Neoadjuvant Chemoimmunotherapy in Recurrent Glioblastoma

A Phase I Trial of Neoadjuvant Chemoimmunotherapy in Recurrent Glioblastoma

The primary purpose of this study is to test the safety of Pembrolizumab and Temozolomide in treating recurrent glioblastoma and to characterize the effect of this treatment on the participants tumor and immune system..

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Pembrolizumab and Temozolomide

Detailed Description

Participants will undergo screening tests to determine if they are eligible to participate. This will involve a complete history and physical examination, vital signs, blood tests including complete blood count (CBC), and serum chemistry (CMP).

Participants will receive one cycle of Temozolomide and Pembrolizumab prior to removing recurrent tumor, followed by three weekly cycles of treatment until progression.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Donald Miller, MD; Phone Number: 502-562-4370; Email: Donald.miller@louisville.edu

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • James Graham Brown Cancer Ctr.
      • Principal Investigator: Donald Miller, MD
      • Contact: Donald Miller, MD; Phone Number: 502-562-4370; Email: Donald.miller@louisville.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

-Inclusion Criteria Patients are eligible to be included in the only if they meet all of the following criteria

1. Histopathologically proven diagnosis of glioblastoma prior to registration, by pathology report;
2. The tumor must be confined to the supratentorial compartment
3. The tumor tissue block from the primary diagnosis must be available to be sent for pathology review, after registration.
4. History/physical examination within 7 days prior to registration
5. Karnofsky performance status ≥ 60 within 7 days prior to registration.

6. 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
7. The patient must have completed chemoradiation with Radiotherapy and Temozolomide of the primary tumor according to standard of care.
8. Patients must have received no more than 3 prior therapies for Recurrent High Grade Glioma.
9. Subjects must have the ability to understand and willingness to sign a written informed consent document.
10. Female subjects 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.
11. 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.
12. 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.

Exclusion Criteria:

-Exclusion Criteria Patients will be excluded from the study if they meet any of the following criteria

1. Previous use of an immunotherapy such as a vaccine therapy, dendritic cell vaccine or intracavitary or convectional enhanced delivery of therapy.
2. Prior invasive malignancy (except non-melanomatous skin cancer) within the previous three years

3. Severe, active co-morbidity defined as follows:

   • Transmural myocardial infarction or unstable angina within the last 6 months prior to registration
   • History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months prior to registration
   • Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease
   • Known history of Tuberculosis or 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
   • Patients with active autoimmune disease or history of autoimmune disease that might recur, will be considered on an individual basis
   • Any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy.
   • Is pregnant or breastfeeding
   • 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.
4. Patient must have < 1.5 cm midline shift pre-operative
5. History of severe hypersensitivity reaction to any monoclonal antibody including pembrolizumab.
6. Patients who cannot safely undergo MRI due to non-MRI compatible pacemaker, or other reason.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: temozolomide; Participants will take Temozolomide pills at home at a dose determined by body weight. They will take the pills for five days every 3 weeks. It will be dispensed by the pharmacy and must be stored in a closed container at room temperature, away from heat, moisture, and direct light and kept from freezing. It will be kept out of the reach of children. Outdated medicine or medicine no longer needed will be returned to the Brown Cancer Center pharmacy for disposal.	Drug: Pembrolizumab and Temozolomide; Characterize the safety and immunologic/genomic/metabolomic effects of neoadjuvant Pembrolizumab and Temozolomide in recurrent glioblastoma.; Other Names: Pembro and Temodar
Experimental: Pembrolizumab; Pembrolizumab will be administered at a dose of 200 mg as an IV infusion through a freely flowing IV. The diluted solution will be administered intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. Other drugs will not be co-administered through the same infusion line. Pembrolizumab doses will be repeated every three weeks.	Drug: Pembrolizumab and Temozolomide; Characterize the safety and immunologic/genomic/metabolomic effects of neoadjuvant Pembrolizumab and Temozolomide in recurrent glioblastoma.; Other Names: Pembro and Temodar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment toxicity	Quantification of the frequency of adverse events in patients treated with neoadjuvant Pembrolizumab and Temozolomide with gross total resection of recurrent glioblastoma.	Change in frequency of adverse events prior to gross total resection or recurrent glioblastoma

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Progression and response to treatment will be determined using the Response Assessment in Neuro-Oncology (RANO) criteria.	Every 8 weeks for 24 months
Neurologic function and quality of life	Using the Neurologic Assessment in Neuro-oncology (NANO) scale on each visit. In addition, the Eastern Cooperative Oncology Group (ECOG) performance status will be monitored.	Every 8 weeks for 24 months
Treatment Toxicity	Quantification of the frequency of adverse events in patients treated with neoadjuvant Pembrolizumab and Temozolomide after gross total resection of recurrent glioblastoma.	Change in frequency of adverse events after gross total resection or recurrent glioblastoma

Collaborators and Investigators

• Sponsor: University of Louisville
• Investigators: Principal Investigator: Donald Miller, MD, University of Louisville/James Graham Brown Cancer Ctr.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Anticipated): January 1, 2025
• Study Completion (Anticipated): January 1, 2025

Study Registration Dates

• First Submitted: September 28, 2022
• First Submitted That Met QC Criteria: January 18, 2023
• First Posted (Estimate): January 26, 2023

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Temozolomide; Pembrolizumab
• Other Study ID Numbers: 22.0676

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No