Glioma Clinical Trial
Official title:
Phase I Study of Dasatinib Plus Protracted Temozolomide in Recurrent Malignant Glioma
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.
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.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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