Clinical Trials /

Personalized NeoAntigen Cancer Vaccine w RT Plus Pembrolizumab for Patients With MGMT Unmethylated, Newly Diagnosed GBM

NCT02287428

Description:

This research study is studying a new type of vaccine as a possible treatment for patients with glioblastoma. This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the intervention to use for further studies. "Investigational" means that the intervention is being studied and that research doctors are trying to find more about it. It also means that the FDA (U.S. Food and Drug Administration) has not approved the Personalized NeoAntigen Cancer Vaccine for any use in patients, including people with glioblastoma. The purpose of the initial study cohort (Cohort 1) is to determine if it is possible to make and administer safely a vaccine against glioblastoma by using information gained from specific characteristics of the participants tumor. It is known that glioblastomas have mutations (changes in genetic material) that are specific to an individual patient's tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that these proteins used in a vaccine may induce strong immune responses, which may help the body fight any tumor cells that could cause the glioblastoma to come back in the future. Three additional cohorts (1a, 1b, & 1c) were added to the study following completion of accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years. The rationale for adding these new cohorts is: 1) to assess the safety and feasibility of NeoVax when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1 administration impacts the immunogenicity of NeoVax. An additional sub-study cohort (1d) is being added for patients whose tumor is MGMT-methylated. Cohort 1d will enroll patients with tumors for which the MGMT status is methylated or partially methylated; patients on cohort 1d will receive standard daily temozolomide during radiation and as adjuvant therapy for up to six cycles following completion of radiation therapy. The rationale for adding cohort 1d is to determine the safety and feasibility of NeoVax when administered with pembrolizumab and temozolomide.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Personalized NeoAntigen Cancer Vaccine w RT Plus Pembrolizumab for Patients With MGMT Unmethylated, Newly Diagnosed GBM
  • Official Title: A Phase I Study of a Personalized NeoAntigen Cancer Vaccine With Radiotherapy Plus Pembrolizumab/MK-3475 Among MGMT Unmethylated, Newly Diagnosed Glioblastoma Patients

Clinical Trial IDs

  • ORG STUDY ID: 14-362
  • SECONDARY ID: 51986
  • NCT ID: NCT02287428

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Personalized NeoAntigen VaccineNeoVaxCoh 1 (Original Cohort): Standard RT Followed by NeoVax
PembrolizumabMK-3475, KeytrudaCoh 1a: Pembrolizumab w Std RT Followed by NeoVax + Pembro
TemozolomideConcurrent temozolomide; Concurrent TMZCoh 1d: Std RT+TMZ Followed by 6 Cyc TMZ + NeoVax + Pembro
TemozolomideAdjuvant temozolomide; Adjuvant TMZCoh 1d: Std RT+TMZ Followed by 6 Cyc TMZ + NeoVax + Pembro

Purpose

This research study is studying a new type of vaccine as a possible treatment for patients with glioblastoma. This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the intervention to use for further studies. "Investigational" means that the intervention is being studied and that research doctors are trying to find more about it. It also means that the FDA (U.S. Food and Drug Administration) has not approved the Personalized NeoAntigen Cancer Vaccine for any use in patients, including people with glioblastoma. The purpose of the initial study cohort (Cohort 1) is to determine if it is possible to make and administer safely a vaccine against glioblastoma by using information gained from specific characteristics of the participants tumor. It is known that glioblastomas have mutations (changes in genetic material) that are specific to an individual patient's tumor. These mutations can cause the tumor cells to produce proteins that appear very different from the body's own cells. It is possible that these proteins used in a vaccine may induce strong immune responses, which may help the body fight any tumor cells that could cause the glioblastoma to come back in the future. Three additional cohorts (1a, 1b, & 1c) were added to the study following completion of accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4 weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years. The rationale for adding these new cohorts is: 1) to assess the safety and feasibility of NeoVax when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1 administration impacts the immunogenicity of NeoVax. An additional sub-study cohort (1d) is being added for patients whose tumor is MGMT-methylated. Cohort 1d will enroll patients with tumors for which the MGMT status is methylated or partially methylated; patients on cohort 1d will receive standard daily temozolomide during radiation and as adjuvant therapy for up to six cycles following completion of radiation therapy. The rationale for adding cohort 1d is to determine the safety and feasibility of NeoVax when administered with pembrolizumab and temozolomide.

Detailed Description

      It is known that glioblastomas have mutations that are specific to an individual patient's
      tumor. These mutations can cause the tumor cells to produce proteins that appear very
      different from the body's own cells. It is possible that these proteins used in a vaccine may
      induce strong immune responses, which may help the body fight any tumor cells that could
      cause glioblastoma to recur.

      Methylguanine methyltransferase (MGMT) is a DNA repair protein which can be increased in some
      cancers, including glioblastoma. MGMT works to repair the DNA of cancer cells that are
      damaged by treatment. If a tumor is found to be "unmethylated", it means there is more MGMT
      present in the tumor than one that is "methylated".

      Methylation of MGMT is believed to make tumor cells more responsive to drugs like
      temozolomide. Studies have shown that temozolomide provides a very small improvement in
      outcome for many patients whose glioblastoma is MGMT-unmethylated.

      Patients with glioblastoma usually receive six weeks of radiation with a daily chemotherapy
      called temozolomide after their surgery, followed by six to twelve months of additional
      temozolomide. In this study, only participants whose tumors are MGMT-methylated will receive
      temozolomide; those participants whose tumors are MGMT-unmethylated will not receive
      temozolomide, as studies have shown that temozolomide provides a very small improvement in
      outcome for many patients whose glioblastoma is MGMT-unmethylated.

      On this trial, an initial cohort of participants (Cohort 1) will receive the Personalized
      NeoAntigen Vaccine (5 priming doses and 2 booster doses over ~ 20 weeks) after having
      completed six weeks of standard radiation. The study will examine the safety of the vaccine
      when given at several different time points and will examine the participant blood cells for
      signs that the vaccine induced an immune response.

      Three additional cohorts (1a, 1b, & 1c) were added to the study following completion of
      accrual to the original study cohort (cohort 1). Each new cohort receives NeoVax and
      radiation therapy as administered to cohort 1 and will also receive pembrolizumab: cohort 1a
      patients will start pembrolizumab w/in 2 weeks after start of RT, and continue every 3 weeks
      for up to 2 years; cohort 1b patients will start pembrolizumab 2-4 weeks after completion of
      NeoVax priming, and continue every 3 weeks for up to 2 years; cohort 1c patients will receive
      a single dose of pembrolizumab administered within 2 weeks after start of RT, re-start 2-4
      weeks after completion of NeoVax priming, and continue every 3 weeks for up to 2 years.

      The rationale for adding cohorts 1a, 1b and 1c is: 1) to assess the safety and feasibility of
      NeoVax when administered with pembrolizumab; and 2) to determine if the timing of anti-PD-1
      administration impacts the immunogenicity of NeoVax.

      An additional sub-study cohort (1d) is being added for patients whose tumor is
      MGMT-methylated. Cohort 1d will enroll patients with tumors for which the MGMT status is
      methylated or partially methylated; patients on cohort 1d will receive standard daily
      temozolomide during radiation and as adjuvant therapy for up to six cycles following
      completion of radiation therapy. The rationale for adding cohort 1d is to determine the
      safety and feasibility of NeoVax when administered with pembrolizumab and temozolomide.
    

Trial Arms

NameTypeDescriptionInterventions
Coh 1 (Original Cohort): Standard RT Followed by NeoVaxExperimentalAfter the screening procedures confirm participant eligible to participate in the research study (must be registered to within 6 weeks of resection): ~ 6 weeks of standard radiation therapy (RT) followed by an RT-recovery period. During that time, participant NeoAntigen Vaccine-Preparation is created (process takes ~ 12 weeks) After participant recovers from RT and vaccine is created, participant will re-screen to confirm participant is eligible to receive study vaccinations. Once registered, participant will proceed to receive study vaccinations: - NeoAntigen Vaccine: NeoVax will be administered on an individual basis using a dosing schedule that incorporates both priming and boost phases (~ 7 months total: 5 priming followed by 2 boost vaccine administrations)
  • Personalized NeoAntigen Vaccine
Coh 1a: Pembrolizumab w Std RT Followed by NeoVax + PembroExperimentalRT: Standard RT (60Gy) over 6 weeks Pembrolizumab: Starts within 2 weeks after start of RT, and continues every 3 weeks for up to 2 years NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 [priming doses], 78 and 134 [booster doses] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing
  • Personalized NeoAntigen Vaccine
  • Pembrolizumab
Coh 1b: Std RT Followed by NeoVax + PembrolizumabExperimentalRT: Standard RT (60Gy) over 6 weeks Pembrolizumab: Starts 2-4 weeks after completion of NeoVax priming, and continues every 3 weeks for up to 2 years NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 [priming doses], 78 and 134 [booster doses] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing
  • Personalized NeoAntigen Vaccine
  • Pembrolizumab
Coh 1c: Std RT (+ 1 dose Pembro) Followed by NeoVax & PemboExperimentalRT: Standard RT (60Gy) over 6 weeks Pembrolizumab: Single dose of pembrolizumab administered within 2 weeks after start of RT; re-starts 2-4 weeks after completion of NeoVax priming, and continues every 3 weeks for up to 2 years. NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 [priming doses], 78 and 134 [booster doses] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing
  • Personalized NeoAntigen Vaccine
  • Pembrolizumab
Coh 1d: Std RT+TMZ Followed by 6 Cyc TMZ + NeoVax + PembroExperimental• RT: Standard RT (60Gy) + concurrent daily temozolomide (TMZ) over 6 weeks. Concurrent TMZ @ 75 mg/m2/day for 6 weeks. Followed by: 6 cycles of Adjuvant temozolomide (TMZ): Starts 4-6 weeks after completion of RT. TMZ (150-200 mg/m2/day) on days 1-5 of each 28-day cycle for 6 cycles. Pembrolizumab: Starts 2-4 weeks after completion of NeoVax priming, and continues every 3 weeks for up to 2 years NeoVax: Starts in the Adjuvant setting - as soon as available after RT - and is administered on days 1, 4, 8, 15, 22 [priming doses], 78 and 134 [booster doses] o NeoVax Day 1 does not have to coincide with Pembrolizumab dosing
  • Personalized NeoAntigen Vaccine
  • Pembrolizumab
  • Temozolomide
  • Temozolomide

Eligibility Criteria

        I. Inclusion Criteria:

        Participants must meet the following criteria on screening examination to be eligible to
        participate in the study (labs/tests/assessments within 14 days prior to initial study
        registration unless otherwise specified)

          -  Participant is willing and able to give written informed consent

          -  Pathologically confirmed WHO grade IV glioblastoma or variants (gliosarcoma,
             glioblastoma with oligodendroglial features, giant cell glioblastoma) with adequate
             tumor material for genomic sequencing. Participants will be eligible if the original
             diagnosis was a lower grade glioma and a subsequent histologic diagnosis of
             glioblastoma or its variants was made, and patient received no prior therapy other
             than surgery

          -  The tumor must be primarily supratentorial in location as determined by diagnostic
             imaging performed preoperatively

          -  Radiographic contrast enhancement attributable to residual tumor on post-operative
             imaging performed within 72 hours of resection must not exceed 1 cm in maximal
             diameter in biperpendicular plances (greater than 1 cm in one plane but less than 1 cm
             in other planes will be allowed)

          -  CT or MRI within 14 days prior to start of study therapy

          -  Age ≥18 years

          -  Karnofsky performance status ≥ 70

          -  Participant is a candidate for, and agrees to receive conventional external beam
             radiotherapy. (Patients screening for Cohort 1d can be actively receiving - or already
             completed - their first line conventional external beam radiotherapy.)

          -  No corticosteroid dosing within 5 days of radiation therapy initiation (Cohorts 1a,
             1b, 1c, & 1d).

          -  Normal hematologic, renal and hepatic function as defined below:

               -  ANC: greater or equal to 1,000 /mcl

               -  Platelets: greater than or equal to 100,000 /mcl

               -  Hemoglobin: greater than or equal to 9 gm/dl

               -  International normalized ratio (INR) or prothrombin time: less than or equal to
                  1.5 times institutional ULN unless subject is receiving anticoagulant therapy as
                  long as PT or PTT is within therapeutic range of intended use of anticoagulants

               -  Activated partial thromboplatin time (aPTT): less than or equal to 1.5 X
                  institutional ULN unless subject is receiving anticoagulant therapy as long as PT
                  or PTT is within therapeutic range of intended use of anticoagulants

               -  Serum creatinine: less than or equal to 1.5 X institutional ULN

               -  Total bilirubin: less than or equal to 1.5 X institutional ULN (or less than or
                  equal to 3.0 X institutional ULN Gilbert's Syndrome) OR Direct bilirubin ≤
                  institutional ULN for subjects with total bilirubin levels > 1.5 institutional
                  ULN

               -  AST (SGOT) and ALT (SGPT): less than or equal to 2.5 X institutional ULN (or less
                  than or equal to 5.0 X institutional ULN Gilbert's Syndrome)

          -  MGMT promoter methylation status determined by an institutional CLIA-approved
             laboratory using a methylation specific PCR assay

          -  Adequate tumor content as determined by institutional pathologist for nucleic acid
             extraction and DNA sequence analysis

          -  Patients unable to undergo magnetic resonance (MR) imaging because of non-compatible
             devices can be enrolled, provided CT scans are obtained and are of sufficient quality.
             Patients without non-compatible devices may not have CT scans performed to meet this
             requirement

          -  An interval of at least 3 weeks between prior surgical resection to start of study
             therapy (or one week for stereotactic biopsy to start of study treatment);

          -  Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum
             sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial, because the
             effects NeoVax on the developing human fetus are unknown

          -  Participants cannot be breast feeding;

          -  Female participants enrolled in the study, who are not free from menses for greater
             than or equal to 2 years, post hysterectomy/oophorectomy, or surgically sterilized,
             must be willing to use either 2 adequate barrier methods or a barrier method plus a
             hormonal method of contraception to prevent pregnancy or to abstain from sexual
             activity throughout the study, starting with visit 1 through 120 days after the last
             dose of the study therapy;

          -  Approved contraceptive methods include for example; intra uterine device, diaphragm
             with spermicide, cervical cap with spermicide, male condoms, or female condom with
             spermicide. Spermicides alone are not an acceptable method of contraception;

          -  Male participants must agree to use an adequate method of contraception starting with
             the first dose of radiation therapy through 120 days after the last dose of study
             therapy.

        II. Exclusion Criteria:

        Participants who exhibit any of the following conditions at either screening timepoint will
        not be eligible for admission into or continuation on the study

          -  Stereotactic biopsy (without further resection);

          -  Tumor primarily localized in the infratentorial compartment or spinal cord - tumors
             with limited infratentorial compartment or spinal cord involvement are eligible;

          -  Radiographic or cytologic evidence of diffuse leptomeningeal extension - tumors with
             limited subependymal involvement are eligible;

          -  Participants who have received or plan to receive any additional treatment for
             glioblastoma aside from surgical resection and conventional radiotherapy (Cohort 1)
             and pembrolizumab (cohorts 1a, 1b and 1c) and temozolomide (cohort 1d), including -
             but not limited to - temozolomide (cohorts 1, 1a, 1b and 1c), stereotactic
             radiosurgery, placement of Gliadel (carmustine; BCNU) wafers, any other intratumoral
             or intracavitary treatment, brachytherapy, Novo-Tumor Treating Fields (Optune), or
             investigational therapeutic agents. (Cohort 1d participants may have already initiated
             or completed their RT with concomitant TMZ, and may have initiated their adjuvant TMZ
             at the time of study entry as long as they do not have evidence of progressive disease
             and have undergone a leukopheresis with adequate mononuclear cell collection.)

          -  Concomitant therapy with any anti-cancer agents, other investigational anti-cancer
             therapies, or immunosuppressive agents including but not limited to methotrexate,
             chloroquine, azathioprine, etc. within six months of study participation;

          -  History of severe allergic reactions attributed to any vaccine therapy for the
             prevention of infectious diseases;

          -  Active, known, or suspected autoimmune disease or immunosuppressive conditions that
             has required systemic treatment in the past 2 years (i.e. with use of disease
             modifying agents, corticosteroids or immunosuppressive drugs) with the exception of
             vitiligo, type 1 diabetes, residual autoimmune-related hypothyroidism requiring
             hormone replacement, or psoriasis not requiring systemic treatment. Replacement
             therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy
             for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
             treatment.

          -  Known chronic infections with HIV, hepatitis B (HBV) or C (HCV), Hepatitis B virus DNA
             and testing for HCV RNA must be undetectable.

          -  Uncontrolled intercurrent illness including, but not limited to ongoing or active
             infection requiring treatment, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia;

          -  Any underlying medical condition, psychiatric condition or social situation that in
             the opinion of the investigator would compromise study administration as per protocol
             or compromise the assessment of AEs;

          -  Planned major surgery;

          -  Pregnant women are excluded from this study because personalized neoantigen peptides
             and poly-ICLC are agents with unknown risks to the developing fetus. Because there is
             an unknown but potential risk of adverse events in nursing infants secondary to
             treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing
             women are excluded from this study;

          -  Individuals with a history of an invasive malignancy are ineligible except for the
             following circumstances; a) individuals with a history of invasive malignancy are
             eligible if disease-free for at least 3 years and are deemed by the investigator to be
             at low risk for recurrence of that malignancy; b) individuals with the following
             cancers are eligible if diagnosed and treated - carcinoma in situ of the breast, oral
             cavity or cervix and basal cell or squamous cell carcinoma of the skin;

        Coh 1a/1b/1c/1d Exclusions:

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used investigational device
             within 4 weeks of the first dose of treatment.

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., less than or equal to Grade1 or at baseline)
             from adverse events due to agents administered more than 4 weeks earlier.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., less than or equal
             to Grade 1 or at baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with less than or equal to Grade 2 neuropathy are an exception to
                  this criterion and may qualify for the study.

               -  Note: If subject received major surgery, subject must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  therapy.

               -  Note: Cohort 1d participants may have already received their radiation therapy
                  with concomitant temozolomide, and may have initiated their adjuvant
                  temozolomide, at the time of study entry as long as they do not have evidence of
                  progressive disease and have undergone a leukopheresis with adequate mononuclear
                  cell collection.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate proved
             the disease is stable (without evidence of progression by imaging for at least four
             weeks prior to the first dose of trial treatment and any neurologic symptoms have
             returned to baseline), have no evidence of new or enlarging brain metastases, and are
             not using steroids for at least 7 days prior to trial treatment. This exception does
             not include carcinomatous meningitis which is excluded regardless of clinical
             stability;

          -  Has known history of, or any evidence of active, non-infectious pneumonitis.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Has received a live vaccine within 30 days of planned start of study therapy. Examples
             of live vaccines include, but are not limited to, the following: measles, mumps,
             rubella, varicella/zoster, yellow fever, rabies, BDG, and Typhoid vaccine.

               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
                  are live attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cohorts 1, 1a, 1b, & 1c: Number of participants with Adverse Events as a measure of safety and tolerability
Time Frame:2 Years
Safety Issue:
Description:To evaluate the safety and tolerability of administering NeoVax plus pembrolizumab among newly diagnosed glioblastoma patients with MGMT unmethylated tumors

Secondary Outcome Measures

Measure:All Cohorts: Number of participants who achieve IFN-γ T-cell response at week 16 via ELISPOT assessments
Time Frame:2 Years
Safety Issue:
Description:This information will be used to assess the induction of neoantigen-specific cellular immune responses following administration of Neovax with or without pembrolizumab.
Measure:Cohorts 1, 1a, 1b, & 1c: Number of participants who are alive without progression at eight months after surgery resection
Time Frame:2 Years
Safety Issue:
Description:Estimate of the proportion of participants alive without disease progression at eight months after resection.
Measure:Cohort 1d: Number of participants who are alive without progression at 11 months after surgery resection
Time Frame:2 years
Safety Issue:
Description:Estimate of the proportion of participants alive without disease progression at eleven months after resection.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Last Updated

August 7, 2020