A Longitudinal Assessment of Tumor Evolution in Patients With Brain Cancer

• ClinicalTrials.gov Identifier: NCT03425292
• Recruitment Status: Active, not recruiting
• First Posted: February 7, 2018
• Last Update Posted: February 21, 2023
• Sponsor: Saint John's Cancer Institute
• Information provided by (Responsible Party): Santosh Kesari, Saint John's Cancer Institute

Tracking Information

• First Submitted Date: January 21, 2018
• First Posted Date: February 7, 2018
• Last Update Posted Date: February 21, 2023
• Actual Study Start Date: March 1, 2018
• Actual Primary Completion Date: September 12, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2018)

Rate of dose limiting toxicities [ Time Frame: first 28 days of treatment ]

treatment-related adverse events that impact administration of treatment

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 22, 2019)

• Treatment-related adverse events [ Time Frame: approximately 7 months ]
  Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
• Tumor response rates [ Time Frame: up to 5 years ]
  Evidence of anti-tumor activity as measured according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.
• Progression free survival (PFS) [ Time Frame: up to 5 years ]
  The duration of time from start of treatment until objective tumor response.
• Overall survival (OS) [ Time Frame: up to 5 years ]
  The duration of time from start of treatment to death.
• Levels of immunotherapeutic agents in specimens [ Time Frame: approximately 4 months ]
  Immunotherapeutic drug levels in specimens.
• Change in clinical molecular profile of tumor tissue after treatment [ Time Frame: approximately 6 months to 1 year ]
  Comparison of tumor tissue molecular profile generated from before and after study treatment.

Original Secondary Outcome Measures (submitted: February 6, 2018)

• Treatment-related adverse events [ Time Frame: approximately 7 months ]
  Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
• Tumor response rates [ Time Frame: up to 5 years ]
  Evidence of anti-tumor activity as measured according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.
• Progression free survival (PFS) [ Time Frame: up to 5 years ]
  The duration of time from start of treatment until objective tumor response.
• Overall survival (OS) [ Time Frame: up to 5 years ]
  The duration of time from start of treatment to death.
• Levels of nivolumab and ipilimumab in specimens [ Time Frame: approximately 4 months ]
  Nivolumab and/or ipilimumab levels in specimens.
• Change in clinical molecular profile of tumor tissue after treatment [ Time Frame: approximately 6 months to 1 year ]
  Comparison of tumor tissue molecular profile generated from before and after study treatment.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Longitudinal Assessment of Tumor Evolution in Patients With Brain Cancer
• Official Title: A Longitudinal Assessment of Tumor Evolution in Patients With Brain Cancer

Brief Summary

The purpose of this study is to test the safety and tolerability of the research study drugs nivolumab, ipilimumab, lomustine, bevacizumab, and temozolomide when used following surgery and before standard therapy with radiation and temozolomide in patients with newly diagnosed high grade glioma.

Additional aims of the study are to:

• Find out side effects (good and bad) of study drug combinations.
• Evaluate any preliminary evidence of anticancer activity of study drug combinations .
• Evaluate tumor characteristics by collecting brain tumor tissue samples.
• Measure the amount of nivolumab and ipilimumab in biospecimens.
• Look at biomarkers in biospecimens.

Detailed Description

Patients having a clinically planned surgical procedure (biopsy or cytoreduction) for a suspected diagnosis of high grade glioma will be approached for participation in this study. Tumor tissue obtained from surgery will be used for histological diagnosis and clinical molecular profiling, and excess tumor tissue will be collected for potential correlative studies. A small sample of blood and CSF for research will also be collected.

Once a diagnosis of high grade glioma is confirmed, the patient will be allocated to one of the study arms. Treatment will be started approximately 7-42 days following surgery once the patient has recovered from surgery. Routine clinical evaluations will be performed prior to treatment initiation and throughout treatment as clinically indicated. Radiographic brain imaging will be performed approximately 21-42 after treatment initiation and then routinely for medical management. Tumor response will be assessed according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) Working Group criteria.

Treatment may continue until the patient experiences unacceptable toxicity or clear disease progression. The determination of whether to stop treatment due to disease progression will be based on the investigator's evaluation of the patient's clinical and radiographic condition, taking into consideration the interpretation of localized inflammatory responses that can mimic radiographic features of tumor progress. Patients discontinuing treatment will have further medical management as directed by their treating physician.

As part of follow-up, if the patient undergoes a surgery, results of clinical molecular profiling will be collected, and excess resected tumor tissue will be collected if available along with blood and CSF for correlative studies. A record of any additional anti-cancer treatments and survival status will be made every three to six months.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Newly Diagnosed High Grade Glioma

Intervention

• Drug: Temozolomide
  concomitant and 5-day adjuvant temozolomide
  Other Name: temodar
• Radiation: conformal brain radiation therapy
  standard radiation therapy for newly diagnosed glioblastoma
• Drug: Nivolumab
  nivolumab 240 mg IV every 2 weeks for the first 28-day cycle, then option to modify to 480 mg IV every 4 weeks
  Other Name: opdivo
• Drug: Ipilimumab
  ipilimumab 1 mg/kg IV every 6 weeks (or every 8 weeks when nivolumab is administered every 4 weeks) for a maximum of 4 doses
  Other Name: yervoy
• Drug: Bevacizumab
  bevacizumab 5 mg/kg IV every 2 weeks (up to 10 mg/kg at treating physician's discretion)
  Other Name: avastin
• Drug: 5-day Temozolomide
  150 mg/m^2 oral, once daily on Days 1-5 of each 28-day cycle (stepwise titration every cycle up to 200 mg/m^2 permitted)
  Other Name: temodar
• Drug: 5-day Temozolomide
  100 mg/m^2 oral, once daily on Days 2-6 of each 6 week course (stepwise titration every cycle up to 200 mg/m^2 permitted)
  Other Name: temodar
• Drug: Lomustine
  100 mg/m^2 oral, on Day 1 of each 6 week course
  Other Name: CCNU
• Drug: Nivolumab monotherapy
  nivolumab 300 mg IV every 2 weeks for the first 28-day cycle, then option to modify to 480 mg IV every 4 weeks
  Other Name: opdivo

Study Arms

• Active Comparator: 1 SOC (closed to enrollment)
  Standard conformal brain radiation therapy with concurrent and adjuvant temozolomide
  Interventions:

  • Drug: Temozolomide
  • Radiation: conformal brain radiation therapy
• Experimental: 2 Nivo
  Nivolumab
  Intervention: Drug: Nivolumab monotherapy
• Experimental: 3 Nivo-Ipi (closed to enrollment)
  Nivolumab plus Ipilimumab
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
• Experimental: 4 Nivo-Ipi-CCNU-TMZ
  Nivolumab plus Ipilimumab plus Lomustine (CCNU) plus 5-day Temozolomide
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Drug: 5-day Temozolomide
  • Drug: Lomustine
• Experimental: 5 Nivo-Ipi-TMZ
  Nivolumab plus Ipilimumab plus 5-day Temozolomide
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Drug: 5-day Temozolomide
• Experimental: 6 Nivo-Ipi-Bev-TMZ
  Nivolumab plus Ipilimumab plus Bevacizumab plus 5-day Temozolomide
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Drug: Bevacizumab
  • Drug: 5-day Temozolomide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 22, 2019): 90
• Original Estimated Enrollment (submitted: February 6, 2018): 45
• Estimated Study Completion Date: March 1, 2024
• Actual Primary Completion Date: September 12, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Participant has the ability to understand and the willingness to provide a signed and dated informed consent form.
2. Participant has the willingness to comply with all study procedures and availability for the duration of the study.
3. Participant is being evaluated for a potential, or known, diagnosis of high grade glioma.
4. Participant is a candidate for brain surgery or has undergone prior surgery and has not received any additional treatment for high grade glioma.
5. Participant is male or female, ≥ 18 years of age.
6. Participant has a Karnofsky Performance Status (KPS) ≥ 60%:

Exclusion Criteria:

1. Participant has received prior anti-cancer treatment for high grade glioma.
2. Participant has a diagnosis of immunodeficiency or active autoimmune disease.
3. Participant is receiving chronic systemic steroid therapy in dosing exceeding 8 mg daily of dexamethasone equivalent or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Note: This is assessed after surgery, prior to starting drug treatment.
4. Participant has received a live vaccine within 28 days prior to the first dose of study agent. Examples of live vaccines include, but are not limited to measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), typhoid vaccine, and intranasal influenza vaccines (e.g., FluMist®).
5. Participant has a severe or uncontrolled medical disorder that would, in the investigator's opinion, impair ability to receive study intervention (i.e., uncontrolled diabetes, chronic renal disease, chronic pulmonary disease or active, uncontrolled infection, psychiatric illness/social situations that would limit compliance with study requirements).
6. Participant is a female of childbearing potential who is pregnant or nursing.
7. Participant has a history of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months.
8. Participant has a history of intestinal perforations, fistula, hemorrhages, and/or hemoptysis ≤ 6 months prior to first study treatment.
9. Participant has active gastrointestinal bleeding.
10. Participant has uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03425292
• Other Study ID Numbers: JWCI-17-0801
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Santosh Kesari, Saint John's Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Saint John's Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Santosh Kesari, MD, PhD; Saint John's Cancer Institute

• PRS Account: Saint John's Cancer Institute
• Verification Date: February 2023