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Pilot Study of Pembrolizumab Combined With Pemetrexed or Abemaciclib for High Grade Glioma

Primary Purpose

High Grade Glioma

Status
Withdrawn
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pembrolizumab
Pemetrexed
Abemaciclib
Sponsored by
Jose Carrillo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for High Grade Glioma focused on measuring Immunotherapy, Pembrolizumab, Pemetrexed, Abemaciclib, Cyclin-dependent kinase 4 (CDK4), Cyclin-dependent kinase 6 (CDK6), Folate antimetabolite

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria for ALL Arms:

  1. Participant or their legal representative has the ability to provide informed consent.
  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.

    Note:Participant must have a diagnosis of high grade (WHO Grade III or IV) glioma following brain surgery to proceed with study treatment.

  4. Participant is a candidate for brain surgery.
  5. Participant is male or female, ≥ 18 years of age.
  6. Participant has a Karnofsky Performance Status ≥ 60%.
  7. Participant has adequate organ function:

    1. ANC at least 1.5 x 10^9/L or greater.
    2. Platelets at least 100 x 10^9/L or greater.
    3. Hemoglobin at least 8 g/dL or greater.
    4. Total bilirubin 1.5 x upper limit of normal (ULN) or lower.
    5. ALT and AST 3 x ULN or lower.
    6. Serum creatinine 1.5 x ULN or lower.

Additional Inclusion Criteria for Arm 1 only:

  1. Participant has the ability to interrupt nonsteroidal anti-inflammatory (NSAIDS) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.
  2. Participant has the ability to take folic acid, Vitamin B12, and dexamethasone according to protocol.
  3. Creatinine clearance ≥ 45 mL/min (calculated using standard Cockcroft and Gault formula).

Additional Inclusion Criteria for Arm 1 only:

1. Participant is able to swallow oral medications.

Exclusion Criteria for ALL Arms:

  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. 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, including, but not limited to:

    1. Uncontrolled diabetes;
    2. Renal disease that requires dialysis;
    3. Pulmonary disorder requiring supplemental oxygen to keep saturation >95% and the situation is not expected to resolve within 2 weeks;
    4. Severe dyspnea at rest or requiring oxygen therapy;
    5. Interstitial lung disease;
    6. History of major surgical resection involving the stomach or small bowel;
    7. Preexisting Crohn's disease;
    8. Ulcerative colitis;
    9. Uncontrolled vasculitis and/or disease with known vasculitis;
    10. Preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea;
    11. Psychiatric illness/social situations that would limit compliance with study requirements.
  6. Participant has an active bacterial infection requiring intravenous antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C).
  7. Participant has a personal history or presence of any of the following cardiovascular conditions:

    1. Syncope of cardiovascular etiology;
    2. Ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation);
    3. Myocardial infraction within 6 months of investigational product administration;
    4. Unstable angina;
    5. Sudden cardiac arrest;
    6. Congestive heart failure (New York Heart Association classification ≥ 3).
  8. Participant is a female of childbearing potential who is pregnant or nursing.

Additional Exclusion Criteria for Arm 1 only:

  1. Participant has third space fluid which cannot be controlled by drainage. For patients who develop or have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before or during initiation of pemetrexed therapy, consideration should be given to draining the effusion prior to dosing. However, if, in the investigator's opinion, the effusion represents progression of disease, the patient should be discontinued from study therapy.
  2. Transaminases greater than 3.0 x ULN, except in presence of known hepatic metastasis, wherein may be up to 5 x ULN.

Sites / Locations

  • John Wayne Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Pembrolizumab plus Pemetrexed

Pembrolizumab plus Abemaciclib

Arm Description

Pembrolizumab plus Pemetrexed

Pembrolizumab plus Abemaciclib

Outcomes

Primary Outcome Measures

Tumor response rates
Evidence of anti-tumor activity as measured according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.

Secondary Outcome Measures

Toxicity assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Proportion of patients experiencing adverse events
Progression free survival (PFS)
The duration of time from start of treatment until objective tumor progression or death.
Overall survival (OS)
The duration of time from start of treatment to death.
Levels of immunotherapeutic agents in specimens
Immunotherapeutic drug levels in specimens.
Change in gene signature of tumor tissue after treatment
Comparison of genetic analysis of tumor tissue collected before and after study treatment.

Full Information

First Posted
November 26, 2019
Last Updated
July 29, 2020
Sponsor
Jose Carrillo
Collaborators
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT04220892
Brief Title
Pilot Study of Pembrolizumab Combined With Pemetrexed or Abemaciclib for High Grade Glioma
Official Title
Pilot Study of Pembrolizumab Combined With Pemetrexed or Abemaciclib for the Treatment of Patients With High Grade Glioma
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Withdrawn
Why Stopped
One of the study drugs will no longer be supplied by manufacturer and the pembrolizumab + abemaciclib study arm is removed due to toxicity seen in other trials.
Study Start Date
July 8, 2020 (Anticipated)
Primary Completion Date
July 8, 2020 (Anticipated)
Study Completion Date
July 8, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jose Carrillo
Collaborators
Eli Lilly and Company

4. Oversight

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

5. Study Description

Brief Summary
The purpose of this study is to evaluate any preliminary evidence of anticancer activity of pembrolizumab combined with either pemetrexed or abemaciclib 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 the side effects (good and bad) of pembrolizumab combined with pemetrexed or abemaciclib; • Evaluate tumor characteristics by collecting brain tumor tissue samples. Measure the amount of pembrolizumab, pemetrexed, and/or abemaciclib that gets in the body by collecting blood and cerebrospinal fluid. Look at biomarkers (biochemical features that can be used to measure the progress of disease or the effects of a drug) in blood and cerebrospinal fluid if available.
Detailed Description
This is a prospective, open-label, multi-arm exploratory study of pembrolizumab in combination with pemetrexed or abemaciclib for the treatment of adult patients with newly diagnosed high grade glioma. 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 may be collected for potential correlative studies. A small sample of blood and cerebrospinal fluid (CSF) for research will also be collected. Once a diagnosis of high grade glioma is confirmed, the patient will be allocated to either Treatment Arm 1 (pembrolizumab + pemetrexed), or Treatment Arm 2 (pembrolizumab + abemaciclib). 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 be directed by their treating physician to either receive a different treatment regimen (e.g., standard radiation therapy with or without chemotherapy) or undergo a clinically-indicated cytoreductive surgery. If another treatment is started, clinical evaluations and response assessments will continue as clinically-indicated and blood and CSF will be collected after the first month, then every three months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
High Grade Glioma
Keywords
Immunotherapy, Pembrolizumab, Pemetrexed, Abemaciclib, Cyclin-dependent kinase 4 (CDK4), Cyclin-dependent kinase 6 (CDK6), Folate antimetabolite

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pembrolizumab plus Pemetrexed
Arm Type
Experimental
Arm Description
Pembrolizumab plus Pemetrexed
Arm Title
Pembrolizumab plus Abemaciclib
Arm Type
Experimental
Arm Description
Pembrolizumab plus Abemaciclib
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda
Intervention Description
200 mg intravenous (IV) every 3 weeks
Intervention Type
Drug
Intervention Name(s)
Pemetrexed
Other Intervention Name(s)
Alimta
Intervention Description
900 mg/m^2 IV every 3 weeks. Supportive medications of ibuprofen, folic acid, vitamin B12, and dexamethasone.
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Other Intervention Name(s)
Verzenio
Intervention Description
150 mg twice a day, by mouth.
Primary Outcome Measure Information:
Title
Tumor response rates
Description
Evidence of anti-tumor activity as measured according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.
Time Frame
one year
Secondary Outcome Measure Information:
Title
Toxicity assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Description
Proportion of patients experiencing adverse events
Time Frame
one year
Title
Progression free survival (PFS)
Description
The duration of time from start of treatment until objective tumor progression or death.
Time Frame
one year
Title
Overall survival (OS)
Description
The duration of time from start of treatment to death.
Time Frame
four years
Title
Levels of immunotherapeutic agents in specimens
Description
Immunotherapeutic drug levels in specimens.
Time Frame
approximately 3 months
Title
Change in gene signature of tumor tissue after treatment
Description
Comparison of genetic analysis of tumor tissue collected before and after study treatment.
Time Frame
approximately 6 months to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for ALL Arms: Participant or their legal representative has the ability to provide informed consent. Participant has the willingness to comply with all study procedures and availability for the duration of the study. Participant is being evaluated for a potential, or known, diagnosis of high grade glioma. Note:Participant must have a diagnosis of high grade (WHO Grade III or IV) glioma following brain surgery to proceed with study treatment. Participant is a candidate for brain surgery. Participant is male or female, ≥ 18 years of age. Participant has a Karnofsky Performance Status ≥ 60%. Participant has adequate organ function: ANC at least 1.5 x 10^9/L or greater. Platelets at least 100 x 10^9/L or greater. Hemoglobin at least 8 g/dL or greater. Total bilirubin 1.5 x upper limit of normal (ULN) or lower. ALT and AST 3 x ULN or lower. Serum creatinine 1.5 x ULN or lower. Additional Inclusion Criteria for Arm 1 only: Participant has the ability to interrupt nonsteroidal anti-inflammatory (NSAIDS) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed. Participant has the ability to take folic acid, Vitamin B12, and dexamethasone according to protocol. Creatinine clearance ≥ 45 mL/min (calculated using standard Cockcroft and Gault formula). Additional Inclusion Criteria for Arm 1 only: 1. Participant is able to swallow oral medications. Exclusion Criteria for ALL Arms: Participant has received prior anti-cancer treatment for high-grade glioma. Participant has a diagnosis of immunodeficiency or active autoimmune disease. 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. This is assessed after surgery, prior to starting drug treatment. 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®). Participant has a severe or uncontrolled medical disorder that would, in the investigator's opinion, impair ability to receive study intervention, including, but not limited to: Uncontrolled diabetes; Renal disease that requires dialysis; Pulmonary disorder requiring supplemental oxygen to keep saturation >95% and the situation is not expected to resolve within 2 weeks; Severe dyspnea at rest or requiring oxygen therapy; Interstitial lung disease; History of major surgical resection involving the stomach or small bowel; Preexisting Crohn's disease; Ulcerative colitis; Uncontrolled vasculitis and/or disease with known vasculitis; Preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea; Psychiatric illness/social situations that would limit compliance with study requirements. Participant has an active bacterial infection requiring intravenous antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C). Participant has a personal history or presence of any of the following cardiovascular conditions: Syncope of cardiovascular etiology; Ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation); Myocardial infraction within 6 months of investigational product administration; Unstable angina; Sudden cardiac arrest; Congestive heart failure (New York Heart Association classification ≥ 3). Participant is a female of childbearing potential who is pregnant or nursing. Additional Exclusion Criteria for Arm 1 only: Participant has third space fluid which cannot be controlled by drainage. For patients who develop or have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before or during initiation of pemetrexed therapy, consideration should be given to draining the effusion prior to dosing. However, if, in the investigator's opinion, the effusion represents progression of disease, the patient should be discontinued from study therapy. Transaminases greater than 3.0 x ULN, except in presence of known hepatic metastasis, wherein may be up to 5 x ULN.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jose A Carrillo, MD
Organizational Affiliation
Saint John's Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
John Wayne Cancer Institute
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Pilot Study of Pembrolizumab Combined With Pemetrexed or Abemaciclib for High Grade Glioma

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