Phase I Study of Dasatinib Plus Protracted Temozolomide in Recurrent Malignant Glioma
Overview
- Phase
- Phase 1
- Intervention
- enzyme-inducing anti-epileptic drugs
- Conditions
- Glioblastoma Multiforme
- Sponsor
- Annick Desjardins
- Locations
- 1
- Primary Endpoint
- Toxicity assessed using CTCAE v.3.0
- Status
- Withdrawn
- Last Updated
- 13 years ago
Overview
Brief Summary
The primary objective of this study is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of dasatinib when combined with protracted, daily temozolomide (TMZ). Secondary objectives are: To further evaluate the safety and tolerability of dasatinib plus protracted, daily TMZ; 2. To evaluate the pharmacokinetics of dasatinib when administered with protracted, daily TMZ among recurrent malignant glioma patients who are on and not on CYP-3A enzyme inducing anti-epileptic drugs (EIAEDs); 3. To evaluate for anti-tumor activity with this regimen in this patient population.
Detailed Description
This is an open-label, single center, one-arm phase I dose-escalation study of dasatinib plus protracted , daily TMZ administered orally on a continuous daily dosing schedule among adult patients with recurrent or relapsing malignant glioma. The study format includes a classical "3+3" dose escalation design to determine the MTD and DLT of dasatinib plus protracted, daily TMZ among recurrent malignant glioma patients. Patients will be stratified based on whether they are receiving EIAED and each stratum will independently dose escalate. Additionally, the study will characterize the safety, tolerability, biologic activity, and pharmacokinetic profile of dasatinib when used in combination with protracted, daily TMZ. Patients will start treatment on day 1 of cycle 1 with dasatinib. For patients undergoing dasatinib pharmacokinetic (PK) analysis, dasatinib will be administered alone until initial PK assessments are collected. Protracted TMZ will be initiated after initial dasatinib PK assessments are collected and will continue to be administered with dasatinib on a continuous daily dosing schedule. The initial dasatinib PK assessments will be collected over 24 hours between days 3-7 of cycle 1. Patients not undergoing dasatinib PK collections will begin both dasatinib and protracted, daily TMZ together on day 1, cycle 1. The protracted, daily TMZ dose will be 50 mg/m² daily for all patients. The dose level of dasatinib will be increased in successive cohorts. Cohorts of 3-6 patients will accrue at each dose level until MTD is defined. Each cohort will consist of a minimum of 3 newly enrolled patients. Intra-patient dose escalation is not permitted. It is estimated that this study will enroll a minimum of 30 patients (up to 4 dose levels/stratum; 3 patients/dose level for levels 1-3 and 6 patients at level 4) and a maximum of 48 patients (6 patients/dose level; 4 dose levels/stratum). Cohorts may be expanded at any dose level for further elaboration of safety and pharmacokinetic parameters as required. The primary safety and efficacy analysis will be conducted on all patient data at the time all patients who are still receiving study drug will have completed at least 4 cycles of treatment. The additional data for any patients continuing to receive study drug past this time, as allowed by the protocol, will be further summarized in a report once these patients either completed or discontinued the study. Prior to the primary analysis, an additional safety report may be prepared. The most common side effects include vomiting, diarrhea, anorexia (loss of appetite), fluid retention, fatigue, headache, rash, hypocalcemia (low calcium level), and decreases in blood counts. Other possible side effects may include nausea, joint pain, muscle aches, generalized pain, abdominal pain, and fever. Rare side effects may include QTc prolongation (heart beat changes), pulmonary edema (fluid around the lungs), difficulty breathing, cough, hemorrhage, gastrointestinal bleeding, pneumonia, cardiac effusion (fluid in the sac surrounding the heart), and cardiac failure. Temodar has been well tolerated by both adults and children with the most common toxicity being mild myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, hepatotoxicity, anorexia, fatigue and hyperglycemia. As in the case with many anti-cancer drugs, Temodar may be carcinogenic. Rats given Temodar have developed breast cancer.
Investigators
Annick Desjardins
Assist Professor of Medicine-Neurology
Duke University
Eligibility Criteria
Inclusion Criteria
- •Patients must have a histologically confirmed diagnosis of a recurrent/progressive WHO Gr.4 malignant glioma (glioblastoma multiforme or gliosarcoma) or WHO Gr.3 malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma or anaplastic mixed glioma). Recurrence will be defined based on the modified MacDonald criteria or based on histopathologic confirmation of tissue obtained via surgical intervention. Patients with prior low-grade glioma are eligible if histologic assessment demonstrates transformation to WHO Gr.III or IV malignant glioma;
- •\> or = to 18 y/o;
- •KPS . or = to 60%;
- •Patients must be presenting in 1st, 2nd or 3rd relapse. Relapse is defined as progression following anti-cancer therapy other than surgery, including non-surgical therapies that are considered standard treatment for high-grade glioma if administered to patients with prior low-grade glioma. Prior therapy must have included external beam radiotherapy;
- •Adequate bone marrow, liver and renal function as assessed by the following: Hematocrit \> or = to 29%, ANC \> or = to 1,500/mm3, Platelet count \> or = to 125,000/mm3, Total bilirubin \< or = to 1.5 x ULN, ALT and AST \< or = to 2.5 x the ULN ( \< or = to 5 x ULN for patients with liver involvement), INR \< 1.5 or a PT/PTT within normal limits (unless on therapeutic anti-coagulation). Patients receiving anti-coagulation treatment with a low-molecular weight heparin will be allowed to participate, however oral warfarin is not permitted except for low-dose warfarin (1mg po DAILY), Creatinine \< 1.5 x ULN, Serum Na, K+, Mg2+, Phosphate and Ca2+ \> or = to Lower Limit of Normal (LLN);
- •An interval of at least 2 weeks between prior surgical resection (1 week for biopsy) and initiation of study regimen;
- •An interval of at least 12 weeks from completion of standard, daily XRT, unless one of the following occurs: a) new area of enhancement on MRI imaging that is outside the XRT field; b) biopsy proven recurrent tumor; c) radiographic evidence of progressive tumor on 2 consecutive scans at least 4 weeks apart;
- •An interval of at least 4 weeks from prior chemotherapy (except nitrosoureas which require 6 weeks) unless there is unequivocal evidence of tumor progression and the patient has recovered from all anticipated toxicities from prior therapy;
- •An interval of a least 14 days from exposure to investigational agents, unless there is unequivocal evidence of tumor progression and the patients has recovered from all anticipated toxicities from prior therapy;
- •Signed written informed consent including HIPAA according to institutional guidelines. A signed informed consent must be obtained prior to any study specific procedures;
Exclusion Criteria
- •Prior dasatinib. Imatinib mesylate in the prior three months;
- •Grade 3 or greater toxicity related to prior TMZ therapy;
- •Prior progression on protracted daily TMZ;
- •Pregnancy or breast feeding;
- •History of significant concurrent illness;
- •More than 3 prior episodes of progressive disease;
- •Significant cardiac disease including any of the following:
- •congestive heart failure \> class II NYHA;
- •unstable angina (anginal symptoms at rest);
- •new onset angina (began within the last 3 months);
Arms & Interventions
1
Subjects taking EIAEDs (CYP3A enzyme-inducing anti-epileptic drugs).
Intervention: enzyme-inducing anti-epileptic drugs
2
Subjects NOT taking EIAEDs (CYP3A enzyme-inducing anti-epileptic drugs).
Intervention: enzyme-inducing anti-epileptic drugs
Outcomes
Primary Outcomes
Toxicity assessed using CTCAE v.3.0
Time Frame: weekly
Secondary Outcomes
- Progression free and overall survival(continuous)
- Radiographic response (modified MacDonald Criteria)(every 28 days)