Clinical Trials /

Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma

NCT04417660

Description:

Background: Thymoma and thymic carcinoma are diseases of the thymus. Platinum-based chemotherapy is the standard treatment for these diseases. But in many cases, the disease returns after treatment. Researchers want to see if a new drug can help. Objective: To see if bintrafusp alfa (M7824) is an effective treatment for thymoma and thymic carcinoma. Eligibility: People age 18 and older who have thymoma or thymic cancer and their disease returned or progressed after treatment with at least one platinum-containing chemotherapy treatment plan, or they have refused standard therapy Design: Participants will be screened under a separate protocol. Their medical, medicine, and treatment history will be reviewed. They will have a tumor biopsy if they do not have a sample. Participants will get the study drug once every 2 weeks as an intravenous infusion. For this, a small plastic tube is put into an arm vein. During the study, participants will undergo the following: Medicine review Physical exam Review of their symptoms and their ability to perform their normal activities Blood and urine tests Thigh muscle scan (using MRI) Tumor assessment (using MRI or CT) Heart and lung function tests Thyroid gland test Skin assessment. Participants may have tumor biopsies. Some of their blood and biopsy samples will be used for gene testing. Participants may take the study drug until their disease worsens or they cannot tolerate treatment. Participants will have follow-up visits 2 and 6 weeks after stopping treatment. Then they will have long-term follow-up visits every 3 months. These may include imaging scans. Visits may be done by phone, with scans (if needed) done at their doctor s office.

Related Conditions:
  • Thymic Carcinoma
  • Thymoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma
  • Official Title: A Phase II, Open-Label Trial of Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 200097
  • SECONDARY ID: 20-C-0097
  • NCT ID: NCT04417660

Conditions

  • Thymic Epithelial Tumor
  • Recurrent Thymoma
  • Thymic Cancer

Interventions

DrugSynonymsArms
M7824Bintrafusp alfa (M7824)

Purpose

Background: Thymoma and thymic carcinoma are diseases of the thymus. Platinum-based chemotherapy is the standard treatment for these diseases. But in many cases, the disease returns after treatment. Researchers want to see if a new drug can help. Objective: To see if bintrafusp alfa (M7824) is an effective treatment for thymoma and thymic carcinoma. Eligibility: People age 18 and older who have thymoma or thymic cancer and their disease returned or progressed after treatment with at least one platinum-containing chemotherapy treatment plan, or they have refused standard therapy Design: Participants will be screened under a separate protocol. Their medical, medicine, and treatment history will be reviewed. They will have a tumor biopsy if they do not have a sample. Participants will get the study drug once every 2 weeks as an intravenous infusion. For this, a small plastic tube is put into an arm vein. During the study, participants will undergo the following: Medicine review Physical exam Review of their symptoms and their ability to perform their normal activities Blood and urine tests Thigh muscle scan (using MRI) Tumor assessment (using MRI or CT) Heart and lung function tests Thyroid gland test Skin assessment. Participants may have tumor biopsies. Some of their blood and biopsy samples will be used for gene testing. Participants may take the study drug until their disease worsens or they cannot tolerate treatment. Participants will have follow-up visits 2 and 6 weeks after stopping treatment. Then they will have long-term follow-up visits every 3 months. These may include imaging scans. Visits may be done by phone, with scans (if needed) done at their doctor s office.

Detailed Description

      Background

        -  Platinum-based chemotherapy is the standard of care for advanced unresectable thymic
           epithelial tumors (TETs). However more than half of these patients experience disease
           recurrence and require second-line therapy.

        -  There are no approved drugs for treatment of recurrent thymoma and thymic carcinoma and
           new therapeutic options are needed for patients who have disease progression on or after
           platinumcontaining therapy.

        -  We have demonstrated the safety and clinical activity of immune checkpoint inhibition in
           patients with recurrent TETs. In an ongoing trial (NCT03076554) we have shown that
           avelumab, an antiprogrammed death ligand-1 (PD-L1) antibody, induces major responses and
           has an acceptable safety profile.

        -  Combination immunotherapy is under evaluation for treatment of various cancers but has
           not been studied for the treatment of TETs. Immunotherapy targeting the PD-1/PD-L1 axis
           can be combined with other immune checkpoint inhibitors, cancer vaccines and
           anti-cytokine therapy.

        -  Bintrafusp alfa, a bifunctional fusion protein that targets PD-L1 and transforming
           growth factor-beta (TGF-beta) has shown activity against heavily pre-treated solid
           tumors including non-small cell lung cancer previously treated with single-agent
           anti-PD-1/PD-L1 inhibitors.

        -  Retrospective analysis of pre-chemotherapy tissue obtained from 20 patients with stage
           IV thymic carcinoma and 13 cases of stage III/IV thymoma, showed TGF- <= expression in
           65%cases of thymic carcinoma and 15% cases of thymoma with a lower median survival among
           patients with thymic carcinoma (30 months versus 63 months).

        -  As part of a phase I clinical trial, treatment with bintrafusp alfa resulted in a brief
           period of disease stabilization and no immune-related adverse events in one patient with
           heavily pre-treated, WHO subtype B3 thymoma with a large disease burden

        -  Further investigation of Bintrafusp alfa in patients with recurrent TETs is needed to
           define the clinical activity and safety of this drug in patients with TETs.

      Primary Objectives:

      -To determine the objective response rate (ORR) to bintrafusp alfa in patients with relapsed
      or refractory thymoma and thymic carcinoma.

      Eligibility:

        -  Patients greater than or equal to age 18 years with histologically confirmed,
           unresectable thymoma or thymiccarcinoma who have previously been treated with at least
           one platinum-containing chemotherapy regimen with progressive disease prior to study
           entry or patients who have refused chemotherapy.

        -  Progressive and measurable disease prior to enrollment

        -  No history of autoimmune disease, with exception of vitiligo, autoimmune thyroid
           disease, or pure red cell aplasia that are adequately managed with medical therapy

        -  Adequate renal, hepatic and hematopoietic function

      Design:

        -  This will be a single-arm, phase II study to determine the clinical activity of
           treatment with Bintrafusp alfa in patients with relapsed or refractory thymoma and
           thymic carcinoma.

        -  Bintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two
           weeks until disease progression or development of intolerable adverse events. The
           two-week period will constitute one cycle.

        -  A Simon optimal two-stage phase II trial design will be used to rule out unacceptably
           low response rate of 20% in favor of an improved response rate of 45%

        -  Patients will be enrolled in 2 disease cohorts, thymoma and thymic carcinoma, with up to
           17 evaluable patients of each tumor type. Accrual ceiling will be set at 38 patients to
           account for inevaluable patients.

        -  Patients who have completed 12 months of treatment with an ongoing response or disease
           stability (for > 6 months) will be given an option of discontinuing active treatment
           with the ability to reinstitute treatment on one occasion if radiological or clinical
           disease activity is noted during follow-up. All eligibility criteria should be met at
           the time of restarting treatment with bintrafusp alfa.

        -  Tumor response will be assessed after completion of every third cycle (6 weeks) using
           modified immune-related RECIST criteria. When possible, an optional tumor biopsy will be
           conducted pretreatment, after 3 doses in patients responding to treatment or at 6 weeks,
           whichever is sooner, to evaluate treatment-related, intra-tumoral changes.

        -  Exploratory objectives include immune correlative studies to analyze immune cell
           subsets, PD-L1 expression and evaluation of soluble factors and intra-tumoral changes
           before and after bintrafusp alfa treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Bintrafusp alfa (M7824)ExperimentalBintrafusp alfa will be administered at a dose of 1200 mg intravenously once every two weeks until diseaseprogression or development of intolerable adverse events.
  • M7824

Eligibility Criteria

        -  INCLUSION CRITERIA:

        2.1.1.1 Patients must have histologically confirmed (by the pathology department/CCR/NCI)
        thymoma or thymic carcinoma.

        2.1.1.2 Patients must have had at least one prior line of platinum-based chemotherapy or
        patient must have refused cytotoxic chemotherapy. Progressive disease must be documented
        prior to study entry and patients must have advanced, unresectable disease that is not
        amenable to surgical resection.

        2.1.1.3 Disease must be measurable with at least 1 unidimensional measurable lesion by
        RECIST 1.1.

        2.1.1.4 Patients must be aged >18 years.

        2.1.1.5 ECOG performance status <1

        2.1.1.6 Patients must have adequate organ and marrow function as defined below:

        -absolute neutrophil count >1,500/mm3

        OR

        >1.5 x 109/L

        -platelets >100,000/mm3

        OR

        > 100 x 109/L

          -  hemoglobin >9g/dL (may have been transfused)

          -  total bilirubin less than or equal to 1.5 x the upper limit of normal range

        (ULN)

        -AST(SGOT)/ALT(SGPT) <1.5 x ULN

        OR

        <5 x ULN for subjects with documented metastatic disease to the liver

        -creatinine clearance greater than or equal to 60 mL/min/1.73 m2 calculated by calculated
        using eGRF in the clinical lab

        2.1.1.7 Negative serum or urine pregnancy test at screening for women of childbearing
        potential (WOCBP). NOTE: WOCBP is defined as any female who has experienced menarche and
        who has not undergone successful surgical sterilization or who is not postmenopausal. If
        necessary, to confirm postmenopausal status an FSH level will be included at screening. The
        effects of Bintrafusp alfa on the developing human fetus are unknown. For this reason,
        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 at least 2 months after the last dose of the drug.

        2.1.1.8 Patients with previously treated brain or CNS metastases are eligible provided that
        the subject has recovered from any acute side effects of radiotherapy and does not require
        treatment with steroids, and any whole brain radiation therapy was completed at least 2
        weeks prior to enrollment.

        2.1.1.9 Ability of subject to understand and the willingness to sign a written informed
        consent document.

        EXCLUSION CRITERIA:

        2.1.2.1 History of allergic reactions attributed to compounds of similar chemical or
        biologic composition to Bintrafusp alfa.

        2.1.2.2 Prior treatment with PD-1 or PD-L1-directed immune checkpoint blockade is not
        permitted. Prior treatment with other immunomodulating drugs such as cancer vaccines is
        permitted based on investigators discretion as long as treatment was not discontinued due
        to life-threatening adverse events (laboratory abnormalities alone with prior therapy will
        not exclude patients from this trial).

        2.1.2.3 Concurrent treatment with a non-permitted drug

        2.1.2.4 Prior anticancer treatment within 14 days before treatment (e.g., cytoreductive
        therapy, radiotherapy [with the exception of palliative bone directed radiotherapy], immune
        therapy, or cytokine therapy except for erythropoietin); major surgery within 14 days
        before treatment (excluding prior diagnostic biopsy); prior systemic therapy (or 5
        halflives of a drug, whichever is shorter) with immunosuppressive agents within 14 days
        before treatment; use of hormonal agents for anti-cancer therapy within 7 days before
        treatment; or use of any investigational drug within 14 days before treatment.

        2.1.2.5 Note: Subjects receiving bisphosphonate or denosumab are eligible provided
        treatment was initiated at least 14 days before treatment.

        2.1.2.6 History of previous malignant disease within the last 2 years with the following
        exceptions: basal or squamous cell carcinoma of the skin, cervical carcinoma in situ,
        ductal carcinoma in situ of the breast, papillary or follicular thyroid carcinoma, and
        nonmuscle invasive bladder cancer.

        2.1.2.7 Active or history of autoimmune disease that might deteriorate when receiving an
        immune-stimulatory agent, with the exception of vitiligo, autoimmune thyroid disease, or
        pure red cell aplasia that are adequately managed with medical therapy. In addition,
        anti-acetylcholine receptor binding and anti-striational antibodies will be checked during
        screening and patients will be ineligible if results are positive, even if there is no
        clinical history of autoimmune disease.

        2.1.2.8 Patients receiving systemic corticosteroids at doses > 10 mg daily prednisone
        equivalent will be excluded. However, patients on inhaled steroids and adrenal replacement
        steroid doses up to 10 mg daily prednisone equivalents are permitted in the absence of
        autoimmune disease as described in exclusion criterion 2.1.2.7

        2.1.2.9 Active infection requiring systemic therapy or significant acute or chronic
        infections including, among others:

          -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
             HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).

          -  Known history of testing positive for HIV or testing positive for HIV at screening or
             known acquired immunodeficiency syndrome.

        HIV-positive TET patients are ineligible because of the risk of developing opportunistic
        infections after treatment with an immune checkpoint inhibitor. Additionally, TET patients
        are at higher risk of developing opportunistic infections due to underlying immune defects.
        Prior cases of disseminated herpes virus, cytomegalovirus and fungal infections have been
        documented in this patient population.

        2.1.2.10 Prior organ transplantation including allogenic stem-cell transplantation.

        2.1.2.11 Persisting toxicity related to prior therapy (NCI CTCAE v. 5 Grade > 1); however,
        alopecia, sensory neuropathy Grade less than or equal to 2, or other Grade less than or
        equal to 2 not constituting a safety risk based on investigator s judgment are acceptable.

        2.1.2.12 Pregnant or lactating women. Pregnant women are excluded from this study because
        Bintrafusp alfa is in the class of agents known as antineoplastics/monoclonal antibodies
        with the potential for teratogenic or abortifacient effects. Because there is an unknown
        but potential risk for adverse events in nursing infants secondary to treatment of the
        mother with Bintrafusp alfa, breastfeeding should be discontinued if the mother is treated
        with Bintrafusp alfa.

        2.1.2.13 Known alcohol or drug abuse.

        2.1.2.14 Uncontrolled intercurrent illness including, but not limited to, symptomatic
        congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
        illness/social situations that would limit compliance with study requirements. All other
        severe acute or chronic medical conditions including immune colitis, inflammatory bowel
        disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
        (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities
        that may increase the risk associated with study participation or study treatment
        administration or may interfere with the interpretation of study results and, in the
        judgment of the investigator, would make the patient inappropriate for entry into this
        study. Participants with history of bleeding diathesis or recent major bleeding events
        considered by the Investigator as high risk for investigational drug treatment are also
        excluded.

        2.1.2.15 Administration of live vaccine within 4 weeks prior to treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:From the start of the treatment until disease progression/recurrence
Safety Issue:
Description:Overall response rate for M7824 based on RECIST criteria

Secondary Outcome Measures

Measure:Duration of response, progression free survival &amp; overall survival
Time Frame:from the start of the treatment until disease progression/recurrence
Safety Issue:
Description:To determine duration of response, progression free survival and overall survival in patients with recurrent thymic epithelial TETs
Measure:Safety &amp; tolerability of M7824
Time Frame:from the start of the treatment until disease progression/recurrence
Safety Issue:
Description:To determine the safety and tolerability of 1200 mg M7824 administered once every 2 weeks in patients with thymoma and thymic carcinoma

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Thymoma
  • thymic cancer
  • Immune Checkpoint Inhibition
  • programmed death ligand 1 (PD-L1)

Last Updated

June 11, 2020