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Ibrutinib and Radiation Therapy with or without Temozolomide in Treating Participants with Newly Diagnosed Methylated or Unmethylated Glioblastoma

Trial Status: Active

This phase I trial studies the best dose of ibrutinib when given together with radiation therapy radiation and with or without temozolomide in treating participants with newly diagnosed methylated or unmethylated glioblastoma. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. It is not yet known whether giving ibrutinib and radiation therapy with or without temozolomide may work better in treating glioblastoma.

Inclusion Criteria

  • ARM 1: Patients must have histologically proven supratentorial unmethylated MGMT glioblastoma.
  • ARM 1: Patients must have gadolinium magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan within 28 days of starting treatment.
  • ARM 1: Patients must have a Karnofsky performance status >= 70% (i.e. the patient must be able to care for himself/herself with occasional help from others).
  • ARM 1: Absolute neutrophil count >= 1500/mm^3.
  • ARM 1: Platelets >= 100,000/mm^3
  • ARM 1: Creatinine =< 1.7 mg/dl
  • ARM 1: Total bilirubin =< 1.5 mg/dl
  • ARM 1: Transaminases =< 3 times above the upper limits of the institutional normal.
  • ARM 1: Patients must be able to provide written informed consent.
  • ARM 1: Patients with the potential for pregnancy or impregnating their partner must agree to follow the acceptable birth control methods to avoid conception. Male and female subjects who agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence from sexual intercourse, or sterilized partner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc) during the period of therapy and for 30 days after the last dose of study drug for females and 90 days for males. Women of childbearing potential must have a negative urine or serum pregnancy test upon study entry. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.
  • ARM 1: Patients must have no concurrent malignancy except curatively treated early stage bladder and prostate cancer that has been completed resected, basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission. Patients with other prior malignancies must be disease-free for >= 3 years.
  • ARM 1: Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) (activated PTT [aPTT] < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder).
  • ARM 1: Patient with any surgery more than stereotactic biopsy are eligible (gross total resection, subtotal resection that include debulking surgery) so that there is enough tissue for MGMT analysis.
  • ARM 2: Patients must have histologically proved methylated MGMT glioblastoma.
  • ARM 2: Patients must have gadolinium MRI or contrast CT scan within 28 days of starting treatment.
  • ARM 2: Patients must have a Karnofsky performance status >= 70% (i.e. the patient must be able to care for himself/herself with occasional help from others).
  • ARM 2: Absolute neutrophil count >= 1500/m^3.
  • ARM 2: Platelets >= 100,000/mm^3.
  • ARM 2: Creatinine =< 1.7 mg/dl.
  • ARM 2: Total bilirubin =< 1.5 mg/dl.
  • ARM 2: Transaminases =< 3 times above the upper limits of the institutional normal.
  • ARM 2: Patients must be able to provide written informed consent.
  • ARM 2: Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Male and female subjects who agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence from sexual intercourse, or sterilized partner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the period of therapy for 30 days after the last dose of study drug for females and 90 days for males. Women of childbearing potential must have a negative urine/serum pregnancy test upon study entry. The anti-proliferative activity of this experimental drug as well as the standard drug (temozolomide) may be harmful to the developing fetus or nursing infant.
  • ARM 2: Patients must have no concurrent malignancy except curatively treated early stage bladder and prostate cancer that has been completed resected, basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission. Patients with other prior malignancies must be disease-free for >= 3 years.
  • ARM 2: PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder).
  • ARM 2: Patient with any surgery more than biopsy are eligible (gross total resection, subtotal resection) so that there is enough tissue for MGMT analysis.

Exclusion Criteria

  • Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
  • Patients who are pregnant or breast-feeding. The anti-proliferative activity of this experimental drug and temozolomide may be harmful to the developing fetus or nursing infant.
  • Patients receiving concurrent therapy for their tumor (i.e. chemotherapeutics or investigational agents).
  • Patients with a concurrent or prior malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin. Patients who have been free of disease (any prior malignancy) for at least 3 years are eligible for this study.
  • Patients who have had repeat craniotomy for tumor therapy after receiving radiation therapy (RT) and temozolomide treatment.
  • Patients who received other chemotherapeutics or investigational agents in addition to their radiation therapy and concomitant temozolomide treatment.
  • Patient has previously taken ibrutinib or any other BTK inhibitor or is allergic to components of the study drug.
  • Concomitant use of warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists or any form of anticoagulation including Low molecular weight heparin.
  • Patient is taking a drug known to be a moderate and strong inhibitor or inducers of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers for at least one week prior to starting the study drug.
  • Current active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification.
  • Patient is using systemic immunosuppressant therapy, including cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of > 5 mg/day of prednisone or the equivalent. Participants must be off of immunosuppressant therapy for at least 21 days prior to the first dose of the study drug. Patients can be on steroids for brain edema.
  • Patient has significant abnormalities on screening electrocardiogram (EKG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis, or myocardial infarction within 6 months of screening.
  • Female subjects who are pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days of last dose of study drug. Male subjects who plan to father a child while enrolled in this study or within 90 days after the last dose of study drug.
  • Patients unwilling or unable to comply with the protocol.
  • Any uncontrolled active systemic infection.
  • Major surgery within 4 weeks of first dose of study drug.
  • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
  • Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  • Recent infection requiring systemic treatment that was completed =< 14 days before the first dose of study drug.
  • Known bleeding disorders (e.g., von Willebrand's disease or hemophilia).

Ohio

Cleveland
Case Comprehensive Cancer Center
Status: ACTIVE
Contact: Manmeet Singh Ahluwalia
Phone: 216-445-6068

PRIMARY OBJECTIVES:

I. To determine maximum tolerated dose (MTD) of ibrutinib with radiation (2 Gy x 30) in patients with unmethylated glioblastoma. (Arm 1)

II. To determine maximum tolerated dose (MTD) of ibrutinib with radiation (2 Gy x 30) and daily temozolomide (TMZ) at 75 mg/m^2 in patients with methylated glioblastoma. (Arm 2)

SECONDARY OBJECTIVES:

I. Safety of combination of ibrutinib with radiation. (Arm 1)

II. Progression free survival (PFS). (Arm 1)

III. Overall survival. (Arm 1)

IV. Safety of combination of ibrutinib with radiation and temozolomide. (Arm 2)

V. Progression free survival (PFS). (Arm 2)

VI. Overall survival. (Arm 2)

OUTLINE: This is a dose-escalation study of ibrutinib. Participants are assigned to 1 of 2 arms.

ARM I (UNMETHYLATED MGMT): Participants receive ibrutinib orally (PO) once daily (QD) and undergo radiation therapy QD for 5 days a week (Monday to Friday) for 6 weeks. After a 4 week break, participants receive ibrutinib PO QD in the absence of disease progression or unacceptable toxicity.

ARM II (METHYLATED MGMT): Participants receive ibrutinib PO QD, temozolomide PO QD, and undergo radiation therapy QD for 5 days a week (Monday to Friday) for 6 weeks. After a 4 week break, participants receive ibrutinib PO QD and temozolomide PO on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses and treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Manmeet Singh Ahluwalia

  • Primary ID CASE2317
  • Secondary IDs NCI-2018-01825
  • Clinicaltrials.gov ID NCT03535350