Radiation Therapy With Temozolomide and Pembrolizumab in Treating Patients With Newly Diagnosed Glioblastoma

Phase I Trial of Radiation Therapy Plus Temozolomide With MK-3475 in Patients With Newly Diagnosed Glioblastoma (GBM)

The purpose of phase I trial is to determine the safest, most effective dose of MK-3475 (pembrolizumab), when used with radiotherapy and temozolomide for treating newly diagnosed patients with glioblastoma (GBM). Temozolomide binds to the deoxyribonucleic acid (DNA), changes it, and triggers the death of tumor cells. MK-3475 is an investigational drug, it is not currently approved by the Federal Drug Administration (FDA) for use in treating GBM but it is approved for treating melanoma. MK-3475 works by targets the local tumor immune-protection in solid tumors. It is hoped the addition of MK-3475 to the usual treatment for GBM will improve the current treatment.

Study Overview

• Status: Terminated
• Conditions: Adult Glioblastoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Drug: Temozolomide; Radiation: Radiation Therapy

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of radiation therapy (RT) + temozolomide (TMZ) + MK-3475 (pembrolizumab) followed by MK-3475 + TMZ x 6 cycles (1 cycle is 9 weeks), MK-3475 can continue for an additional 12 months.

SECONDARY OBJECTIVES:

Safety of MK-3475 in GBM.

TERTIARY OBJECTIVES:

I. To determine if there is a correlation of programmed cell death 1 (PD1) or programmed cell death 1 ligand 1 (PDL1) expression and T-cell infiltrate in pathology from first and, if applicable, second surgical specimens with outcome.

II. Assess changes in peripheral T-cell activation and tryptophan metabolites. III. Correlate o-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) status with outcome.

OUTLINE: This is a phase I, dose-escalation study of pembrolizumab, followed by a phase II study.

RT PORTION: Patients undergo focal RT over 42 days, and receive concurrent temozolomide orally (PO) once daily (QD) on days 1-42 and pembrolizumab IV over 30 minutes on days 1, 22, and 43.

POST-RT: After completion of RT, patients receive temozolomide PO QD on days 1-5 and 29-34 of course 1 and days 1-5 and 29-33 of subsequent courses, and pembrolizumab IV over 30 minutes on days 1, 22, and 43. Treatment repeats every 9 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients deriving benefit may continue to receive pembrolizumab for an additional 12 months.

After completion of study treatment, patients are followed up every 2-4 months.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed newly diagnosed glioblastoma; patients with an initial diagnosis of a lower-grade glioma are eligible if a subsequent biopsy was determined to be glioblastoma and they received no prior treatment
• No prior treatment with radiation or chemotherapy for their GBM
• No prior treatment with carmustine wafers

• Patients who have undergone recent surgery:

  • Must be a minimum of 14 days from surgery
  • Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of registration
  • Magnetic resonance imaging (MRI) within 72 hours of surgery OR 4 weeks from surgery
• Karnofsky performance status >= 70%
• Stable or decreasing dose of corticosteroids within 5 days prior to treatment
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days 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
• Patients need not have measurable or evaluable disease
• Absolute neutrophil count (ANC) > 1.5 x 10^9/L
• Platelet count > 100 x 10^9/L; or
• Hemoglobin (Hb) > 9.0 g/dL within 7 days prior to enrollment; note: the use of transfusion or other intervention to achieve Hb >= 9 g/dL is acceptable
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in patients diagnosed with Gilbert's disease)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• Alkaline phosphatase (ALP) =< 2.5 x ULN
• Serum creatinine < 1.5 x ULN
• International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (APTT) as follows: in the absence of therapeutic intent to anticoagulate the patient: INR < 1.5 or PT < 1.5 x ULN or aPTT < 1.5 x ULN; in the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks before registration

• Females of child-bearing potential (FOCBP) and males must agree to use two adequate contraception methods (give examples, e.g. hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 120 days following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

  • NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

    • Has not undergone a hysterectomy or bilateral oophorectomy
    • Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study

Exclusion Criteria:

• Any prior treatment for the patients GBM
• Has a known diagnosis of immunodeficiency (human immunodeficiency virus [HIV] 1/2 antibodies) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment excluding steroids; attempts should be made to have patient on lowest possible dose of steroids
• History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study
• Has evidence of or a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis
• Has an active infection requiring systemic antibiotics within 7 days of registration

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator; examples include

  • Hypertension (defined as 160/95) that is not controlled on medication
  • Ongoing or active infection requiring systemic treatment
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations or substance abuse disorders that would limit compliance with study requirements
  • Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days prior to the first dose of trial treatment
• Patients receiving any other investigational agents within 30 days prior to the first dose of trial treatment
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 are not eligible; known hypersensitivity to any excipients of MK-3475

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (RT, temozolomide, pembrolizumab); RT PORTION: Patients undergo focal RT over 42 days, and receive concurrent temozolomide PO QD on days 1-42 and pembrolizumab IV over 30 minutes on days 1, 22, and 43. POST-RT: After completion of RT, patients receive temozolomide PO QD on days 1-5 and 29-34 of course 1 and days 1-5 and 29-33 of subsequent courses, and pembrolizumab IV over 30 minutes on days 1, 22, and 43. Treatment repeats every 9 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients deriving benefit may continue to receive pembrolizumab for an additional 12 months.

Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Methazolastone; RP-46161; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Radiation: Radiation Therapy; Undergo focal RT; Other Names: Cancer Radiotherapy; Irradiate; Irradiated; Irradiation; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; RADIATION

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The dose-limiting toxicity of Radiation Therapy With Temozolomide and Pembrolizumab will be evaluated	Any dose-limiting toxicity (DLT) experienced during the first cycle (9 weeks) of study treatment, will be determined. The Maximum Tolerated Dose (MTD) will constitute the RP2D	9 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of Pembrolizumab	Adverse events will be described descriptively by giving frequencies of each event by type, severity, frequency, timing and attribution graded according to CTCAE version 4.0.	Up to 30 days after the last dose of study drug

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Methylguanine-DNA methyltransferase (MGMT) status	Correlate MGMT status with outcome based on tumor tissue that will be analyzed	Baseline
PDL1 expression in tumor	Tumor tissue will be analyzed to assess for PDL-1 levels	Baseline
Peripheral T-cell activation	Tumor tissue will be analyzed to collect peripheral markers of T-Cell activation	Up to 108 weeks (12 courses post-RT)
T-cell infiltrate in tumor	Tumor tissue will be analyzed to assess for T-cell infiltration	Baseline
Tryptophan metabolites	Tumor tissue will be analyzed to collect peripheral markers of tryptophan metabolites	Baseline

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: National Cancer Institute (NCI); Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Karan Dixit, MD, Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2015
• Primary Completion (Actual): May 10, 2016
• Study Completion (Actual): February 12, 2020

Study Registration Dates

• First Submitted: August 19, 2015
• First Submitted That Met QC Criteria: August 20, 2015
• First Posted (Estimated): August 21, 2015

Study Record Updates

• Last Update Posted (Actual): November 18, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 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; Immune Checkpoint Inhibitors; Temozolomide; Pembrolizumab
• Other Study ID Numbers: NU 15C01 (Other Identifier: Northwestern University); P30CA060553 (U.S. NIH Grant/Contract); NCI-2015-00736 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); STU00200883