Clinical Trials /

Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma

NCT04201873

Description:

This phase I trial studies the side effects and how well of pembrolizumab and a vaccine therapy (ATL-DC vaccine) work in treating patients with glioblastoma that has come back (recurrent) and can be removed by surgery (surgically accessible). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vaccines, such as ATL-DC vaccine, may help the body build an effective immune response to kill tumor cells. Giving pembrolizumab and ATL-DC vaccine may work better in treating patients with glioblastoma compared to ATL-DC alone.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma
  • Official Title: Phase I Surgical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters for the PD-1 Antibody Pembrolizumab With Autologous Tumor Lysate-Pulsed Dendritic Cell Vaccination in Patients With Surgically Accessible Recurrent/Progressive Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 19-001090
  • SECONDARY ID: NCI-2019-07994
  • SECONDARY ID: 19-001090
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04201873

Conditions

  • Recurrent Glioblastoma

Interventions

DrugSynonymsArms
Dendritic Cell Tumor Cell Lysate VaccineDC tumor cell lysate vaccine, dendritic cell-pulsed tumor cell lysate vaccineGroup A (pembrolizumab, ATL-DC, poly ICLC)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Group A (pembrolizumab, ATL-DC, poly ICLC)
Poly ICLCHiltonol, Poly I:Poly C with Poly-L-Lysine Stabilizer, poly-ICLC, PolyI:PolyC with Poly-L-Lysine Stabilizer, Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose, Polyriboinosinic-Polyribocytidylic Acid-Polylysine Carboxymethylcellulose, Stabilized Polyriboinosinic/Polyribocytidylic AcidGroup A (pembrolizumab, ATL-DC, poly ICLC)

Purpose

This phase I trial studies the side effects and how well of pembrolizumab and a vaccine therapy (ATL-DC vaccine) work in treating patients with glioblastoma that has come back (recurrent) and can be removed by surgery (surgically accessible). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vaccines, such as ATL-DC vaccine, may help the body build an effective immune response to kill tumor cells. Giving pembrolizumab and ATL-DC vaccine may work better in treating patients with glioblastoma compared to ATL-DC alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the influence of pembrolizumab on the cell cycle-related genetic signature
      within the tumor microenvironment of progressive/recurrent glioblastoma.

      II. To evaluate the influence of adjuvant autologous tumor lysatepulsed dendritic cell
      (ATL-DC) vaccination on peripheral T cell responses.

      III. To evaluate the safety and tolerability of pembrolizumab and ATL-DC vaccination in
      progressive/recurrent glioblastoma.

      SECONDARY OBJECTIVES:

      I. To estimate the 6 month progression-free survival (PFS6) based on Response Assessment in
      Neuro-Oncology (RANO) criteria in patients treated on both arms of the clinical trial.

      II. To calculate the overall survival of recurrent glioblastoma patients treated on both arms
      of the clinical trial.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the associations between exploratory biomarkers, clinical outcomes, and
      adverse events which include:

      Ia. Estimating the correlation of quantitative assessments of tumor infiltrating lymphocyte
      (TIL) density or the interferon (IFN) gamma-associated genetic signature with clinical
      responses to pembrolizumab and ATL-DC in recurrent glioblastoma patients.

      Ib. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS and overall
      survival (OS) as defined by RANO.

      Ic. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS, and OS as defined
      by immunotherapy RANO (iRANO).

      Id. Exploring whether oligoclonal T cell populations within tumor tissue are similarly
      expanded in peripheral blood after ATL-DC vaccination and/or pembrolizumab, and correlating
      with clinical responses.

      Ie. Exploring whether changes in specific magnetic resonance imaging (MRI) parameters
      correlate with tumor and peripheral blood immune responses.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      GROUP A: Beginning 14 days prior to scheduled surgery, patients receive pembrolizumab
      intravenously (IV) over 30 minutes. After surgery, patients receive pembrolizumab IV over 30
      minutes on day 1. Cycle repeats every 3 weeks in the absence of disease progression or
      unacceptable toxicity. Patients also receive ATL-DC intradermally (ID) with poly ICLC
      intramuscularly (IM) every 2 weeks for up to 3 doses in the absence of disease progression or
      unacceptable toxicity.

      GROUP B: Beginning 14 days prior to scheduled surgery, patients receive placebo IV. After
      surgery, patients receive placebo IV on day 1. Cycle repeats every 3 weeks in the absence of
      disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC
      IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 3
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Group A (pembrolizumab, ATL-DC, poly ICLC)ExperimentalBeginning 14 days prior to scheduled surgery, patients receive pembrolizumab IV over 30 minutes. After surgery, patients receive pembrolizumab IV over 30 minutes on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.
  • Dendritic Cell Tumor Cell Lysate Vaccine
  • Pembrolizumab
  • Poly ICLC
Group B (placebo, ATL-DC, poly ICLC)Active ComparatorBeginning 14 days prior to scheduled surgery, patients receive placebo IV. After surgery, patients receive placebo IV on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.
  • Dendritic Cell Tumor Cell Lysate Vaccine
  • Poly ICLC

Eligibility Criteria

        Inclusion Criteria:

          -  Participants with histologically confirmed diagnosis of surgically accessible
             recurrent/progressive glioblastoma will be enrolled in this study

          -  Be at first or second relapse (Note: relapse is defined as progression following
             initial therapy, i.e., radiation +/- chemotherapy. For participants who had prior
             therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be
             considered the first relapse)

          -  Must be undergoing surgery that is clinically indicated, and eligible for resection
             with the expectation that the surgeon is able to resect at least 2 gram of tumor for
             lysate and research with low risk of inducing neurological injury

          -  A male participant must agree to use a contraception during the treatment period and
             for at least 120 days after the last dose of study treatment and refrain from donating
             sperm during this period

          -  A female participant who has childbearing potential must have negative urine or serum
             pregnancy test 72 hrs prior to the first dose and be willing to use adequate method of
             contraception for course of study and 120 days after last dose

          -  The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial

          -  Have unequivocal evidence for contrast enhancing tumor progression by RANO criteria
             based on MRI scan within 14 days prior to randomization

          -  Have a minimum tumor size of 2 x 2 cm^2 based on MRI scan prior to surgery

          -  An interval of the following durations prior to randomization:

               -  At least 28 days from prior surgical resection

               -  At least 7 days from prior stereotactic biopsy

               -  At least 12 weeks from prior radiotherapy, unless there is unequivocal histologic
                  confirmation of tumor progression

               -  At least 23 days from prior chemotherapy

               -  At least 42 days from nitrosureas

          -  Have sufficient archival tumor tissue confirming glioblastoma or variants for
             submission following registration. The following amount of tissue is required: 1
             formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 10 FFPE
             ,unstained slides (5um thick)

          -  Have a Karnofsky performance status (KPS) >= 70

          -  Absolute neutrophil count (ANC) >= 1500/uL (uL=microliter) (collected within 14 days
             prior to the start of study treatment)

          -  Platelets >= 100 000/uL (collected within 14 days prior to the start of study
             treatment)

          -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (collected within 14 days prior to the start
             of study treatment)

               -  Criteria must be met without erythropoietin dependency and without packed red
                  blood cell (pRBC) transfusion within last 2 weeks

          -  Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
             clearance >= 30 mL/min for participant with creatinine levels > 1.5 x institutional
             ULN (collected within 14 days prior to the start of study treatment) (glomerular
             filtration rate [GFR] can also be used in place of creatinine or creatinine clearance
             [CrCl])

               -  Creatinine clearance (CrCl) should be calculated per institutional standard

          -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
             bilirubin levels > 1.5 x ULN (collected within 14 days prior to the start of study
             treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT[) =< 2.5 x
             ULN (=< 5 x ULN for participants with liver metastases) (collected within 14 days
             prior to the start of study treatment)

          -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
             participant is receiving anticoagulant therapy as long as PT or activated partial
             thromboplastin time (aPTT) is within therapeutic range of intended use of
             anticoagulants (collected within 14 days prior to the start of study treatment)

          -  aPTT =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT
             or aPTT is within therapeutic range of intended use of anticoagulants (collected
             within 14 days prior to the start of study treatment)

        Exclusion Criteria:

          -  A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test
             within 72 hours prior to randomization. If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4, OX-40, CD137)

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to randomization

               -  Note: Participants must have recovered from all adverse events (AEs) due to
                  previous therapies to =< grade 1 or baseline. Participants with =< grade 2
                  neuropathy may be eligible

               -  Note: If participant received major surgery, they must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  study treatment

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system
             (CNS) disease

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             calmette-guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (eg, FluMist) are live attenuated vaccines and are not allowed

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment

               -  Note: Participants who have entered the follow-up phase of an investigational
                  study may participate as long as it has been 4 weeks after the last dose of the
                  previous investigational agent

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years

               -  Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
                  of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in
                  situ) that have undergone potentially curative therapy are not excluded

          -  Has known tumor primarily localized to the brainstem or spinal cord

          -  Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known history of human immunodeficiency virus (HIV)

          -  Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
             reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV]
             ribonucleic acid [RNA] is detected) infection. Note: no testing for hepatitis B and
             hepatitis C is required unless mandated by local health authority

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

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

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of trial treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Cell cycle-related signature
Time Frame:Up to 6 years
Safety Issue:
Description:Two-sample T-test with Bonferroni adjustment will be used to compare the increase number of expanded TCR clones after dendritic cell (DC) vaccination with PD-1 blockade in Group A versus (vs) DC vaccination with a placebo in Group B.

Secondary Outcome Measures

Measure:6 month progression-free survival (PFS6)
Time Frame:At 6 months
Safety Issue:
Description:Efficacy will be measured by percent PFS6 as defined by Response Assessment in Neuro-Oncology (RANO) criteria. Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate. Percent PFS6 will be estimated from the KM curves and compared to historical controls.
Measure:Overall survival (OS)
Time Frame:Up to 6 years
Safety Issue:
Description:OS will be compared using log rank test.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

December 13, 2019