Clinical Trials /

Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)

NCT03277638

Description:

The purpose of this study is to test the side effects and efficacy of using Laser Interstitial Thermotherapy (LITT) combined with Pembrolizumab. LITT is a minimally invasive surgical technique that uses a laser to heat brain tumors. Pembrolizumab is an investigational (experimental) drug that works by helping participants' immune system work correctly to detect and fight cancer cells. Pembrolizumab is experimental because it is not approved by the Food and Drug Administration (FDA), for this use, though it is approved to treat other cancers.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)
  • Official Title: Phase I/II Study of Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM)

Clinical Trial IDs

  • ORG STUDY ID: CASE3316
  • NCT ID: NCT03277638

Conditions

  • Glioblastoma, Adult

Interventions

DrugSynonymsArms
Pembrolizumab at 7 days priorPembrolizumabPembrolizumab injections 7 days before surgery
Pembrolizumab at 14 days postPembrolizumabPembrolizumab injections 14 days after surgery
Pembrolizumab at 35 days postPembrolizumabPembrolizumab injections 35 days after surgery

Purpose

The purpose of this study is to test the side effects and efficacy of using Laser Interstitial Thermotherapy (LITT) combined with Pembrolizumab. LITT is a minimally invasive surgical technique that uses a laser to heat brain tumors. Pembrolizumab is an investigational (experimental) drug that works by helping participants' immune system work correctly to detect and fight cancer cells. Pembrolizumab is experimental because it is not approved by the Food and Drug Administration (FDA), for this use, though it is approved to treat other cancers.

Detailed Description

      Primary Objectives:

        1. Phase I: To determine the optimal timing for combining LITT and pembrolizumab in
           patients with rGBM:

           • To determine the feasibility, safety, tolerability and side effect profiles for
           combining LITT and pembrolizumab at various time points pre-LITT vs. post-LITT (Phase
           I).

        2. Phase II: To estimate the response to pembrolizumab combined with LITT in patients with
           rGBM;

           • To estimate the response rate after treatment with LITT combined with pembrolizumab in
           patients with rGBM (Phase II).

        3. To collect and record the side effect profiles for combining LITT and pembrolizumab
           (Phase I and Phase II).

      Secondary Objectives:

        1. To determine the effect of pembrolizumab on systemic immune microenvironment in patients
           with rGBM.

        2. To determine the effect of pembrolizumab on the intra-tumoral immunosuppressive
           microenvironment within rGBM.

        3. Secondary for Phase II, to estimate progression free survival (PFS) and overall survival
           (OS) after treatment with LITT combined with pembrolizumab in patients with rGBM (Phase
           II).

        4. Measure radiological response using both conventional RANO criterion, a modified RANO
           (RANOi) designed specifically for immunotherapy response assessment, as well as MRI
           fingerprinting (MRF), recently demonstrated by the PI and collaborators to accurately
           and precisely distinguish recurrent GBM from radiation injury.

        5. Correlate clinical and radiological response to known biomarkers of GBM such as
           Isocitrate Dehydrogenase 1 (IDH-1) mutations, Isocitrate Dehydrogenase 2 (IDH-2)
           mutations, Methyl-Guanine Methyl Transferase (MGMT) promoter methylation, Phosphatase
           and tensin homologue (PTEN) loss and KI-67.

      Study Design:

      The Phase I component will involve up to two of a possible 3 cohorts of 3-4 patients each for
      a total of 6-8 evaluable patients. Each patient will undergo a stereotactic biopsy. If GBM or
      Gliosarcoma is confirmed by frozen section, patients will undergo LITT then treatment with
      200 mg pembrolizumab IV. Cohort I will receive pembrolizumab on post operative day 14 and
      every 3 weeks thereafter. In the event that one patient suffers non-hematologic toxicity of
      grade 3 or more, or if hematologic toxicity is grade 4 or higher, the investigators will
      delay the 2nd dose of pembrolizumab by 3 weeks and a 4th patient will be accrued. If there
      are two patients in the initial cohort with non-hematologic toxicities grade 3, or if
      hematological toxicity in two patients is grade 4 or higher, the second cohort will delay
      initiation of pembrolizumab until post operative day 35 after LITT. Conversely, if there are
      no non-hematologic adverse events (AEs) of grade 3 or higher, the investigators will proceed
      to cohort IB using the same dose of pembrolizumab given 7 days prior to surgery, then every 3
      weeks. Similarly, feasibility and safety will be addressed as above in deciding whether or
      not to proceed to the next cohort.

      The Phase II component of the study will consist of additional patients receiving
      pembrolizumab at the earliest tolerated time post LITT:

        -  14 days post-op

        -  -7 days pre-op;

        -  35 days post-opto achieve a total of 23 evaluable patients at the earliest tolerated
           dose.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab injections 7 days before surgeryExperimentalPatients will have intravenous pembrolizumab 7 days before surgery with Laser Interstitial Thermotherapy
  • Pembrolizumab at 7 days prior
Pembrolizumab injections 14 days after surgeryExperimentalPatients will have intravenous pembrolizumab 14 days after surgery with Laser Interstitial Thermotherapy
  • Pembrolizumab at 14 days post
Pembrolizumab injections 35 days after surgeryExperimentalPatients will have intravenous pembrolizumab 35 days after surgery with Laser Interstitial Thermotherapy
  • Pembrolizumab at 35 days post

Eligibility Criteria

        Inclusion Criteria:

          -  Histopathologically proven diagnosis of glioblastoma or gliosarcoma prior to
             registration by pathology report;

          -  The tumor must be confined to the supratentorial compartment

          -  The Formaldehyde Fixed-Paraffin Embedded tumor tissue block must be available to be
             sent for retrospective central pathology review after registration).

          -  History/physical examination within 7 days prior to registration

          -  Karnofsky performance status ≥ 60 within 7 days prior to registration

          -  Adequate Organ Function Laboratory Values

               -  Absolute neutrophil count (ANC) ≥1,500/mcL

               -  Platelets ≥100,000/mcL

               -  Hemoglobin ≥9.0 g/gL or ≥5.6 mmol/L, without recent transfusion

               -  Creatine ≤1.7 x upper limit of normal (ULN) or Measure or Calculated creatinine
                  clearance ≥ 60.0mL/min for subject with creatinine levels > 1.5 X institutional
                  ULN (GFR can also be used in place of creatinine or CrCl)

               -  Total bilirubin ≤ 1.5 x ULN or Direct bilirubin ≤ ULN for subjects with total
                  bilirubin levels > 1.5 x ULN

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for subjects with liver
                  metastases

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN unless
                  subject is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants

               -  Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants

          -  Adequate hematologic function based on complete blood count (CBC)/differential within
             7 days prior to registration defined as follows:

               -  Absolute neutrophil count ≥ 1,500 cells/mm3;

               -  Platelet count ≥ 100,000 cells/mm3

               -  Hgb > 9 g/dL (can be achieved with transfusion)

          -  Adequate renal function within 7 days prior to registration defined as follows:

               -  Blood Urea Nitrogen (BUN) ≤ 30 mg/dl and

               -  Serum creatinine ≤ 1.7 mg/dl

          -  Adequate hepatic function within 7 days prior to registration defined as follows:

               -  Total bilirubin (except patients with Gilbert's Syndrome, who are eligible for
                  the study but exempt from the total bilirubin eligibility criterion) ≤ 2.0 mg/dl
                  and

               -  Alanine Aminotransferase (ALT) and Aspartate Amino Transferase (AST) ≤ 2.5 x ULN

          -  The patient must have completed chemoradiation with Radiotherapy and Temozolomide of
             the primary tumor according to standards of care

          -  The treating physician expects that the patient will not require more than physiologic
             replacement dose of steroids defined as 32 mg of cortisone per day or its equivalent.

          -  Patients must have received no more than 3 prior therapies for Recurrent High Grade
             Glioma

          -  Subjects must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of study medication.
             If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required.

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year.

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

          -  Tumor diameter in the plane perpendicular to LITT trajectory must be ≤ 3.5 cm in
             diameter

          -  It must be the surgeon's expectation that ≥ 90 of the tumor can be treated with LITT
             to the yellow thermal damage threshold (TdT) line (ie, 43 degrees for 2 min)

          -  Tumor must be Unifocal & Unilateral

        Exclusion Criteria:

          -  Use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or
             intracavitary or convectional enhanced delivery of therapy in the past

          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
             for a minimum of 3 years

          -  Severe, active co-morbidity defined as follows:

               -  Unstable angina within the last 6 months prior to registration

               -  Transmural myocardial infarction within the last 6 months prior to registration

               -  Evidence of recent myocardial infarction or ischemia by the findings of S-T
                  elevations of ≥ 2 mm using the analysis of an EKG performed within 7 days prior
                  to registration

               -  New York Heart Association grade II or greater congestive heart failure requiring
                  hospitalization within 12 months prior to registration

               -  History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
                  within 6 months prior to registration

               -  Serious and inadequately controlled cardiac arrhythmia

               -  Significant vascular disease (e.g., aortic aneurysm, history of aortic
                  dissection) or clinically significant peripheral vascular disease

               -  Evidence of bleeding diathesis or coagulopathy

               -  Serious or non-healing wound, ulcer, or bone fracture or history of abdominal
                  fistula, gastrointestinal perforation, intra-abdominal abscess major surgical
                  procedure, open biopsy, or significant traumatic injury within 28 days prior to
                  registration, with the exception of the craniotomy for tumor resection.

               -  Known history of Tuberculosis

               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time
                  of registration

               -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness
                  requiring hospitalization or precluding study therapy at the time of registration

               -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

               -  Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease
                  Control and Prevention (CDC) definition; note, however, that HIV testing is not
                  required for entry into this protocol. The need to exclude patients with AIDS
                  from this protocol is necessary because the treatments involved in this protocol
                  may be significantly immunosuppressive and worsen the patient's HIV symptoms.

               -  Active connective tissue disorders, such as lupus or scleroderma, which in the
                  opinion of the treating physician may put the patient at high risk for
                  immunologic toxicity.

               -  History of (non-infectious) pneumonitis that required steroids, evidence of
                  interstitial lung disease or active, non-infectious pneumonitis

               -  Patients with active autoimmune disease or history of autoimmune disease that
                  might recur, which may affect vital organ function or require immune suppressive
                  treatment including systemic corticosteroids, should be excluded. These include
                  but are not limited to patients with a history of immune related neurologic
                  disease, multiple sclerosis, autoimmune (demyelinating) neuropathy,
                  Guillain-Barre syndrome or Chronic Inflammatory Demyelinating Polyneuropathy,
                  myasthenia gravis; systemic autoimmune disease such as Systemic Lupus
                  Erythematosus, connective tissue diseases, scleroderma, inflammatory bowel
                  disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a
                  history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
                  phospholipid syndrome should be excluded because of the risk of recurrence or
                  exacerbation of disease.

               -  Of note, patients with vitiligo, endocrine deficiencies including thyroiditis
                  managed with replacement hormones including physiologic corticosteroids are
                  eligible. Patients with rheumatoid arthritis and other arthropathies, Sjögren's
                  syndrome and psoriasis controlled with topical medication and patients with
                  positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies
                  should be evaluated for the presence of target organ involvement and potential
                  need for systemic treatment but should otherwise be eligible.

               -  Any other major medical illnesses or psychiatric impairments that in the
                  investigator's opinion will prevent administration or completion of protocol
                  therapy.

               -  Has a known additional malignancy that is progressing or requires active
                  treatment. Exceptions include basal cell carcinoma of the skin or squamous cell
                  carcinoma of the skin that has undergone potentially curative therapy or in situ
                  cervical cancer.

               -  Has known active central nervous system (CNS) metastases and/or carcinomatous
                  meningitis. Subjects with previously treated brain metastases may participate
                  provided they are 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 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 (eg, thyroxine, insulin, or
                  physiologic corticosteroid replacement therapy for adrenal or pituitary
                  insufficiency, etc.) is not considered a form of systemic treatment.

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

               -  Has an active infection requiring systemic therapy?

               -  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.

               -  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 trial, starting with the pre-screening or screening
                  visit through 120 days after the last dose of trial treatment.

               -  Has received prior therapy with an anti-Programmed Death 1 (PD-1), anti-
                  Programmed Death-ligand 1 (PD-L1), or anti- Programmed Death-ligand 1 (PD-L2)
                  agent.

               -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV ½ antibodies).

               -  Has known active Hepatitis B (e.g., HbsAg reactive) or Hepatitis C (eg, HCV RNA
                  [qualitative] is detected).

               -  Has received a live vaccine within 30 days of planned start of study therapy. ---
                  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.

          -  Patient must have < 1.0 cm midline shift pre-operative

          -  History of severe hypersensitivity reaction to any monoclonal antibody including
             pembrolizumab.

          -  Patients who cannot safely undergo MRI due to non-MRI compatible pacemaker, or other
             reason.

          -  Patients who have tumors for which the Gd-enhancing mass appears to be covered ≤ 90%
             using 2 catheters and assuming a 3.0 cm diameter based on pre-operative planning are
             unlikely to have adequate LITT and thus ineligible for the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I Objective: Optimal timing of LITT with pembrolizumab
Time Frame:Up to 24 months after beginning Pembrolizumab
Safety Issue:
Description:Response rates for the Phase II component will be calculated and compared to historical controls using chi-square tests or Fishers exact tests.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:Up to 24 months after beginning Pembrolizumab
Safety Issue:
Description:defined as time from diagnosis to documented progression
Measure:overall survival
Time Frame:Up to 24 months after beginning Pembrolizumab
Safety Issue:
Description:defined as time from diagnosis to death
Measure:The proportion of patients who achieve progression free survival at 6 months (PFS6)
Time Frame:Up to 6 months after diagnosis
Safety Issue:
Description:Proportion of patients who do not progress at 6 months
Measure:The proportion of patients who achieve progression free survival at 12 months (PFS12)
Time Frame:Up to 12 months after diagnosis
Safety Issue:
Description:Proportion of patients who do not progress at 12 months
Measure:The proportion of patients who achieve progression free survival at 24 months (PFS24)
Time Frame:Up to 24 months after diagnosis
Safety Issue:
Description:Proportion of patients who do not progress at 24 months

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Case Comprehensive Cancer Center

Trial Keywords

  • recurrent glioblastoma
  • brain cancer

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