RAD001 Study in Treatment of Relapsed or Refractory Acute Lymphocytic Leukemia
Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) for Patients With Relapsed or Refractory Acute Lymphocytic Leukemia (ALL)
2 other identifiers
interventional
24
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_1 leukemia
Started Nov 2009
Typical duration for phase_1 leukemia
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 27, 2009
CompletedFirst Posted
Study publicly available on registry
August 28, 2009
CompletedStudy Start
First participant enrolled
November 1, 2009
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2015
CompletedStudy Completion
Last participant's last visit for all outcomes
December 1, 2015
CompletedResults Posted
Study results publicly available
May 31, 2018
CompletedFebruary 27, 2019
February 1, 2019
6.1 years
August 27, 2009
December 22, 2016
February 5, 2019
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Maximum Tolerated Dose [MTD] Determination by Number of Participants With Dose Limiting Toxicity (DLT)
The Maximum tolerated dose (MTD) was the highest dose level at which fewer than 2 of 6 patients developed a dose limiting toxicity (DLT) in the first two cycles of therapy. A 3 by 3 design was used for dose escalation in the phase I portion of the study. A dose-limiting toxic effect (DLT) was defined as a clinically significant adverse event or abnormal laboratory value directly attributable to everolimus and assessed as unrelated to disease progression, intercurrent illness, or concomitant medications, occurring during the first or second cycle of therapy, that met any of the following criteria: CTCAE version 3.0 grade 3 increased AST or ALT for 7 days, CTCAE grade 4 increased AST or ALT of any duration, or any other clinically significant CTCAE grade 3 or 4 toxic effect. Electrolyte abnormalities (changes in glucose, chemistries, liver enzymes, pancreatic enzymes) correctable by optimal therapy and without clinical impact were not considered DLTs.
Following first two dose cycles (21 days/each), up to 42 days
Overall Response Rate (OR) Where OR = CR + CRp + CRi
Number of participants out of total treated who experienced a complete response response according to RECIST criteria either (CR + CRp) CR Without Platelet Recovery. Response (CR + CRp) defined as Complete remission (CR): Disappearance of all clinical and/or radiologic evidence of disease. Neutrophil count \> 1.0 x10\^9/L, platelet count \> 100 x10\^9/L, and blasts \< 5% in a normocellular or hypercellular marrow. Complete remission without platelet recovery (CRp): Peripheral blood and marrow parameters as for CR, but with platelet count \> 20 x 10\^9/L and \< 100 x 10\^9/L in the absence of platelet transfusions. CR with incomplete blood count recovery (CRi): Same as CR but platelets ≤ 100,000/mcl and/or neutrophils ≤ 1,000/mcl.
8 courses of treatment, up to 24 weeks
Secondary Outcomes (1)
Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg)
Up to 20 cycles of study drugs (21 day cycles) or till disease progression
Study Arms (2)
Phase I: RAD001 + Combination Chemo
EXPERIMENTALOptimal dose finding of Everolimus (RAD001) beginning dose 5 mg + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Cycles 1, 3, 5, \& 7 and Methotrexate \& Cytarabine (Ara-C) during Cycles 2, 4, 6, \& 8. First chemotherapy combination Hyper-CVAD = Cyclophosphamide, Vincristine, Adriamycin (doxorubicin), and Dexamethasone; Second chemotherapy combination Methotrexate and Ara-C.
Phase II: MTD RAD001 + Combination Chemo
EXPERIMENTALMTD dose of Everolimus + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Cycles 1, 3, 5, \& 7 and Methotrexate \& Ara-C during Cycles 2, 4, 6, \& 8.
Interventions
Beginning dose of 5 mg tablets every other day by mouth followed by a big glass of water. First dose will occur 1 day before receiving chemotherapy.
300 mg/m\^2 intravenous (IV) over 3 hours every 12 hours x 6 doses on Days 1, 2, 3 (total dose 1800 mg/m2).
2 mg IV on Day 4 and Day 11 ± 2 days.
50 mg/m\^2 IV over 24 hours via central venous catheter on day 4, after last dose of Cyclophosphamide given.
40 mg IV or orally daily days 1-4 ± 2 days and days 11-14 ± 2 days.
600 mg/m\^2 IV continuous infusion daily for 24 hours days 1-3.
200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours day 1.
3 gm/m\^2 IV over 2 hours every 12 hours for 4 doses on days 2, 3.
50 mg IV over 2 hours approximately every 12 hours for 6 doses days 1-3.
10 mcg/kg/day (rounded) within 72 ± 48 hours after completion of chemotherapy until neutrophil recovery 1 x 109/L or higher. Pegfilgrastim (given at 6 mg subcutaneous for one dose approximately 24 hours after completion of the chemotherapy) may be substituted for G-CSF.
Eligibility Criteria
You may qualify if:
- 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 kinase-containing therapy.
- Age \>/= 10 years.
- Eastern Cooperative Oncology Group (ECOG) performance status \</= 3.
- 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.
- Adequate renal function with serum creatinine \</= 1.5 x ULN, unless proven to be related to disease infiltration.
- 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.
- 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.
- Signed informed consent.
You may not qualify if:
- 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.
- Prior treatment with or known hypersensitivity to an mammilian target of rapamycin (mTOR) inhibitor (sirolimus, temsirolimus, everolimus).
- Major surgery within 4 weeks of start of study drug.
- Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix, or basal or squamous cell carcinomas of the skin.
- 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 Association 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).
- continuation of #5: Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. Hepatitis B virus (HBV) DNA and hepatitis C virus (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.
- Known history of HIV seropositivity.
- 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).
- 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.)
- 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.
- Patients should not receive immunization 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.
- Patients who have developed pleural effusion while on dasatinib therapy.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- M.D. Anderson Cancer Centerlead
- Novartiscollaborator
Study Sites (1)
University of Texas MD Anderson Cancer Center
Houston, Texas, 77030, United States
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Marina Konopleva, MD, PHD/Professor, Leukemia
- Organization
- The University of Texas (UT) MD Anderson Cancer Center
Study Officials
- STUDY CHAIR
Marina Konopleva, MD, PHD
M.D. Anderson Cancer Center
Publication Agreements
- PI is Sponsor Employee
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 27, 2009
First Posted
August 28, 2009
Study Start
November 1, 2009
Primary Completion
December 1, 2015
Study Completion
December 1, 2015
Last Updated
February 27, 2019
Results First Posted
May 31, 2018
Record last verified: 2019-02