of the Principal Investigator or
             Medical Monitor, indicated the subject is a poor candidate for the clinical trial or
             would jeopardize the subject or the integrity of the data obtained.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate for patients with TNBC
Time Frame:one year
Safety Issue:
Description:To determine if the addition BN-Brachyury and M7824 improves overall response rates (ORR) in triple negative breast cancer (TNBC).

Secondary Outcome Measures

Measure:Progression-free survival for patients with TNBC
Time Frame:one year
Safety Issue:
Description:To determine if adding BN-Brachyury to M7824 improves PFS in TNBC.
Measure:Progression-free survival for patients with HER2+BC
Time Frame:one year
Safety Issue:
Description:To determine if adding BN-Brachyury, M7824, and/or entinostat to T-DM1 increases the PFS in patients with metastatic HER2+ metastatic breast cancer who progressed on initial treatment with THP (or intolerant to THP).
Measure:Change in stromal TILs
Time Frame:one year
Safety Issue:
Description:To determine if adding BN-Brachyury, M7824, and/or entinostat to T-DM1 increases stromal TILs (as measured by the Salgado method) in metastatic deposits in patients with metastatic HER2+ metastatic breast cancer.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immuno-oncology
  • Immunotherapy
  • Vaccine
  • Invasive Breast Cancer

Last Updated

March 7, 2020