Phase I/II study of Hyper-CVAD plus RAD001 (everolimus) for patients with relapsed or refractory acute lymphocytic leukemia
The goal of Phase I of this clinical research study is to find the highest tolerable dose of RAD001 (everolimus) when given in combination with the standard chemotherapy regimens to patients with ALL. The goal of Phase II of this study is to learn if the drug combinations can help to control ALL. The safety of these drug combinations will be also studied in both phases.
Disease Group: Leukemia
Treatment Agent: 6-mercaptopurine,Citrovorum,Cyclophosphamide,Cytarabine,Dexamethasone,Doxorubicin,G-CSF,Methotrexate,MESNA,Pegfilgrastim,Prednisone,RAD001,Solumedrol,Vincristine Sulfate
Treatment Location: Only at MD Anderson
Estimatated Length of Stay in Houston: For hyper-CVAD (odd) courses, 4-5 days; for high-dose methotrexate/cytarabine ;(even) courses for 3-4 days. Frequency-approximately every 21-28 days, for 8 ;courses total.
Return Visit: 1-3 times weekly for course 1, then every 1-2 weeks during course 2-8 if administered at MDACC. If components of the courses 3-8 and maintenance chemotherapy are delivered by the local oncologist, the participants must come to MDACC monthly.
Home Care: RAD001 will be self-administered continuously at home. G-CSF can be ;administered at home.
Primary: To establish the safety (dose-limiting toxicity [DLT] and maximum tolerated dose [MTD]), and efficacy (complete and overall response rate) of the RAD001 in combination with the hyper-CVAD regimen. Secondary: To analyze the effects of RAD001 on AKT/mTOR signaling pathways in leukemic blasts.
IRB Review and Approval Date: 11/18/2009
Recruitment Status: Not Accepting
Projected Accrual: N/A
1) Refractory or relapsed acute lymphocytic leukemia (ALL) or
lymphoblastic lymphoma (LL). Patients expressing Philadelphia chromosome
(Ph+) are eligible if they have failed a prior tyrosine
2) Age >/= 10 years.
3) ECOG performance status </= 3.
4) Adequate liver function with serum bilirubin </= 1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) </= 2.5 x ULN, unless proven to be related to disease infiltration.
5) Adequate renal function with serum creatinine </= 1.5 x ULN, unless proven to be related to disease infiltration.
6) No symptomatic pulmonary disease. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) >/= 50% of expected, corrected for hemoglobin.
7) Fasting serum cholesterol </= 300 mg/dL (or </= 7.75 mmol/L); fasting triglycerides </= 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
8) Signed informed consent.
1) Systemic chemotherapy within 7 days (with the exception of
hydroxyurea and/or dexamethasone) prior to starting therapy and
recovered from persistent acute toxicity (> grade 1) from that
therapy, unless there is evidence of rapidly progressive disease.
Concurrent therapy for central nervous system (CNS) prophylaxis or
treatment for CNS relapse is permitted.
2) Prior treatment with or known hypersensitivity to an mTOR inhibitor (sirlimus, temsirolimus, everolimus).
3) Major surgery within 4 weeks of start of study drug.
4) Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix, or basal or squamous cell carcinomas of the skin.
5) Severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study: a. Symptomatic congestive heart failure of New York Heart Assocation Class III or IV. b. Unstable angina pectoris or myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia. c. Uncontrolled severe infections. d. Liver disease such as cirrhosis, or severe hepatic impairment (Child-Pugh class C).
6) continuation of #5: Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
7) Known history of HIV seropositivity.
8) Impairment of gastrointestinal function of gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, malabsorption syndrome or small bowel resection).
9) Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Childbearing potential is a sexually mature woman who: 1)has not undergone a hysterectomy or bilateral oophorectomy; 2)has not been naturally postmenopausal for at least 24 consecutive months. Adequate contraception must be used throughout the trial and for eight weeks after the last dose of study drug, by both sexes. (Women of child bearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of therapy.)
10) Male patient whose sexual partner(s) are women of child bearing potential who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment.
11) Patients should not receive immunzation with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
12) Patients who have developed pleural effusion while on dasatinib therapy.
Information and next steps
Phase I/Phase II
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