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Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)

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ClinicalTrials.gov Identifier: NCT03018288
Recruitment Status : Recruiting
First Posted : January 12, 2017
Last Update Posted : December 3, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

GBM refers to a specific kind of brain cancer called glioblastoma. The standard treatment for GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune therapy that is now used to treat other cancers. The addition of pembrolizumab to the standard treatment of radiation and temozolomide has been shown to be well tolerated. Researchers want to see if adding a vaccine made from the person s own tumor will improve the effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the time of surgery is called HSPPC-96.

Objectives:

To see if the adding pembrolizumab and HSPPC-96 improves the standard treatment for glioblastoma multiforme.

Eligibility:

Adults at least 18 years old with glioblastoma.

Design:

Participants will be screened with typical cancer tests:

Brain scan

Medical history

Blood and urine tests

Questions about quality of life and symptoms

These tests will be repeated throughout the study.

Participants will have surgery to remove their tumor. A tissue sample from the tumor will be sent to a lab. A vaccine will be made from it.

Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and placebo. Participants will not know which they get.

Participants will get radiation for 6 weeks.

Participants will take temozolomide by mouth before each treatment.

Participants will get pembrolizumab by IV for 30 minutes 3 times over the radiation cycle.

Participants will keep taking the 2 drugs every few weeks for about a year. Some may take pembrolizumab for an additional year.

Most participants will get the vaccine or placebo after radiation. They will get it 5 times over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2 years.

Participants will repeat the screening tests when they stop study treatment. They will also have follow-up phone calls.


Condition or disease Intervention/treatment Phase
Glioblastoma Drug: Pembrolizumab Biological: HSPPC-96 Drug: Temozolomide Other: Placebo Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind Phase II Trial of Surgery, Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)
Actual Study Start Date : September 21, 2017
Estimated Primary Completion Date : January 9, 2021
Estimated Study Completion Date : January 9, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/RT+TMZ+Pembrolizumab
Standard treatment with experimental treatment (pembro) added
Drug: Pembrolizumab
Pembrolizumab at 200mg will be administered on day 1 as a 30 minute IV infusion (prior to RT) every 3 weeks during RT on days 1, 22 and 43. At one year, if patients are doing well they may continue pembolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.

Drug: Temozolomide
TMZ will be administered on day 1 of radiation therapy (before RT treatment) and continue throughout RT at the dose of 75 mg/m2. Post RT: The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose escalation to 200 mg/m2/day (days 29-33) and for all subsequent treatment if no treatment-related adverse events greater than Grade 2 are noted. TMZ will be given for 6 cycles.

Experimental: 2/RT+TMZ+Pembrolizumab+ HSPPC-96 Vaccine
Standard treatment with experimental treatment (pembro+ vaccine) added
Drug: Pembrolizumab
Pembrolizumab at 200mg will be administered on day 1 as a 30 minute IV infusion (prior to RT) every 3 weeks during RT on days 1, 22 and 43. At one year, if patients are doing well they may continue pembolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.

Biological: HSPPC-96
One week post RT, patients will receive weekly x 4 a dose of HSPPC-96 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of TMZ. HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if patients are doing well they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.

Drug: Temozolomide
TMZ will be administered on day 1 of radiation therapy (before RT treatment) and continue throughout RT at the dose of 75 mg/m2. Post RT: The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose escalation to 200 mg/m2/day (days 29-33) and for all subsequent treatment if no treatment-related adverse events greater than Grade 2 are noted. TMZ will be given for 6 cycles.

Placebo Comparator: 3/RT+TMZ+Pembrolizumab + Placebo Vaccine
Standard treatment with experimental treatment and placebo added
Drug: Pembrolizumab
Pembrolizumab at 200mg will be administered on day 1 as a 30 minute IV infusion (prior to RT) every 3 weeks during RT on days 1, 22 and 43. At one year, if patients are doing well they may continue pembolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.

Drug: Temozolomide
TMZ will be administered on day 1 of radiation therapy (before RT treatment) and continue throughout RT at the dose of 75 mg/m2. Post RT: The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose escalation to 200 mg/m2/day (days 29-33) and for all subsequent treatment if no treatment-related adverse events greater than Grade 2 are noted. TMZ will be given for 6 cycles.

Other: Placebo
One week post RT, patients will receive weekly x 4 a dose of HSPPC-96 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of TMZ. HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if patients are doing well they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available.




Primary Outcome Measures :
  1. To determine whether the one-year overall survival (OS) is improved in newly diagnosed MGMT unmethylated GBM patients treated with RT + TMZ + Pembrolizumab followed by Pembrolizumab + TMZ +/- HSPPC-96 x 6 cycles (1 cycle is 9 weeks) months. [ Time Frame: one year ]
    One-year overall survival



Information from the National Library of Medicine

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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:

Pre Surgery (Step 1)

  • MRI findings consistent with a suspected GBM or a histologically confirmed newly diagnosed GBM that has not been treated and would benefit from further surgical resection. As vaccine needs to be generated from the patient s tumor, patients will need to be identified prior to definitive surgery.
  • Age greater than or equal to 18 years on day of signing informed consent.
  • Karnofsky performance status greater than or equal to 70%.
  • Tumor must be supratentorial only.
  • Stereotactic biopsy will not be allowed unless there is plans for second surgery to remove greater than or equal to 80 % of the tumor.
  • No prior treatment with radiation or chemotherapy for their GBM.
  • No prior treatment with carmustine wafers.

Post-Surgery for vaccine or placebo (Step 2):

  • Pathology must be a GBM, MGMT promoter region determined to be unmethylated and IDH wild type. Greater than or equal to 80 % resection of contrast enhanced tumor on post operative MRI is required for randomization, otherwise treatment will occur on the ancillary arm.
  • Treatment must be initiated greater than or equal to 14 days and < 6 weeks from surgery.
  • Craniotomy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of radiation. Radiation must start within 6 weeks of surgery.
  • Dexamethasone dose should be less than or equal to 4 mg/day or steroid equivalent prior to starting treatment. If higher doses are needed, consult with Study Chair.
  • Female subjects of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required.
  • Patients must have adequate organ and bone marrow function within 14 days prior to step 2 registration, as defined below:

    • Absolute neutrophil count (ANC) > 1.5 (SqrRoot) 10(9)/L; platelet count > 100 (SqrRoot) 10(9)/L; and hemoglobin (Hb) >9.0 g/dL within 7 days prior to step 2 registration. Note: The use of transfusion or other intervention to achieve Hb greater than or equal to 9.0 g/dL is acceptable.
    • Total bilirubin < 1.5 (SqrRoot) ULN (except in patients diagnosed with Gilbert s disease)
    • AST (SGOT), ALT (SGPT), and alkaline phosphatase (ALP) < 2.5 (SqrRoot) ULN
    • Serum creatinine < 1.5 (SqrRoot) ULN
    • International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (APTT) as follows: In the absence of therapeutic intent to anticoagulate the patient: INR < 1.5 or PT < 1.5(SqrRoot) ULN or aPTT < 1.5(SqrRoot) ULN. In the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks before registration.
  • Females of child-bearing potential (FOCBP) and males must agree to use two adequate contraception methods (give examples, e.g. hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 120 days following completion of therapy. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Male patients who father a child should notify the treating physician.

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

  1. Has not undergone a hysterectomy or bilateral oophorectomy
  2. Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)

    • Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.
    • Diagnosis must be made by surgical excision.
    • Patients should not be on antibiotics for any infection but post operative antibiotics are allowed if used prophylactically but should be completed prior to starting RT.

EXCLUSION CRITERIA:

  • Patients who are receiving any other investigational agents.
  • Known history of immunodeficiency (HIV). This medical entity can be exacerbated by PD-1 blockade.
  • Any form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment excluding steroids. Attempts should be made to have patient on lowest possible dose of steroids. These medical entities can be exacerbated by PD-1 blockade.
  • History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Patients who have undergone a bne marrow or stem-cell transplant for any malignancy are excluded.
  • Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires chronic systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen s syndrome will not be excluded from the study.
  • Has a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis.
  • Has an active infection requiring systemic antibiotics within 10 days of surgery.
  • 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.

Examples include:

  • Hypertension (defined as 160/95) that is not controlled on medication
  • Ongoing or active infection requiring systemic treatment
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations or substance abuse disorders that would limit compliance with study requirements
  • Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient s safety or study endpoints.

    • 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.
    • The effects of pembrolizumab and HSPPC-96 on the developing human fetus are unknown. For this reason and because checkpoint inhibitors and immunotherapeutic vaccines as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry,and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
    • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
    • On treatment for Hepatitis B or Hepatitis C or history of TB.
    • Has received a live vaccine within 30 days prior to the first dose of trial treatment
    • Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Pembrolizumab are not eligible. Known hypersensitivity to any excipients of Pembrolizumab.

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): NCT03018288


Contacts
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Contact: Ukeme S Ikiddeh-Barnes (240) 858-7083 ukeme.ikiddeh-barnes@nih.gov

Locations
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United States, Arizona
Barrow Neurological Institute Recruiting
Phoenix, Arizona, United States, 85013
Contact: Surasak Phuphanich, M.D.    602-406-6274      
United States, Florida
UF Health Cancer Center at Orlando Health Recruiting
Orlando, Florida, United States, 32806
Contact: Nicholas Avgeropoulos, M.D.    321-841-6059    Erica.Jones@orlandohealth.com   
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Priya Kumthekar, M.D.    312-695-4772    anne.mendelke@nm.org   
Northshore University Health System Recruiting
Evanston, Illinois, United States, 60026
Contact: Ryan Merrell, M.D.    847-570-2025    plada@northshore.org   
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
United States, Michigan
Henry Ford Health Systems Recruiting
Detroit, Michigan, United States, 48202
Contact: Tobias Walbert, M.D.    313-916-2490    SSARVES1@hfhs.org   
United States, North Carolina
University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Simon Khagi, M.D.    919-962-8834    michael_roxas@med.unc.edu   
United States, South Carolina
MUSC Hollings Cancer Center Recruiting
Charleston, South Carolina, United States, 29425
Contact: David Cachia, M.D.    843-792-3855    hamrickr@musc.edu   
United States, Texas
Texas Oncology-Austin Brain Tumor Center Recruiting
Austin, Texas, United States, 78705
Contact: Morris Groves, M.D.    512-421-4100    morris.groves@usoncology.com   
Baylor University Medical Center Recruiting
Dallas, Texas, United States, 75246
Contact: Karen Fink, M.D.    214-820-0111    karenfin@baylorhealth.edu   
University Of Texas SW Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Edward Pan, M.D.    214-648-8310    Darren.Fleming@utsouthwestern.edu   
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Howard Colman, M.D.    801-587-4702      
United States, Washington
University of Washington Medical Center Recruiting
Seattle, Washington, United States, 98195
Contact: Lynne Taylor, M.D.    206-221-1538    avmartin@uw.edu   
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mark R Gilbert, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03018288     History of Changes
Other Study ID Numbers: 170034
17-C-0034
First Posted: January 12, 2017    Key Record Dates
Last Update Posted: December 3, 2019
Last Verified: November 27, 2019

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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 National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Malignant Gliomas
Immunotherapy
Additional relevant MeSH terms:
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Glioblastoma
Pembrolizumab
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action