Clinical Trials /

Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)

NCT03493945

Description:

Background: Immunotherapy drugs help the body to fight cancer. Scientists think that combining some of these drugs will make them work better than when used alone. This may be true for many types of cancer, including castration-resistant prostate cancer (CRPC). Objective: To test if the combination of the drugs BN-brachyury, M7824, ALT-803, and Epacadostat is safe and shrinks tumors. Eligibility: People ages 18 and older with CRPC or another metastatic cancer Design: Participants will be screened with: - Medical history - Physical exam - CT or MRI scans - Possible bone imaging - Blood, urine, and heart tests - Possible tumor biopsy Participants will be treated with a 2-, 3- or 4-drug combinations of the following study drugs in 2-week cycles: - Participants will receive M7824 by IV once every 2 weeks. - Participants will receive ALT-803 by injection once every 2 weeks. They will record any skin changes at the injection site in a diary. - Participants will receive BN-brachyury as 4 injections to different limbs. They will get the first 3 doses 2 weeks apart. Then they will get doses every 4 weeks for 6 months, then every 3 months for 2 years, then every 6 months. - Participants will take Epacadostat orally every 12 hours. They will keep a pill diary. Participants will have physical exams and blood and urine tests at the start of each cycle. They may have scans every 12 weeks. Participants will continue treatment until their disease gets worse or they cannot tolerate the side effects. Participants will have a follow-up visit 4-5 weeks after they stop treatment. They will have a physical exam and blood tests. They may be asked to return for scans every 3 months.

Related Conditions:
  • Malignant Solid Tumor
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)
  • Official Title: Phase I/II Study of Immunotherapy Combination BN-Brachyury Vaccine, M7824, ALT-803 and Epacadostat (QuEST1)

Clinical Trial IDs

  • ORG STUDY ID: 180078
  • SECONDARY ID: 18-C-0078
  • NCT ID: NCT03493945

Conditions

  • Metastatic Prostate Cancer
  • Prostate Cancer
  • Prostate Neoplasm
  • Advanced Solid Tumors
  • Solid Tumor

Interventions

DrugSynonymsArms
M7824Arm 1.1
ALT-803Arm 1.1
MVA-BN-BrachyuryArm 2.1A
FPV-BrachyuryArm 2.1B
EpacadostatArm 2.3A

Purpose

Background: Immunotherapy drugs help the body to fight cancer. Scientists think that combining some of these drugs will make them work better than when used alone. This may be true for many types of cancer, including castration-resistant prostate cancer (mCRPC). Objective: To test if the combination of the drugs BN-brachyury, M7824, ALT-803, and Epacadostat is safe and shrinks tumors. Eligibility: People ages 18 and older with mCRPC or another metastatic cancer Design: Participants will be screened with: - Medical history - Physical exam - CT or MRI scans - Possible bone imaging - Blood, urine, and heart tests - Possible tumor biopsy Participants will be treated with a 2-, 3- or 4-drug combinations of the following study drugs in 2-week cycles: - Participants will receive M7824 by IV once every 2 weeks. - Participants will receive ALT-803 by injection once every 2 weeks. They will record any skin changes at the injection site in a diary. - Participants will receive BN-brachyury as 4 injections to different limbs. They will get the first 3 doses 2 weeks apart. Then they will get doses every 4 weeks for 6 months, then every 3 months for 2 years, then every 6 months. - Participants will take Epacadostat orally every 12 hours. They will keep a pill diary. Participants will have physical exams and blood and urine tests at the start of each cycle. They may have scans every 12 weeks. Participants will continue treatment until their disease gets worse or they cannot tolerate the side effects. Participants will have a follow-up visit 4-5 weeks after they stop treatment. They will have a physical exam and blood tests. They may be asked to return for scans every 3 months.

Detailed Description

      Background:

        -  PD-1/PD-L1 signaling appears to be a major inhibitor of activated T cell anti-tumor
           immune responses. The rapid, deep and durable responses seen in various malignancies
           with PD-1/PD-L1 targeted agents demonstrate that blockade of this axis is key to
           facilitating immune responses within the tumor microenvironment (TME).

        -  Prostate cancer is poorly recognized by T cells. Lack of an immune response is one
           explanation for the lower response rates (<15%) observed with anti-PD-1/PD-L1 therapies
           for prostate cancer.

        -  Increasing response rates will likely require therapeutic nullification of multiple
           immune deficits by combining immunotherapies that generate tumor-specific T cells
           (vaccine), dampen the inhibitory milieu of the TME, and enhance T and NK cell activity
           within the TME.

        -  A quick efficacy seeking trial, utilizing sequential arms offers a means to identify
           signals of activity for combinations of immunotherapy, added sequentially, in metastatic
           castrate resistant prostate cancer (mCRPC) patients.

        -  BN-Brachyury is a novel recombinant vector-based therapeutic cancer vaccine designed to
           induce an enhanced immune response against brachyury, which is overexpressed in many
           solid tumor types, including prostate adenocarcinoma. BN-Brachyury collectively refers
           to the priming doses (MVA-BN-Brachyury) and the boost doses (FPV-Brachyury) of the
           vaccine platform.

        -  M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1
           (PD-L1) antibody and the extracellular domain of transforming growth factor beta (TGF-
           beta) receptor type 2, a TGF-beta trap. M7824 can also mediate antibody-dependent
           cellular cytotoxicity in vitro.

        -  ALT-803 is an IL-15/IL-15R alpha superagonist complex that can enhance NK cell mediated
           ADCC and T-cell cytotoxicity.

        -  Synergistic anti-tumor effects have been observed in vitro when combining M7824 and
           ALT-803, and in vivo when combining these agents with tumor vaccine in animal models.

        -  IDO1 is overexpressed in many solid tumors and can contribute to immune escape by tumor
           cells. INCB024360 (Epacadostat) is an IDO1 inhibitor under investigation in combination
           with different immunotherapies in treatment of various malignancies.

        -  In treating of mCRPC, we hypothesize that these agents and their effects will be
           complementary. Tumor-specific T cells generated by vaccine may become more functional in
           a TME following treatment with M7824 and Epacadostat. ALT-803 can further enhance the
           activity of antigen-specific T cells as well as NK cells.

      Objective:

      -To determine if there is clinical benefit to any of a set of 3 possible treatments for
      patients with mCRPC:

        -  BN-Brachyury + M7824

        -  BN-Brachyury + M7824 + ALT-803

        -  BN-Brachyury + M7824 + ALT-803 + Epacadostat

      Eligibility:

        -  Adults with histologically proven mCRPC, or metastatic solid tumor of any type for which
           there is no standard treatment or standard treatment has failed.

        -  Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.

        -  Patients with acquired immune defects, active systemic autoimmune disease, history of
           organ transplant, history of chronic infections, or history of active inflammatory bowel
           disease are excluded.

      Design:

        -  Open label Phase I/II trial with following randomization during the expansion. Phase I:
           Cohort 1, Arm 1.1

           --Up to 18 patients with any solid tumor will be enrolled in dose escalation Cohort 1
           for treatment in Arm 1.1 (flat dose of M7824 + different dose levels of ALT-803).

        -  Phase IIA: expansion with sequential enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

             -  Concurrently with the enrollment to Arm 1.1, 13 patients with mCRPC will start
                enrollment in Cohort 2 for treatment in Arm 2.1 (M7824 + BN-Brachyury).

             -  When safe dosing of ALT-803 is identified during Phase I, 13 patients have enrolled
                in arm 2.1 and the first 6 patients, treated in Arm 2.1, have met safety
                requirements, 13 patients with mCRPC will start enrollment in Cohort 2 for
                treatment in Arm 2.2 (M7824 + BN-Brachyury + ALT-803).

             -  When 13 patients have enrolled in Arm 2.2 and the first 6 patients, treated in Arm
                2.2, have met safety requirements, 13 patients with mCRPC will start enrollment in
                Cohort 2 for treatment in Arm 2.3 (M7824 + BN-Brachyury + ALT-803 + Epacadostat).

        -  Phase IIB: expansion with randomized enrollment into Cohort 2, Arms 2.1, 2.2. and 2.3

             -  Each Arm in Cohort 2: 2.1, 2.2 and 2.3 will be open for additional enrollment (25
                evaluable patients total) when the initial 13 patients have accrued, safety
                requirements are meet and a positive signal (defined as Objective Response by
                RECIST 1.1 or sustained PSA decrease greater than or equal to 30% sustained for >
                21 days) in greater than or equal to 2 patients is shown.

             -  If only one arm is open for additional enrollment, patients will be directly
                assigned to this arm. If 2 arms are open for additional enrollment, patients will
                be randomized between these 2 open arms. If 3 arms are open for additional
                enrollment, patients will be randomized among these 3 open arms.

        -  If there are greater than or equal to 6 of 25 patients with a positive signal of
           activity in any expansion arm, that arm will be considered of interest for future
           studies.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1.1ExperimentalM7824 + ALT-803
  • M7824
  • ALT-803
Arm 2.1AExperimentalM7824 + BN-Brachyury
  • M7824
  • MVA-BN-Brachyury
  • FPV-Brachyury
Arm 2.1BExperimentalM7824 + BN-Brachyury
  • M7824
  • MVA-BN-Brachyury
  • FPV-Brachyury
Arm 2.2AExperimentalM7824 + BN-Brachyury + ALT-803
  • M7824
  • ALT-803
  • MVA-BN-Brachyury
  • FPV-Brachyury
Arm 2.2BExperimentalM7824 + BN-Brachyury + ALT-803
  • M7824
  • ALT-803
  • MVA-BN-Brachyury
  • FPV-Brachyury
Arm 2.3AExperimentalM7824 + BN-Brachyury + ALT-803 + Epacadostat
  • M7824
  • ALT-803
  • MVA-BN-Brachyury
  • FPV-Brachyury
  • Epacadostat
Arm 2.3BExperimentalM7824 + BN-Brachyury + ALT-803 + Epacadostat
  • M7824
  • ALT-803
  • MVA-BN-Brachyury
  • FPV-Brachyury
  • Epacadostat

Eligibility Criteria

        -  INCLUSION CRITERIA:

        Patients must have histologically or cytologically confirmed any solid tumor (Cohort 1) or
        prostate cancer (Cohort 2). No prior treatment other than testosterone lowering therapy for
        mCRPC is required.

        For the Cohort 1, eligible patients must have a histologically, cytologically or
        radiographically proven metastatic or locally advanced solid tumor of any type, for which
        there is no curative standard therapy or standard therapy has failed.

        Castrate testosterone level (less than 50ng/dl or 1.7nmol /L). (Patients with a malignancy
        other than prostate cancer are excluded from this criterion).

        Radiological confirmation of metastatic disease, or

        Progressive disease at study entry defined as one or more of the following criteria
        occurring in the setting of castrate levels of testosterone:

        --Radiographic progression defined as any new or enlarging bone lesions or growing lymph
        node disease, consistent with prostate cancer

        OR

        --PSA progression defined by sequence of rising values separated by greater than 1 week

        (2 separate increasing values over a minimum of 1 ng/ml (PCWG3 PSA eligibility criteria).
        If patients had been on flutamide, PSA progression is documented 4 weeks or more after
        withdrawal. For patients on bicalutamide or nilutamide disease progression is documented 6
        or more weeks after withdrawal. The requirement for a 4-6 week withdrawal period following
        discontinuation of flutamide, nilutamide or bicalutamide only applies to patients who have
        been on these drugs for at least the prior 6 months. For all other patients they must stop
        bicalutamide, nilutamide or flutamide the day prior to enrollment.

        Asymptomatic or mildly symptomatic form prostate cancer; no use of regularly scheduled
        opiate analgesics for prostate cancer-related pain. (Patients with a malignancy other than
        prostate cancer are excluded from this criterion).

        Patients must agree to continuation of androgen deprivation therapy (ADT) with a
        gonadotropin-releasing hormone analogue/antagonist or bilateral orchiectomy.

        (Patients with a malignancy other than prostate cancer are excluded from this criterion).

        Age greater than or equal to 18 years.

        ECOG performance status less than or equal to 1

        Patients must have normal organ and marrow function as defined below:

          -  Absolute neutrophil count greater than or equal to 1000/mcL

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

          -  Hemoglobin greater than or equal to 9.0 g/dL

          -  Total bilirubin within normal institutional limits; in patients with

        Gilbert s, less than or equal to 3.0 mg/dL

          -  AST (AGOT)/ALT (AGPT) less than or equal to 2.5X upper limit of normal. For subjects
             with liver involvement in their tumor, AST less than or equal to 3.5. (SqrRoot) ULN,
             ALT less than or equal to 3.5 (SqrRoot) ULN, and bilirubin less than or equal to 3.0
             is acceptable

          -  Creatinine within 1.5X upper limit of normal institutional limits

        The effects of BN-Brachyury, M7824, ALT-803, and Epacadostat on the developing human fetus
        are unknown. For this reason, men and women must agree to use adequate contraception
        (hormonal or barrier method of birth control; abstinence) prior to study entry, during the
        study and maintain such contraception until 4 months following the last dose of any study
        agent. Should a woman become pregnant or suspect she is pregnant while she or her partner
        is participating in this study, she should inform her partner s treating physician
        immediately.

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

        Patients with successfully treated HCV are eligible if HCV viral load is undetectable.

        EXCLUSION CRITERIA:

        Patients who are immunocompromised as follows:

          -  Human immunodeficiency virus positivity due to the potential for decreased tolerance,
             and potential to be at risk for severe side effects with immunotherapies. These
             concerns are relevant to all drugs, as drug-drug interactions among antiretrovirals
             and immunotherapies are yet uncharacterized.

          -  Chronic administration (defined as daily or every other day for continued use greater
             than 14 days) of systemic corticosteroids or other immune suppressive drugs, within 28
             days before treatment on study. Nasal, or inhaled steroid, topical steroid creams and
             eye drops for small body areas are allowed.

          -  Patients who have undergone allogeneic peripheral stem cell transplantation, or solid
             organ transplantation requiring immunosuppression

               -  Active autoimmune disease, except patients with type 1 diabetes mellitus,
                  vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current
                  immunosuppression, or with other endocrine disorders on replacement hormones or
                  are not excluded if the condition is well controlled.

        Prostate cancer patients with a history of brain/leptomeningeal metastasis, since these
        patients have a very poor prognosis and immunotherapy may take time to lead to beneficial
        clinical effects. Patients with brain or CNS metastases enrolling to arm 1.1 are eligible
        if they are status post definitive radiotherapy or surgery, and are asymptomatic

        History of allergic reactions attributed to compounds of similar chemical or biologic
        composition to study agents to be used in the cohort the subject will be enrolled into.

        Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or
        tobramycin).

        Any condition which, in the opinion of the investigator, would prevent full participation
        in this trial (including the long-term follow-up), or would interfere with the evaluation
        of the trial endpoints.

        Patients with prior investigational drug, chemotherapy, immunotherapy or any prior
        radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to
        enrollment, except if the investigator has assessed that all residual treatment-related
        toxicities have resolved or are minimal and feel the patient is otherwise suitable for
        enrollment.

        Uncontrolled intercurrent acute or chronic illness including, but not limited to, ongoing
        or active infection, symptomatic congestive heart failure (New York Heart Association Class
        I), hepatic disease, unstable angina pectoris, serious cardiac arrhythmia, requiring
        medication, uncontrolled hypertension (SBP greater than 170/ DBP greater than 105) or
        psychiatric illness/social situations within 12 months that would limit compliance with
        study requirements. Patients with a history of bleeding diathesis or recent (within 3
        months) clinically significant bleeding event are also excluded.

        Use of herbal products that may decrease PSA levels (e.g. saw palmetto)

        Patients who have had chemotherapy for metastatic castration-resistant prostate cancer
        within the past year. (Patients who have had docetaxel for metastatic castration sensitive
        per CHAARTED data may enroll as long as they did not have progressive disease while on
        docetaxel and are 3 months removed from treatment, with all treatment related toxicities
        resolving to at least grade 1.)

        Patients who have undergone major surgery within 4 weeks of enrollment. A biopsy will not
        preclude a patient from starting study.

        Patients with a history of hepatitis B (HBV) are excluded due to potential risk for viral
        reactivation and resulting liver injury in persons with latent HBV
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine if there is clinical benefit to any of a set of 3 possibletreatments for patients with mCRPC.
Time Frame:2 years
Safety Issue:
Description:Best treatment combination for patients with mCRPC

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immunotherapy
  • Combined Treatment
  • PD-1/PD-L1
  • Tumor-Specific T Cells
  • Novel Cancer Vaccine

Last Updated

August 16, 2019