Clinical Trials /

Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS in Recurrent GBM

NCT03961971

Description:

This phase I trial studies the side effects of stereotactic radiosurgery with MBG453 and spartalizumab in treating patients with recurrent glioblastoma multiforme (GBM). Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor to more precisely target the cancer. Monoclonal antibodies, such as MBG453 and spartalizumab may interfere with the ability of tumor cells to grow and spread. Giving stereotactic radiosurgery together with immunotherapy may be a better treatment for GBM.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS in Recurrent GBM
  • Official Title: A Phase I Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS in Recurrent GBM

Clinical Trial IDs

  • ORG STUDY ID: J18150
  • SECONDARY ID: IRB00104226
  • NCT ID: NCT03961971

Conditions

  • Glioblastoma Multiforme

Interventions

DrugSynonymsArms
MBG453spartalizumab, stereotactic radiosurgeryTreatment (MBG453, spartalizumab, stereotactic radiosurgery)

Purpose

This phase I trial studies the side effects of stereotactic radiosurgery with MBG453 and spartalizumab in treating patients with recurrent glioblastoma multiforme (GBM). Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor to more precisely target the cancer. Monoclonal antibodies, such as MBG453 and spartalizumab may interfere with the ability of tumor cells to grow and spread. Giving stereotactic radiosurgery together with immunotherapy may be a better treatment for GBM.

Detailed Description

      Primary Objectives To determine safety of MBG453 given in combination with spartalizumab and
      SRS in patients with recurrent GBM.

      Secondary Objectives

      To assess the preliminary anti-tumor activity using the following measures:

        1. To estimate overall survival

        2. To estimate progression-free survival

        3. To estimate Radiographic Response (RANO and iRANO)

        4. To evaluate pain for patients undergoing the treatment of anti-TIM3 and anti-PD1 in
           combination with SRS

      Exploratory Objectives

        1. To assess the effects of MGB453, spartalizumab and their combination with SRS on immune
           cells in peripheral blood, including but not limited to the T cell compartments, myeloid
           cells, and serum proteins (cytokines and other immune modulators).

        2. To assess the pharmacodynamic activity in tumor tissue and peripheral blood in treated
           subjects who undergo tumor biopsies as clinically indicated.

        3. To explore potential associations between biomarker measures and anti-tumor activity by
           analyzing markers of inflammation, immune activation, host tumor growth factors, and
           tumor-derived proteins in the pre-treatment and on-treatment setting.

        4. To explore characteristics of tumor immune microenvironment change after the treatment.

      OUTLINE:

      Patients receive MBG453 and spartalizumab intravenously (IV) over 30 minutes each on Day 1.
      Patients then undergo stereotactic radiosurgery on Day 8 per standard of care. Courses with
      MBG453 and spartalizumab repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (MBG453, spartalizumab, stereotactic radiosurgery)ExperimentalPatients receive MBG453 and spartalizumab IV over 30 minutes on Day 1. Patients then undergo stereotactic radiosurgery on Day 8. Courses with MBG453 and spartalizumab repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • MBG453

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must provide written informed consent prior to any screening procedures.

          2. Age 18 years or older.

          3. Willing and able to comply with scheduled visits, treatment plan and laboratory tests

          4. Subjects must have histologically proven WHO Grade IV Glioblastoma or gliosarcoma AND
             A.) The target, including resection cavity of recurrence and contrast enhancing
             imaging abnormaility must have a size of 4 cm or less in maximal dimension B) Must
             have received first-line multimodal therapy with surgery (resection or biopsy)
             followed by temozolomide (unless known MGMT promoter unmethylated) and radiation
             (subjects with GBM must have received temozolomide and radiation concurrently).
             Patients must have completed at least 21 days of combination temozolomide and
             radiation treatment.

             BC) Must be in first recurrence of either GBM or gliosarcoma. Recurrence must be
             confirmed by diagnostic biopsy/surgery with local pathology review OR
             contrast-enhanced MRI measurable by RANO criteria. An interval of at least 12 weeks
             after the end of combination temozolomide and radiation therapy is required unless
             there is i.) Histopathologic confirmation of recurrent tumor, or ii) new enhancement
             on MRI outside of the radiotherapy treatment field

          5. Prior gamma knife, stereotactic radiosurgery, or other focal high-dose radiotherapy is
             allowed but the subject must have either histopathologic confirmation of recurrent
             tumor, or new enhancement on MRI outside of the radiotherapy treatment field

          6. Archived tumor tissue available from initial diagnosis of Grade IV GBM or gliosarcoma

          7. Patient has available tumor for MGMT methylation status

          8. Karnofsky Performance Status ≥ 70

          9. Must have ability to undergo MRI scans

         10. Must be > 30 days since last chemotherapy

         11. Measureable disease defined as ≥ 1 cm (patients may have gross total resection, but
             should have measurable disease preoperatively)

         12. Patient has recovered from severe toxicity of prior therapy

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

             WBC ≥ 2,000/mcL absolute neutrophil count ≥ 1,500/mcL platelets ≥ 100,000/mcL
             hemoglobin ≥ 9.0 g/dL lymphocytes > 1,000/mcL total bilirubin ≤ 1.5X institutional
             upper limit of normal AST/ALT ≤ 3.0 X institutional upper limit of normal creatinine ≤
             1.5X institutional upper limit of normal OR Creatinine clearance (CrCl) ≥ 50 mL/min
             (using the Cockcroft-Gault formula)

         14. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test within -7 days prior to the start of therapy. Women must not be breastfeeding.

         15. Women of child bearing potential (WOCBP) and men must use a reliable form of
             contraception during the study treatment period and for 150 days following the last
             dose of study drug. In order for a woman to be determined not of child-bearing
             potential, she must have ≥ 12 months of non-therapy-induced amenorrhea or be
             surgically sterile.

        Exclusion Criteria:

          1. History of other malignancy, unless the patient has been disease-free for at least 3
             years. Adequately treated basal cell carcinoma or squamous cell skin cancer is
             acceptable regardless of time, as well as localized prostate carcinoma or cervical
             carcinoma in situ after curative treatment.

          2. Any known metastatic extracranial or leptomeningeal disease.

          3. Evidence of acute intracranial / intra-tumoral hemorrhage

          4. Receiving greater than 4 mg dexamethasone/day (or equivalent amount of an alternative
             corticosteroid) for a minimum of 5 days prior to screening visit. *NOTE: Subjects with
             an autoimmune condition requiring systemic treatment with either corticosteroids (> 10
             mg daily prednisone or equivalent) or other immunosuppressive medications within 14
             days of randomization. Inhaled or topical steroids, and adrenal replacement steroid
             doses > 10 mg daily prednisone or equivalent, are permitted in the absence of active
             autoimmune disease

          5. Prior treatment with immunotherapies, bevacizumab, or experimental anti-cancer
             therapies

          6. Pregnant or nursing (lactating) women

          7. Known positive history of HIV, active Hepatitis B, and/or active Hepatitis C
             infection.

          8. Subjects with active, or recent history of known or suspected autoimmune disease.
             Subjects with Type 1 diabetes mellitus, hypothyroidism only requiring hormone
             replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger are permitted to enroll

          9. Major surgery, outside of a craniotomy/resection, within 2 weeks of the first dose of
             study treatment (mediastinoscopy, insertion of a central venous access device, and
             insertion of a feeding tube are not considered major surgery).

         10. Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within
             4 weeks of initiation of study treatment

         11. Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the subject to receive protocol therapy, or
             interfere with the interpretation of study results.

         12. Subjects with interstitial lung disease that is symptomatic or may interfere with the
             detection or management of suspected drug-related pulmonary toxicity

         13. History of evidence upon physical/neurological examination of other central nervous
             system condition (i.e. seizures, abscess) unrelated to cancer, unless adequately
             controlled by medication or considered not potentially interfering with protocol
             treatment.

         14. History of allergy or hypersensitivity to study drug components.

         15. Prisoners or subjects who are involuntarily incarcerated.

         16. Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (e.g. infections disease) illness.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with serious adverse events (SAE) graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 5.0
Time Frame:Up to 12 weeks after first dose of study treatment
Safety Issue:
Description:Number of participants experiencing SAEs, as defined by NCI CTC v5.0

Secondary Outcome Measures

Measure:Proportion of participants who experience grade 3 or higher toxicity, graded according to the NCI CTC v5.0
Time Frame:Up to 100 days after completion of study treatment
Safety Issue:
Description:Proportion of participants who experience grade 3 or higher toxicity, graded according to the NCI CTC v5.0
Measure:Progression-free survival
Time Frame:From the date of initial diagnosis (at surgery) until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Progression-free survival estimated using the Kaplan-Meier method. Progression as defined by Response Assessment in Neuro-oncology (RANO) criteria: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.
Measure:Overall survival
Time Frame:From the date of initial diagnosis until the date of death from any cause assessed up to 24 months
Safety Issue:
Description:Overall survival as estimated using the Kaplan-Meier method.
Measure:Objective Response
Time Frame:From date of baseline scan until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Proportion of participants who have objective PR or CR during the course of treatment and a measurable disease indicated in baseline scan. Progression is defined by Response Assessment in Neuro-oncology (RANO) criteria: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • Immunotherapy

Last Updated