Clinical Trials /

Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)

NCT03018288

Description:

Background: GBM refers to a specific kind of brain cancer called glioblastoma. The standard treatment for GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune therapy that is now used to treat other cancers. The addition of pembrolizumab to the standard treatment of radiation and temozolomide has been shown to be well tolerated. Researchers want to see if adding a vaccine made from the person s own tumor will improve the effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the time of surgery is called HSPPC-96. Objectives: To see if the adding pembrolizumab and HSPPC-96 improves the standard treatment for glioblastoma multiforme. Eligibility: Adults at least 18 years old with glioblastoma. Design: Participants will be screened with typical cancer tests: Brain scan Medical history Blood and urine tests Questions about quality of life and symptoms These tests will be repeated throughout the study. Participants will have surgery to remove their tumor. A tissue sample from the tumor will be sent to a lab. A vaccine will be made from it. Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and placebo. Participants will not know which they get. Participants will get radiation for 6 weeks. Participants will take temozolomide by mouth before each treatment. Participants will get pembrolizumab by IV for 30 minutes 3 times over the radiation cycle. Participants will keep taking the 2 drugs every few weeks for about a year. Some may take pembrolizumab for an additional year. Most participants will get the vaccine or placebo after radiation. They will get it 5 times over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2 years. Participants will repeat the screening tests when they stop study treatment. They will also have follow-up phone calls.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)
  • Official Title: A Randomized, Double Blind Phase II Trial of Surgery, Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)

Clinical Trial IDs

  • ORG STUDY ID: 170034
  • SECONDARY ID: 17-C-0034
  • NCT ID: NCT03018288

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Pembrolizumab2/RT+TMZ+Pembrolizumab+HSPPC-96
HSPPC-962/RT+TMZ+Pembrolizumab+HSPPC-96
Temozolomide2/RT+TMZ+Pembrolizumab+HSPPC-96

Purpose

Background: GBM refers to a specific kind of brain cancer called glioblastoma. The standard treatment for GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune therapy that is now used to treat other cancers. The addition of pembrolizumab to the standard treatment of radiation and temozolomide has been shown to be well tolerated. Researchers want to see if adding a vaccine made from the person s own tumor will improve the effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the time of surgery is called HSPPC-96. Objectives: To see if the adding pembrolizumab and HSPPC-96 improves the standard treatment for glioblastoma multiforme. Eligibility: Adults at least 18 years old with glioblastoma. Design: Participants will be screened with typical cancer tests: Brain scan Medical history Blood and urine tests Questions about quality of life and symptoms These tests will be repeated throughout the study. Participants will have surgery to remove their tumor. A tissue sample from the tumor will be sent to a lab. A vaccine will be made from it. Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and placebo. Participants will not know which they get. Participants will get radiation for 6 weeks. Participants will take temozolomide by mouth before each treatment. Participants will get pembrolizumab by IV for 30 minutes 3 times over the radiation cycle. Participants will keep taking the 2 drugs every few weeks for about a year. Some may take pembrolizumab for an additional year. Most participants will get the vaccine or placebo after radiation. They will get it 5 times over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2 years. Participants will repeat the screening tests when they stop study treatment. They will also have follow-up phone calls.

Detailed Description

      Background:

        -  Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite
           aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these
           tumors almost always recur.

        -  Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to
           standard therapy which consists of concurrent radiation with temozolomide chemotherapy
           after maximal surgical resection in patients with newly diagnosed disease and salvage
           chemotherapy with either rechallenge with temozolomide or an alternative alkylating
           agent such as CCNU or cisplatin. To date, none of the combination strategies have
           demonstrated clinical benefit. Furthermore, in subjects with an unmethylated MGMT
           (O6-methylguanine-DNA methyltransferase) promoter temozolomide has only modest benefit
           and salvage therapies have not demonstrated a significant impact in this subject group
           underscoring the need for more research.

        -  Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking
           specific immune responses that may produce a more sustained and less toxic effect than
           conventional therapy. Heat-shock proteins (HSPs), which function as intracellular
           chaperones, can be used to deliver a variety of tumor antigens to antigen presenting
           cells for immune stimulation.

        -  Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein
           glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including
           autologous antigenic peptides (aka vaccine ). Heat shock proteins (HSP) are molecules
           that respond to cellular stress and counteract abnormal protein folding. They are known
           to modulate immune responses, especially the HSP gp-96. In a stressful environment, such
           as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects the
           tumor and leads to resistance to therapy. HSP expression is associated with cellular
           proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis.

        -  Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of
           the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its
           ligands, PD-L1 and PD-L2. Additionally, pembrolizumab is thought to also have activity
           in the peripherally circulating T-effector cells by reversing lymphocyte exhaustion. It
           is currently FDA approved for use in patients with unresectable or metastatic melanoma
           and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF
           inhibitor and NSCLC with elevated PDL1 in the tumor. recurrent or metastatic HNSCC with
           disease progression on or after platinum-containing chemotherapy. It is also FDA
           approved for with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease
           has progressed after other treatments and with tumors that express a protein called
           PD-L1 and for the treatment of patients with recurrent or metastatic head and neck
           squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing
           chemotherapy

        -  This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-
           1 inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are MGMT
           promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and will provide
           important data on immune-modulatory effect of this combination. This may be of
           particular value in patients with high peripheral PD-L1 expression, but also the value
           of PD-1 added to standard GBM therapy. As vaccine needs to be generated from the patient
           s tumor, patients will need to be identified prior to surgery.

      Eligibility:

        -  MRI findings consistent with a suspected GBM or histologically confirmed newly diagnosed
           GBM that has not been treated and would benefit from further surgical resection.

        -  Tumor must be supratentorial.

        -  GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be allowed
           unless there is plan for second surgery to remove greater than or equal to 80 % of the
           tumor) and patients tumors must not have MGMT promoter methylation and must be IDH
           wildtype.

        -  No prior treatment with radiation or chemotherapy for their GBM.

        -  Age greater than or equal to 18 years on day of signing informed consent

      Objective:

      - The primary endpoint is to determine whether the one year overall survival (OS) rate is
      improved in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and
      are IDH wildtype treated with RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab +
      HSPPC-96 vaccine or Placebo vaccine x 6 cycles (1 cycle is 9 weeks).

      Design:

        -  This will be a randomized, double blind phase II trial of surgery, RT + TMZ +
           Pembrolizumab followed by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed GBM
           patients whose tumors have an unmethylated MGMT promotor and are IDH wildtype.

        -  Subjects will be assigned to intervention based on tumor resection and ability to
           generate vaccine as follows:

             -  If < 80 % of tumor removed, <7 g of tumor is resected or HSPPC-96 cannot be
                generated, subjects will be treated on the ancillary cohort of RT+TMZ
                +Pembrolizumab followed by TMZ+ Pembrolizumab.

             -  If greater than or equal to 80% of contrasting enhanced tumor removed (based on T1
                Post contrast MRI using cross sectional measurement), greater than or equal to 7 g
                of tumor is resected and sufficient HSPPC-96 is generated, subjects will be
                included in the main cohort and will be randomized on a 1:1 basis to receive:

                  1. RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo

                     OR

                  2. RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-96

        -  Approximately 8 potentially eligible patients are seen per month, and it is anticipated
           that at least 1-2 per month will be accrued per site.
    

Trial Arms

NameTypeDescriptionInterventions
1/RT+TMZ+PembrolizumabExperimentaltumor does not meet criteria (ancillary group)
  • Pembrolizumab
  • Temozolomide
2/RT+TMZ+Pembrolizumab+HSPPC-96Experimentaltumor meets criteria randomized vaccine group
  • Pembrolizumab
  • HSPPC-96
  • Temozolomide
3/RT+TMZ+Pembrolizumab +PlaceboPlacebo Comparatortumor meets criteria randomized placebo group
  • Pembrolizumab
  • Temozolomide

Eligibility Criteria

        -  INCLUSION CRITERIA:

        Pre Surgery (Step 1)

          -  MRI findings consistent with a suspected GBM or a histologically confirmed newly
             diagnosed GBM that has not been treated and would benefit from further surgical
             resection. As vaccine needs to be generated from the patient s tumor, patients will
             need to be identified prior to definitive surgery.

          -  Age greater than or equal to 18 years on day of signing informed consent.

          -  Karnofsky performance status greater than or equal to 70%.

          -  Tumor must be supratentorial only.

          -  Stereotactic biopsy will not be allowed unless there is plans for second surgery to
             remove greater than or equal to 80 % of the tumor.

          -  No prior treatment with radiation or chemotherapy for their GBM.

          -  No prior treatment with carmustine wafers.

        Post-Surgery for vaccine or placebo (Step 2):

          -  Pathology must be a GBM, MGMT promoter region determined to be unmethylated and IDH
             wild type. Greater than or equal to 80 % resection of contrast enhanced tumor on post
             operative MRI is required for randomization, otherwise treatment will occur on the
             ancillary arm.

          -  Treatment must be initiated greater than or equal to 14 days and < 6 weeks from
             surgery.

          -  Craniotomy site must be adequately healed and free of drainage or cellulitis, and the
             underlying cranioplasty must appear intact at the time of radiation. Radiation must
             start within 6 weeks of surgery.

          -  Dexamethasone dose should be less than or equal to 4 mg/day or steroid equivalent
             prior to starting treatment. If higher doses are needed, consult with Study Chair.

          -  Female subjects of childbearing potential should have a negative urine or serum
             pregnancy within 7 days prior to receiving the first dose of study medication. If the
             urine test is positive or cannot be confirmed as negative, a negative serum pregnancy
             test will be required.

          -  Patients must have adequate organ and bone marrow function within 14 days prior to
             step 2 registration, as defined below:

               -  Absolute neutrophil count (ANC) > 1.5 (SqrRoot) 10(9)/L; platelet count > 100
                  (SqrRoot) 10(9)/L; and hemoglobin (Hb) >9.0 g/dL within 7 days prior to step 2
                  registration. Note: The use of transfusion or other intervention to achieve Hb
                  greater than or equal to 9.0 g/dL is acceptable.

               -  Total bilirubin < 1.5 (SqrRoot) ULN (except in patients diagnosed with Gilbert s
                  disease)

               -  AST (SGOT), ALT (SGPT), and alkaline phosphatase (ALP) < 2.5 (SqrRoot) ULN

               -  Serum creatinine < 1.5 (SqrRoot) ULN

               -  International normalized ratio (INR), prothrombin time (PT), or activated partial
                  thromboplastin time (APTT) as follows: In the absence of therapeutic intent to
                  anticoagulate the patient: INR < 1.5 or PT < 1.5(SqrRoot) ULN or aPTT <
                  1.5(SqrRoot) ULN. In the presence of therapeutic intent to anticoagulate the
                  patient: INR or PT and aPTT within therapeutic limits (according to the medical
                  standard in the institution) and the patient has been on a stable dose of
                  anticoagulants for at least 2 weeks before registration.

          -  Females of child-bearing potential (FOCBP) and males must agree to use two adequate
             contraception methods (give examples, e.g. hormonal or barrier method of birth
             control; abstinence) prior to study entry, for the duration of study participation,
             and for 120 days following completion of therapy. Should a female patient become
             pregnant or suspect she is pregnant while participating in this study, she should
             inform her treating physician immediately. Male patients who father a child should
             notify the treating physician.

        NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal
        ligation, or remaining celibate by choice) who meets the following criteria:

          1. Has not undergone a hysterectomy or bilateral oophorectomy

          2. Has had menses at any time in the preceding 12 consecutive months (and therefore has
             not been naturally postmenopausal for > 12 months)

               -  Patients must have the ability to understand and the willingness to sign a
                  written informed consent prior to registration on study.

               -  Diagnosis must be made by surgical excision.

               -  Patients should not be on antibiotics for any infection but post operative
                  antibiotics are allowed if used prophylactically but should be completed prior to
                  starting RT.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Known history of immunodeficiency (HIV). This medical entity can be exacerbated by
             PD-1 blockade.

          -  Any form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment excluding steroids. Attempts should be made to have patient on lowest
             possible dose of steroids. These medical entities can be exacerbated by PD-1 blockade.

          -  History of another malignancy in the previous 3 years, with a disease-free interval of
             < 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin, or in situ cervical cancer that has undergone potentially
             curative therapy. Patients who have undergone a bne marrow or stem-cell transplant for
             any malignancy are excluded.

          -  Has an active autoimmune disease requiring systemic treatment within the past 3 months
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires chronic systemic steroids or immunosuppressive agents. Subjects with vitiligo
             or resolved childhood asthma/atopy would be an exception to this rule. Subjects that
             require intermittent use of bronchodilators or local steroid injections will not be
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement or
             Sjorgen s syndrome will not be excluded from the study.

          -  Has a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis.

          -  Has an active infection requiring systemic antibiotics within 10 days of surgery.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject s
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

        Examples include:

          -  Hypertension (defined as 160/95) that is not controlled on medication

          -  Ongoing or active infection requiring systemic treatment

          -  Symptomatic congestive heart failure

          -  Unstable angina pectoris

          -  Cardiac arrhythmia

          -  Psychiatric illness/social situations or substance abuse disorders that would limit
             compliance with study requirements

          -  Any other illness or condition that the treating investigator feels would interfere
             with study compliance or would compromise the patient s safety or study endpoints.

               -  Is pregnant or breastfeeding, or expecting to conceive or father children within
                  the projected duration of the trial, starting with the pre-screening or screening
                  visit through 120 days after the last dose of trial treatment.

               -  The effects of pembrolizumab and HSPPC-96 on the developing human fetus are
                  unknown. For this reason and because checkpoint inhibitors and immunotherapeutic
                  vaccines as well as other therapeutic agents used in this trial are known to be
                  teratogenic, women of child-bearing potential and men must agree to use adequate
                  contraception (hormonal or barrier method of birth control; abstinence) prior to
                  study entry,and for the duration of study participation. 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.

               -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,
                  or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
                  ipilimumab or any other antibody or drug specifically targeting T-cell
                  co-stimulation or checkpoint pathways).

               -  On treatment for Hepatitis B or Hepatitis C or history of TB.

               -  Has received a live vaccine within 30 days prior to the first dose of trial
                  treatment

               -  Patients who have a history of allergic reactions attributed to compounds of
                  similar chemical or biologic composition to Pembrolizumab are not eligible. Known
                  hypersensitivity to any excipients of Pembrolizumab.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine whether the one-year overall survival (OS) is improved in newly diagnosed MGMT unmethylated GBM patients treated with RT + TMZ + Pembrolizumab followed by Pembrolizumab + TMZ +/- HSPPC-96 x 6 cycles (1 cycle is 9 weeks) months.
Time Frame:one year
Safety Issue:
Description:One-year overall survival

Details

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

Trial Keywords

  • Malignant Gliomas
  • Immunotherapy

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