Clinical Trials /

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

NCT04220892

Description:

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.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • 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 Prior to Radiochemotherapy

Clinical Trial IDs

  • ORG STUDY ID: JWCI-18-0702 (I3Y-US-I011)
  • NCT ID: NCT04220892

Conditions

  • High Grade Glioma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaPembrolizumab plus Abemaciclib
PemetrexedAlimtaPembrolizumab plus Pemetrexed
AbemaciclibVerzenioPembrolizumab plus Abemaciclib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab plus PemetrexedExperimentalPembrolizumab plus Pemetrexed
  • Pembrolizumab
  • Pemetrexed
Pembrolizumab plus AbemaciclibExperimentalPembrolizumab plus Abemaciclib
  • Pembrolizumab
  • Abemaciclib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor response rates
Time Frame:one year
Safety Issue:
Description:Evidence of anti-tumor activity as measured according to immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.

Secondary Outcome Measures

Measure:Toxicity assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03.
Time Frame:one year
Safety Issue:
Description:Proportion of patients experiencing adverse events
Measure:Progression free survival (PFS)
Time Frame:one year
Safety Issue:
Description:The duration of time from start of treatment until objective tumor progression or death.
Measure:Overall survival (OS)
Time Frame:four years
Safety Issue:
Description:The duration of time from start of treatment to death.
Measure:Levels of immunotherapeutic agents in specimens
Time Frame:approximately 3 months
Safety Issue:
Description:Immunotherapeutic drug levels in specimens.
Measure:Change in gene signature of tumor tissue after treatment
Time Frame:approximately 6 months to 2 years
Safety Issue:
Description:Comparison of genetic analysis of tumor tissue collected before and after study treatment.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jose Carrillo

Trial Keywords

  • Immunotherapy
  • Pembrolizumab
  • Pemetrexed
  • Abemaciclib
  • Cyclin-dependent kinase 4 (CDK4)
  • Cyclin-dependent kinase 6 (CDK6)
  • Folate antimetabolite

Last Updated

January 6, 2020