RAD001 Study in Treatment of Relapsed or Refractory Acute Lymphocytic Leukemia
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| ClinicalTrials.gov Identifier: NCT00968253 |
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Recruitment Status :
Completed
First Posted : August 28, 2009
Results First Posted : May 31, 2018
Last Update Posted : February 27, 2019
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Sponsor:
M.D. Anderson Cancer Center
Collaborator:
Novartis
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Leukemia Acute Lymphocytic Leukemia | Drug: Everolimus (RAD001) Drug: Cyclophosphamide Drug: Vincristine Drug: Doxorubicin Drug: Dexamethasone Drug: Mesna Drug: Methotrexate Drug: Ara-C (Cytarabine) Drug: Methylprednisone Drug: G-CSF | Phase 1 Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 24 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) for Patients With Relapsed or Refractory Acute Lymphocytic Leukemia (ALL) |
| Study Start Date : | November 2009 |
| Actual Primary Completion Date : | December 2015 |
| Actual Study Completion Date : | December 2015 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Phase I: RAD001 + Combination Chemo
Optimal 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. |
Drug: Everolimus (RAD001)
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.
Other Name: Afinitor Drug: Cyclophosphamide 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).
Other Names:
Drug: Vincristine 2 mg IV on Day 4 and Day 11 ± 2 days. Drug: Doxorubicin 50 mg/m^2 IV over 24 hours via central venous catheter on day 4, after last dose of Cyclophosphamide given.
Other Names:
Drug: Dexamethasone 40 mg IV or orally daily days 1-4 ± 2 days and days 11-14 ± 2 days.
Other Name: Decadron Drug: Mesna 600 mg/m^2 IV continuous infusion daily for 24 hours days 1-3.
Other Name: Mesnex Drug: Methotrexate 200 mg/m^2 IV over 2 hours followed by 800 mg/m^2 IV over 22 hours day 1. Drug: Ara-C (Cytarabine) 3 gm/m^2 IV over 2 hours every 12 hours for 4 doses on days 2, 3.
Other Names:
Drug: Methylprednisone 50 mg IV over 2 hours approximately every 12 hours for 6 doses days 1-3.
Other Names:
Drug: G-CSF 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.
Other Names:
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Experimental: Phase II: MTD RAD001 + Combination Chemo
MTD 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.
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Drug: Everolimus (RAD001)
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.
Other Name: Afinitor Drug: Cyclophosphamide 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).
Other Names:
Drug: Vincristine 2 mg IV on Day 4 and Day 11 ± 2 days. Drug: Doxorubicin 50 mg/m^2 IV over 24 hours via central venous catheter on day 4, after last dose of Cyclophosphamide given.
Other Names:
Drug: Dexamethasone 40 mg IV or orally daily days 1-4 ± 2 days and days 11-14 ± 2 days.
Other Name: Decadron Drug: Mesna 600 mg/m^2 IV continuous infusion daily for 24 hours days 1-3.
Other Name: Mesnex Drug: Methotrexate 200 mg/m^2 IV over 2 hours followed by 800 mg/m^2 IV over 22 hours day 1. Drug: Ara-C (Cytarabine) 3 gm/m^2 IV over 2 hours every 12 hours for 4 doses on days 2, 3.
Other Names:
Drug: Methylprednisone 50 mg IV over 2 hours approximately every 12 hours for 6 doses days 1-3.
Other Names:
Drug: G-CSF 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.
Other Names:
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Primary Outcome Measures :
- Maximum Tolerated Dose [MTD] Determination by Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Following first two dose cycles (21 days/each), up to 42 days ]
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.
- Overall Response Rate (OR) Where OR = CR + CRp + CRi [ Time Frame: 8 courses of treatment, up to 24 weeks ]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.
Secondary Outcome Measures :
- Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg) [ Time Frame: Up to 20 cycles of study drugs (21 day cycles) or till disease progression ]Response 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. Partial remission (PR): Peripheral blood count recovery as for CR, with decrease in marrow blasts by > 50% from pretreatment values with no more than 25% leukemia/lymphoma cells in the marrow. Nonresponder, Other: All other responses will be considered failures.
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| Ages Eligible for Study: | 10 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00968253
Locations
| United States, Texas | |
| University of Texas MD Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis
Investigators
| Study Chair: | Marina Konopleva, MD, PHD | M.D. Anderson Cancer Center |
Additional Information:
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT00968253 |
| Other Study ID Numbers: |
2009-0100 NCI-2011-01814 ( Registry Identifier: NCI CTRP ) |
| First Posted: | August 28, 2009 Key Record Dates |
| Results First Posted: | May 31, 2018 |
| Last Update Posted: | February 27, 2019 |
| Last Verified: | February 2019 |
Keywords provided by M.D. Anderson Cancer Center:
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Acute Lymphocytic Leukemia ALL Hyper-CVAD Everolimus 6-mercaptopurine Citrovorum Cyclophosphamide Cytarabine Dexamethasone |
Doxorubicin G-CSF Methotrexate MESNA Pegfilgrastim Prednisone RAD001 Solumedrol Vincristine Sulfate |
Additional relevant MeSH terms:
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Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cytarabine Dexamethasone Methylprednisolone Methylprednisolone Acetate Methylprednisolone Hemisuccinate Prednisolone |
Prednisolone acetate Cyclophosphamide Doxorubicin Methotrexate Vincristine Everolimus Lenograstim Prednisolone hemisuccinate Prednisolone phosphate Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents |