Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL)
Overview[ - collapse ][ - ]
Purpose | H. Lee Moffitt Cancer Center and Research Institute will be the Sunshine Project Coordinator, but will not be recruiting locally. The purpose of the trial is to study the clinical and biological effects of metformin in combination with standard systemic chemotherapy in a disease (relapsed ALL) that has a dismal outcome, as well as to do a dose escalation study to find the Maximum Tolerated Dose (MTD) of metformin in conjunction with ALL therapy. There have also been analysis of patients enrolled on trials who were diabetics on metformin and their outcome was better than patients on the same trial that were not on metformin as their antihyperglycemic. |
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Condition | Acute Lymphoblastic Leukemia |
Intervention | Drug: Metformin Drug: Vincristine Drug: Dexamethasone Drug: PEG-asparaginase Drug: Doxorubicin Drug: Intrathecal chemotherapy |
Phase | Phase 1 |
Sponsor | H. Lee Moffitt Cancer Center and Research Institute |
Responsible Party | H. Lee Moffitt Cancer Center and Research Institute |
ClinicalTrials.gov Identifier | NCT01324180 |
First Received | March 24, 2011 |
Last Updated | December 3, 2013 |
Last verified | December 2013 |
Tracking Information[ + expand ][ + ]
First Received Date | March 24, 2011 |
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Last Updated Date | December 3, 2013 |
Start Date | March 2011 |
Estimated Primary Completion Date | July 2014 |
Current Primary Outcome Measures | Maximum Tolerated Dose (MTD) [Time Frame: 45 days] [Designated as safety issue: No]MTD determined by Dose Limiting Toxicity (DLT), any time during the first course of therapy. Dose Limiting Toxicities: Any Grade 3 or 4 non-hematological toxicity by Common Toxicity Criteria for Adverse Effects (CTCAE) version 4.0 felt to be probably or definitely related to the study agent, persistent marrow aplasia at day 44, lactic acidosis for grade 3 or 4, grade 3 and 4 hypoglycemia. |
Current Secondary Outcome Measures |
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Descriptive Information[ + expand ][ + ]
Brief Title | Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and Metformin for Relapsed Childhood Acute Lymphoblastic Leukemia (ALL) |
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Official Title | A Phase I Window, Dose Escalating and Safety Trial of Metformin in Combination With Induction Chemotherapy in Relapsed Refractory Acute Lymphoblastic Leukemia: Metformin With Induction Chemotherapy of Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) |
Brief Summary | H. Lee Moffitt Cancer Center and Research Institute will be the Sunshine Project Coordinator, but will not be recruiting locally. The purpose of the trial is to study the clinical and biological effects of metformin in combination with standard systemic chemotherapy in a disease (relapsed ALL) that has a dismal outcome, as well as to do a dose escalation study to find the Maximum Tolerated Dose (MTD) of metformin in conjunction with ALL therapy. There have also been analysis of patients enrolled on trials who were diabetics on metformin and their outcome was better than patients on the same trial that were not on metformin as their antihyperglycemic. |
Detailed Description | This will be a phase I protocol of Vincristine, Dexamethasone, Doxorubicin, and PEG-asparaginase (VPLD) and metformin conducted in the Sunshine Project sites for children with recurrent ALL. All sites will be eligible to open this study, provided they agree to adhere to all study procedures and make a good faith effort to obtain all pharmacodynamic and pharmacokinetic evaluations requested. |
Study Type | Interventional |
Study Phase | Phase 1 |
Study Design | Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment |
Condition | Acute Lymphoblastic Leukemia |
Intervention | Drug: Metformin Will be dosed orally BID as per dose level of subject as defined in dose escalation schema. Both liquid and tablet forms are allowed and can be chosen based on convenience. Metformin will be continued throughout the cycle until Day 28 or until the patient is removed from study (e.g. to pursue new lines of therapy such as transplant), whichever occurs sooner. Drug: Vincristine 1.5 mg/m^2/dose IV push (maximum single dose 2 mg) on days 2, 9, 16 and 23 Other Names:
10 mg/m^2/day divided BID Take dexamethasone by mouth days 2-15 Other Names:
2500 IU's/m^2/day Intramuscular injection (IM) or intravenous infusion per institutional standard on days 3, 9, 16 and 23 If the patient develops an allergic reaction to PEG while being treated on this protocol, eliminate all future doses of PEG and substitute Erwinia if not intolerant of Erwinia and has no history of pancreatitis. Patients will receive Erwinase® 25,000 IU/m^2 x 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase on the original protocol. Other Names:
60 mg/m^2/day IV over 15 minutes on day 2 Other Names:
IT cytarabine given intrathecally to all patients on day 1 of each cycle. Dose defined by age. May be given with staging lumbar puncture before enrollment, but must be within 72 hours of starting therapy. If not done at study entry or before, may be done on Day 2 prior to doxorubicin administration. 30 mg for patients age 1-1.99 50 mg for patients age 2-2.99 70 mg for patients greater than 3 years of age IT methotrexate given Intrathecally to all patients who are CNS negative at study entry on day 16 at the dose defined by age. Other Names:
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Study Arm (s) | Experimental: VLPD Regimen Induction will consist of vincristine, dexamethasone, doxorubicin and PEG asparaginase (so called VPLD - dexamethasone is substituted for prednisone and PEG asparaginase is substituted for L-asparaginase) in combination with metformin. Eligible patients will receive 24 hours of metformin followed by induction. Intrathecal chemotherapy with standard dose cytarabine will be administered at the start of each cycle, with central nervous system (CNS) therapy afterwards determined by findings on staging lumbar puncture. |
Recruitment Information[ + expand ][ + ]
Recruitment Status | Recruiting |
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Estimated Enrollment | 18 |
Estimated Completion Date | July 2014 |
Estimated Primary Completion Date | July 2014 |
Eligibility Criteria | Inclusion Criteria: - ALL or lymphoblastic lymphoma patients in first or higher relapse. - Male or Female age 1-30 years at initial diagnosis. - Signed informed consent. - Karnofsky / Lansky score above 50%. - No known contraindications to intended therapies. - Prior anthracycline exposure: Patients must have had less than 350 mg/m^2 lifetime exposure of anthracycline chemotherapy. - It must be at least 6 months since the last treatment with a "VPLD" induction/re-induction type regimen (i.e. anthracycline, steroid, asparaginase and vincristine). - Patients must have adequate organ function. - Adequate renal function defined as serum creatinine < 1.5 x upper limit of normal (ULN) for age. - Total bilirubin < 1.5 X ULN for age. - Alanine transaminase (ALT) < 5 X ULN for age, unless the elevation is disease-related. - Adequate cardiac function as defined as shortening fraction of > 27% by echocardiogram or ejection fraction > 45% by gated radionuclide study. Exclusion Criteria: - Significant renal impairment. - Patients planning on receiving other investigational agents while on this study. - Patients planning on receiving other anti-cancer therapies while on this study. - Patients with active infection defined as positive blood culture within 48 hours of study registration, need for supplemental oxygen or vasopressors within 48 hours of study entry. - No corticosteroids allowed aside from dexamethasone treatment directed at leukemia. - Patients who are allergic to PEG-asparaginase or who cannot tolerate any asparaginase, either because of history of pancreatitis or allergy, will go on study without asparaginase. - Known intolerance to doxorubicin, metformin, or vincristine. - Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure. - Patients may be on hydroxurea until the first dose of metformin is to be given. - Patients must have recovered from the acute side effects of all prior anticancer therapy. - At least 1 week from prior cytotoxic chemotherapy. - At least 4 weeks from craniospinal irradiation. - At least 4 months since hematopoietic stem cell transplant (HSCT) with no evidence of active graft-versus-host disease (GVHD). - Pregnant or lactating women. |
Gender | Both |
Ages | 1 Year |
Accepts Healthy Volunteers | No |
Contacts | Contact: Kathleen Manning 813-745-7412 kathleen.manning@moffitt.org |
Location Countries | United States |
Administrative Information[ + expand ][ + ]
NCT Number | NCT01324180 |
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Other Study ID Numbers | MCC-16601 |
Has Data Monitoring Committee | Yes |
Information Provided By | H. Lee Moffitt Cancer Center and Research Institute |
Study Sponsor | H. Lee Moffitt Cancer Center and Research Institute |
Collaborators | Pediatric Cancer Foundation |
Investigators | Study Chair: John M. Goldberg, M.D. Holtz Children's Hospital University of Miami Miller School of MedicinePrincipal Investigator: Damon Reed, M.D. H. Lee Moffitt Cancer Center and Research Institute |
Verification Date | December 2013 |
Locations[ + expand ][ + ]
University of Florida Shands Cancer Center | Gainesville, Florida, United States, 32610 Contact: Heather Rogers | 352-265-0027 | heatherrogers@ufl.eduPrincipal Investigator: William Slayton, M.D. Recruiting |
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Nemours Children's Clinic | Jacksonville, Florida, United States, 32207 Contact: Mary Lawlor-Barry | 904-697-3817 | mbarry@nemours.orgPrincipal Investigator: Scott Bradfield, M.D. Recruiting |
Holtz Children's Hospital University of Miami Miller School of Medicine | Miami, Florida, United States, 33136 Contact: Myriam Zayas | 305-243-7846 | MZayas2@med.miami.eduPrincipal Investigator: John M. Goldberg, M.D. Recruiting |
M.D. Anderson of Orlando | Orlando, Florida, United States, 32806 Contact: Stephanie Garber, R.N. | 321-841-3837 | stephanie.garber@orlandohealth.comPrincipal Investigator: Robert Sutphin, M.D. Recruiting |
All Children's Hospital | St. Petersburg, Florida, United States, 33701 Contact: Frances Hamblin | 727-767-2423 | frances.hamblin@allkids.orgPrincipal Investigator: Gregory Hale, M.D. Recruiting |
Montefiore Medical Center, The Children's Hospital at Montefiore | Bronx, New York, United States, 10467 Contact: Catherine Stanford | 718-741-2356 | cstanfor@montefiore.orgPrincipal Investigator: Jonathan Gill, M.D. Recruiting |