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Peptide Targets for Glioblastoma Against Novel Cytomegalovirus Antigens (PERFORMANCE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02864368
Recruitment Status : Active, not recruiting
First Posted : August 12, 2016
Last Update Posted : August 13, 2020
Sponsor:
Collaborators:
Annias Immunotherapeutics, Inc.
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Gary Archer Ph.D., Duke University

Tracking Information
First Submitted Date  ICMJE July 26, 2016
First Posted Date  ICMJE August 12, 2016
Last Update Posted Date August 13, 2020
Actual Study Start Date  ICMJE December 7, 2016
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2016)
  • Incidence of Treatment-related Adverse Events [ Time Frame: 2 weeks after the 3rd vaccine, which is approximately 12 weeks after consent and thereafter, continually through study completion ]
    To assess the safety of PEP-CMV vaccination in combination with adjuvant TMZ, the percentage of patients with unacceptable toxicity will be estimated within each arm. All patients who received any PEP-CMV vaccine will be included in these analyses.
  • Immunologic Response [ Time Frame: Through study completion, an average of 1.5 years ]
    To determine the TMZ regimen that produces the highest number of T cells that specifically secrete Interferon-gamma (IFNƴ) by ELISPOT in response to component A of PEP-CMV or the highest antibody responses to CMV Glycoprotein B (gB) by ELISA
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2016)
Antigen Loss [ Time Frame: Through study completion, an average of 1.5 years ]
To determine if tumors are CMV antigen negative by immunohistochemical analysis for the presence of the antigen pp65 at the time of disease progression/recurrence
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Peptide Targets for Glioblastoma Against Novel Cytomegalovirus Antigens
Official Title  ICMJE Peptide Targets for Glioblastoma Against Novel Cytomegalovirus Antigens
Brief Summary Newly diagnosed glioblastoma (GBM) patients with complete or partial surgical resection who are CMV seropositive patients will be eligible to enroll on this trial. Patients will be enrolled following standard of care chemoradiation and prior to initiation of post-radiation cycles of temozolomide (TMZ) provided they meet all eligibility criteria. Eligible patients will receive a tetanus-diphtheria (Td) vaccination. Patients will then be randomized to one of two arms of the study: Arm 1 will received standard TMZ and Arm 2 will receive dose-intensified TMZ. All patients will receive a pre-conditioning injection of tetanus on day 22 of the first post-radiation cycle of TMZ. The following day, patients will receive the first of 3 intradermal (i.d.) injections of the study drug cytomegalovirus peptide (PEP-CMV), which contains what is referred to as Component A. Vaccines #2 and #3 will be given at 2 week intervals. Patients who are MGMT (O[6]-methylguanine-DNA methyltransferase) unmethylated will receive one adjuvant cycle of the TMZ regimen according to their assigned randomized arm. Patients who are MGMT methylated or whose methylation status is inconclusive will continue with up to 12 cycles of TMZ. After the completion of a patient's last TMZ cycle, vaccines will continue every 4-6 weeks for a maximum number of 20 vaccines (unless tumor progression occurs).
Detailed Description

Patients may be enrolled following radiation therapy and prior to initiation of post-radiation therapy cycles of adjuvant TMZ provided they meet all eligibility criteria. After signing main consent, patients will undergo immune monitoring blood work and Tetanus-diphtheria booster vaccination with 0.5 mL of Td (tetanus, diphtheria toxoid, adsorbed). After meeting all eligibility criteria, patients will be randomized to one of two arms:

  • Arm 1 will receive standard TMZ (150-200 mg/m^2/day on days 1-5 of each 28-day cycle) with vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle
  • Arm 2 will receive dose-intensified TMZ (75-100 mg/m^2/day on days 1-21 of each 28-day cycle) with vaccination on day 23 (-1 day, +2 days) of each TMZ cycle.

Each arm will have approximately 13 patients. For both arms, the patients must be screened at Duke within 3 +/- 1 weeks after completion of standard of care radiation. For both arms, the initial cycle of adjuvant TMZ will begin as soon as possible following randomization. For Arm 1, the adjuvant TMZ cycle(s) will be given as described above. If a patient has an MGMT unmethylated tumor, they will discontinue TMZ after the 1st cycle.

All patients will receive a tetanus pre-conditioning injection in the right groin on day 22 (+1 day) of cycle 1 of adjuvant TMZ. On the following day, patients will receive the study vaccine prepared as follows: 500 µg of PEP-CMV Component A mixed with Montanide ISA-51 intradermally administered with half in the right groin and half in the left groin. Vaccines #2 and #3 will be given at 2 week intervals (+ 3 days), which will result in a ~35-day delay before starting TMZ cycle 2. MGMT unmethylated patients will not receive subsequent cycles of TMZ, but will continue to receive vaccines approximately every 4 (+2) weeks.

An unacceptable toxicity will be defined as any ≥ Grade 3 toxicity possibly, probably, or definitely related to the PEP-CMV vaccine with some exceptions. The prevalence of unacceptable toxicities occurring during the vaccinations administered concurrently with temozolomide will be continuously monitored. If more than 25% of accrued patients experience unacceptable toxicities, then accrual will be suspended and reported toxicity will be carefully reviewed to determine if modifications to the protocol treatment should occur. Peptide vaccinations employing Montanide ISA-51 as adjuvants have generally been well tolerated in human patients in numerous phase I-III trials.

Patients will be imaged with contrast-enhanced MRI within 2 weeks (+3 days) after vaccine 3 and then approximately every 8 weeks. RANO criteria will be used for assessment of pseudo-progression, and patients demonstrating definitive progression will be removed from study. Blood for immune monitoring will be obtained as well at several time points.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Glioblastoma Multiforme
Intervention  ICMJE
  • Drug: 5-day TMZ
    Chemotherapy agent FDA approved to treat newly-diagnosed glioblastoma given as cycles of 150-200 mg/m^2/day on days 1-5 of each 28 day cycle
    Other Names:
    • temozolomide
    • Temodar
  • Drug: 21-day TMZ
    Chemotherapy agent FDA approved to treat newly-diagnosed glioblastoma given as cycles of dose-intensified TMZ (75-100 mg/m2/day on days 1-21 of each 28 day cycle)
    Other Names:
    • temozolomide
    • Temodar
  • Biological: PEP-CMV
    500 µg of PEP-CMV Component A (a synthetic long peptide) mixed with Montanide ISA-51 intradermally administered in the right groin and, 2 hours later, 500 µg of PEP-CMV Component B (a neutralizing antibody epitope from human CMV glycoprotein B conjugated to Keyhole Limpet Hemocyanin) mixed in 150 µg of GM-CSF intradermally administered in the left groin
  • Drug: Tetanus-Diphtheria booster
    At time of enrollment, after signing consent and undergoing immune monitoring blood work, patients will receive Tetanus-diphtheria booster vaccination with 0.5 mL of Td (tetanus, diphtheria toxoid, absorbed)
    Other Names:
    • Td
    • tetanus
  • Drug: Tetanus Pre-Conditioning
    All patients will receive a tetanus pre-conditioning injection in the right groin intradermally on day 22 (±1 day) of the first post-radiation cycle of TMZ
    Other Names:
    • Td
    • Tetanus-Diphtheria
    • tetanus
Study Arms  ICMJE
  • Experimental: 5-day TMZ
    All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.
    Interventions:
    • Drug: 5-day TMZ
    • Biological: PEP-CMV
    • Drug: Tetanus-Diphtheria booster
    • Drug: Tetanus Pre-Conditioning
  • Experimental: 21-day TMZ
    All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of dose-intensified TMZ (75-100 mg/m^2/day on days 1-21 of each 28 day cycle) with PEP-CMV vaccination on day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.
    Interventions:
    • Drug: 21-day TMZ
    • Biological: PEP-CMV
    • Drug: Tetanus-Diphtheria booster
    • Drug: Tetanus Pre-Conditioning
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 27, 2018)
70
Original Estimated Enrollment  ICMJE
 (submitted: August 10, 2016)
45
Estimated Study Completion Date  ICMJE June 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Histopathologically proven newly-diagnosed primary glioblastoma with complete or partial surgical resection. Biopsy not acceptable.
  3. Patients must be CMV seropositive.
  4. The tumor must be supratentorial.
  5. Karnofsky performance status of ≥ 70.
  6. Stable or decreasing steroid dose (≤ 4 mg/day) at time of post-XRT adjuvant TMZ initiation. If patients are decreasing steroid use, once they are at 2 mg/day, they may be supplemented with physiologic replacement hydrocortisone therapy (20-30 mg/day in divided doses), at the discretion of the treating oncologist.
  7. Hematology: ANC ≥ 1500 cells/µL, Platelet count ≥ 100,000 cells/µL, Hemoglobin ≥ 9.0 g/dl
  8. Chemistry: ALT/AST ≤ 3.0 times the upper limit of normal (ULN), Total bilirubin ≤ 1.5 mg x ULN (Exception: Patient has known Gilbert's Syndrome or patient has suspected Gilbert's Syndrome, for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.)

Exclusion Criteria:

  1. Radiographic or cytologic evidence of leptomeningeal or multifocal disease at any time prior to study entry.
  2. Prior conventional antitumor therapy, other than steroids, RT or TMZ therapy given for glioblastoma.
  3. Pregnant or need to breast feed during the study period.
  4. Not adhering to pregnancy prevention recommendations.
  5. Active infection requiring intravenous antibiotics or an unexplained febrile (> 101.5 F) illness.
  6. Immunosuppressive disease or human immunodeficiency virus infection.
  7. Patients with unstable or severe intercurrent medical conditions such as severe heart or lung disease.
  8. Allergic or unable to tolerate TMZ for any reason. Any patient that successfully completed at least 5 weeks of Temodar during standard of care XRT/TMZ and whose blood counts meet the eligibility requirements (inclusion #7) within 4 weeks post XRT/TMZ is eligible.
  9. Patients with previous inguinal lymph node dissection, radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies.
  10. Prior allogeneic solid organ transplant.
  11. Currently receiving or ever received immunosuppressive therapy for an autoimmune disorder or an organ transplant.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02864368
Other Study ID Numbers  ICMJE Pro00034208_1
2R42CA153845-02 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gary Archer Ph.D., Duke University
Study Sponsor  ICMJE Gary Archer Ph.D.
Collaborators  ICMJE
  • Annias Immunotherapeutics, Inc.
  • National Institutes of Health (NIH)
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: David Ashley, MBBS, FRACP, PhD Duke University
PRS Account Duke University
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP