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

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ClinicalTrials.gov Identifier: NCT03961971
Recruitment Status : Not yet recruiting
First Posted : May 23, 2019
Last Update Posted : May 27, 2019
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Drug: MBG453 Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of Anti-Tim-3 in Combination With Anti-PD-1 and SRS in Recurrent GBM
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (MBG453, spartalizumab, stereotactic radiosurgery)
Patients 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.
Drug: MBG453
Patients 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.
Other Names:
  • spartalizumab
  • stereotactic radiosurgery




Primary Outcome Measures :
  1. 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 ]
    Number of participants experiencing SAEs, as defined by NCI CTC v5.0


Secondary Outcome Measures :
  1. 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 ]
    Proportion of participants who experience grade 3 or higher toxicity, graded according to the NCI CTC v5.0

  2. 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 ]
    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.

  3. Overall survival [ Time Frame: From the date of initial diagnosis until the date of death from any cause assessed up to 24 months ]
    Overall survival as estimated using the Kaplan-Meier method.

  4. 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 ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03961971


Contacts
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Contact: Kelly Szajna Szajna, RN, BSN 410-502-4081 kszajna1@jhmi.edu
Contact: Whitney Isennock, RN, MSN 410-955-7008 wwebb10@jhmi.edu

Locations
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United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Kelly Szajna Szajna    410-502-4081    kszajna1@jhmi.edu   
Contact: Whitney Isennock    4109557008    wwebb10@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Michael Lim, MD Johns Hopkins University/Sidney Kimmel Cancer Center

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03961971     History of Changes
Other Study ID Numbers: J18150
IRB00104226 ( Other Identifier: JHM IRB )
First Posted: May 23, 2019    Key Record Dates
Last Update Posted: May 27, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Immunotherapy

Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue