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Title Phase I Study of MK-1775 with Radiation and Temozolomide in Patients with Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients with Recurrent Glioblastoma

IRB ABTC1202

CC 13-927

Hospital Main Campus

Phase Phase 1

Disease Brain, Glioblastoma

Drug Temozolomide

Description

Primary Objectives

1. The primary objective of the Phase I portion of the clinical trial is to determine the maximum tolerated doses (MTD) of AZD1775 (MK-1775) in combination with the current standard of care (radiotherapy/temozolomide for concomitant therapy and temozolomide for adjuvant therapy) for treating patients with newly diagnosed glioblastoma.
2. To define the MTD of AZD1775 (MK-1775) in combination with 6 weeks of daily (M-F) radiotherapy (RT) and concomitant temozolomide (TMZ) administered at 75 mg/m^2/day in patients with newly diagnosed glioblastoma (Arm 1)
3. To define the MTD of AZD1775 (MK-1775) in combination with adjuvant TMZ administered at 150 mg/m²/day-200 mg/m²/day for 5 days every 28 days in patients with glioblastoma after concurrent RT/TMZ (Arm 2)

Secondary Objectives

1. To characterize the safety profile of AZD1775 (MK-1775) in combination with RT and concomitant TMZ (Arm 1) and AZD1775 (MK-1775) with adjuvant TMZ (Arm 2) in patients with newly diagnosed glioblastoma
2. To assess the pharmacokinetic (PK) profile of AZD1775 (MK-1775) in combination with upfront radiation/TMZ and adjuvant TMZ in patients with newly diagnosed glioblastoma

Intratumoral Correlatives/Pharmacokinetics Objectives

1. To determine the intratumoral concentration of AZD1775 (MK-1775) achieved in patients treated with the putative MTD
2. To characterize the time course of AZD1775 (MK-1775) in extracellular fluid within brain tumors following a single oral dose of drug by microdialysis
3. To characterize MGMT methylation and P53 pathway status, also P-gp and weel expression levels in patients with newly diagnosed glioblastoma treated with standard therapy in combination with AZD1775 (MK-1775)

Inclusion Criteria

1. Patients must be 18 years of age or older.
2. Patients must have a tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of glioblastoma completed and signed by a pathologist. (See Section 9.5.4)
3. Patients must have a Karnofsky Performance Status ≥ 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
4. Patients must have the following organ and marrow function:
   • Absolute neutrophil count ≥ 1,500/mcL
   • Platelets ≥ 100,000/mcL
   • Hemoglobin ≥ 9 g/dL
   • Total bilirubin ≤ institutional upper limit of normal
   • AST (SGOT)/ALT (SGPT) ≤ 3 x institutional upper limit of normal

   If above the institutional upper limit of normal but <3 times institutional upper limit of normal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient.

   • Creatinine ≤ institutional upper limit of normal OR
   • Creatinine clearance ≥ 60 ml/min/1.73m² for patients with creatinine levels above institutional normal
   • APTT ≤ 1.5 x institutional upper limit of normal
5. Patients must be able to provide written informed consent.
6. Patients must have MRI within 21 days of starting treatment.
7. Women of childbearing potential must have a negative serum pregnancy test prior to study entry. Women of childbearing potential and men must agree to use two birth control methods (either two barrier methods or a barrier method plus a hormonal method) or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
8. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with prior malignancies must be disease-free for ≥ five years.
9. Patients must be maintained on a stable corticosteroid regimen (no increase for 5 days) prior to the start of treatment.
10. Patients must be able to swallow whole capsules.

Phase I Patients

1. Phase I patients must have histologically proven glioblastoma.
2. Phase I patients must have recovered from the immediate post-operative period.
3. Phase I patients going on Arm 1 or Combination Dose Cohort must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor. Glucocorticoid therapy is allowed.
4. Phase I patients going on Arm 2 must have received planned treatment with radiation therapy and concomitant temozolomide at least 28 days but no more than 49 days prior to starting treatment on this study. Patients must have received at least 80% of planned temozolomide and radiation therapy with no grade 3 or grade 4 toxicity (except lymphopenia) attributed to the temozolomide. Arm 2 patients may not have received any other prior chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor. Prior Gliadel Wafers are allowed. Glucocorticoid therapy is allowed.

Intratumoral Drug Distribution Study Patients

1. Intratumoral Drug Distribution patients must have prior histologically proven glioblastoma that is progressive or recurrent following radiation therapy +/- chemotherapy.
2. Intratumoral Drug Distribution patients must be undergoing repeat surgery that is clinically indicated as determined by their care providers.
3. Intratumoral Drug Distribution patients must have measurable contrast-enhancing progressive or recurrent glioblastoma by MRI within 21 days of starting treatment. Patient must be able to tolerate MRIs.
4. Intratumoral Drug Distribution patients may have an unlimited number of prior therapy regimens.
5. Intratumoral Drug Distribution patients must have recovered from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible:
   • 12 weeks from the completion of radiation
   • 6 weeks from a nitrosourea chemotherapy
   • 3 weeks from a non-nitrosourea chemotherapy
   • 4 weeks from any investigational (not FDA-approved) agents
   • 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., tarceva, hydroxychloroquine, bevacizumab, etc.)

Exclusion Criteria

1. Patients receiving any other investigational agents are ineligible.
2. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or AZD1775 (MK-1775) are ineligible. The AZD1775 (MK-1775) Investigator Brochure and the temozolomide package insert can be referenced for more information.
3. Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs. Patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of AZD1775 (MK-1775).
4. Patients may not be on drugs known to be moderate or potent inhibitors/inducers of CYP3A4, sensitive substrates of CYP3A4, or substrates of CYP3A4 with narrow therapeutic windows (see Section 4.6, Prohibited Medication During Study).
5. Patients may not be on anti-coagulants (warfarin, etc.) other than low-molecular weight heparin (LMWH).
6. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
7. Pregnant women are excluded from this study because AZD1775 (MK-1775) has potential for teratogenic or abortifacients effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775 (MK-1775), breastfeeding should be discontinued if the mother is treated with AZD1775 (MK-1775).
8. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD1775 (MK-1775). In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.