Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
Primary Purpose
Acute Promyelocytic Leukemia
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tretinoin and Arsenic Trioxide
Sponsored by
About this trial
This is an interventional treatment trial for Acute Promyelocytic Leukemia focused on measuring Tretinoin, all-trans retinoic acid, ATRA, Vesanoid, Arsenic Trioxide, ATO, Trisenox, 11-040
Eligibility Criteria
Inclusion Criteria:
- Previously untreated patients with a morphologic diagnosis of APL, confirmed by demonstration of t(15;17) using conventional cytogenetics OR florescence in situ hybridization (FISH), OR a positive RT-PCR assay for PML-RAR at the subject's local institution.
- Age ≥18 years. Karnofsky performance status of ≥ 60%.
- Adequate renal function as demonstrated by a serum creatinine ≤ 2.0 mg/dl or a creatinine clearance of > 60 ml/min.
- Adequate hepatic function as demonstrated by a bilirubin < 2.0 mg/dl (unless attributable to Gilbert's disease) and an alkaline phosphatase, AST, and ALT ≤ 2.5 times the upper limit of normal.
- Normal cardiac function as demonstrated by a left ventricular ejection fraction ≥ 50% on echocardiogram or MUGA scan.
- QTc ≤ 500 msec on baseline ECG.
- Negative serum pregnancy test in women of childbearing potential.
- Ability to swallow oral medication.
- Men and women of child-bearing potential must be willing to practice an effective method of birth control during treatment and at least 4 months after treatment is finished.
- Patients with central nervous system involvement by APL are eligible and may receive concomitant treatment with radiation therapy and/or intrathecal chemotherapy in accordance with standard medical practice.
Exclusion Criteria:
- Previous treatment for APL, except tretinoin, which may be given for up to 7 days prior to study entry.
- Active serious infections not controlled by antibiotics.
- Pregnant women or women who are breast-feeding.
- Concurrent active malignancy requiring immediate therapy.
- Clinically significant cardiac disease (NY Heart Association Class III or IV), including chronic arrhythmias, or pulmonary disease.
- Other serious or life-threatening conditions deemed unacceptable by the principal investigator.
Sites / Locations
- University of Southern California
- Northwestern University
- National Heart, Lung, and Blood Institute (NIH)
- Memorial Sloan Kettering at Basking Ridge
- Memorial Sloan Kettering Monmouth
- Memorial Sloan Kettering Cancer Center @ Suffolk
- Memorial Sloan Kettering Westchester
- Memorial Sloan Kettering Cancer Center
- New York Presbyterian Hospital-Weill Medical College of Cornell University
- Memorial Sloan Kettering at Mercy Medical Center
- Cleveland Clinic
- Princess Margaret Hospital/Ontario Cancer Institute
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Tretinoin and Arsenic Trioxide
Arm Description
This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission.
Outcomes
Primary Outcome Measures
To Determine the Rate of Molecular Remission
after induction with combined tretinoin and ATO (along with idarubicin in patients with high-risk disease or who develop leukocytosis) in APL.
Secondary Outcome Measures
Participants Who Experienced a Complete Remission
after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis).
To Determine the Proportion of Patients in Molecular Remission
after each course of postremission therapy.
To Determine the Disease-free and Event-free Survival of Patients
treated with this program.
To Determine the Toxicity of This Treatment Program
including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated.
To Characterize the Differentiation of APL Cells During Treatment
with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood
Explore the in Vivo Induction of Telomerase-dependent Cell Death
by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression
Full Information
NCT ID
NCT01404949
First Posted
July 27, 2011
Last Updated
November 2, 2021
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Northwestern University, New York Presbyterian Hospital, University of Southern California, Princess Margaret Hospital, Canada, National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT01404949
Brief Title
Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
Official Title
Phase II Study of Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
July 2011 (undefined)
Primary Completion Date
February 1, 2021 (Actual)
Study Completion Date
February 1, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Northwestern University, New York Presbyterian Hospital, University of Southern California, Princess Margaret Hospital, Canada, National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
5. Study Description
Brief Summary
The purpose of this study is to find what effects, good and/or bad, treatment with two drugs has on leukemia. The first medicine is tretinoin (also called all-trans retinoic acid, ATRA, or Vesanoid). It is an approved medicine that causes the leukemia cells in APL to mature. It is related to vitamin A. The second is arsenic trioxide (Trisenox). It is an approved medicine for APL that comes back after earlier treatment.
APL is most often treated with tretinoin and standard chemotherapy drugs. These chemotherapy drugs can cause infection and bleeding. They can also damage the heart and normal bone marrow cells. This can lead to a second leukemia years later.
In this study, the investigators are using tretinoin and arsenic trioxide together. Both drugs work to treat APL. They have been used together in only a limited number of people. The investigators want to use these drugs together to reduce the amount of standard chemotherapy and decrease side effects. The patient will receive standard chemotherapy with a drug called idarubicin only if they have a higher chance of the leukemia coming back or a higher risk of side effects.
Detailed Description
Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two divided doses (25 mg/m2 in patients <20 years of age) for 35 days and ATO 0.15 mg/kg IV daily for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for 4 doses will be added during induction on day 2 if the presenting WBC is >10,000/μl, or if the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because of the increased risk of the APL differentiation syndrome and relapse in these patients. Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for the APL differentiation syndrome. All patients will then receive four courses of consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 25 doses.
Patients with high-risk disease or who received Idarubicin during Induction may receive intrathecal cytarabine as CNS prophylaxis given by the treating physician during consolidation, at the discretion of the site PI. High-risk patients will also receive maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years. Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses. Disease status will be monitored with serial analyses of peripheral blood samples using RT-PCR for PML-RARα mRNA. Patients will be followed until relapse, death, loss to follow-up, or removal from study.
Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance treatments will be given as an outpatient. Consolidation may also be given at the patient's local institution. Intrathecal cytarabine treatments will be administered as an outpatient.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Promyelocytic Leukemia
Keywords
Tretinoin, all-trans retinoic acid, ATRA, Vesanoid, Arsenic Trioxide, ATO, Trisenox, 11-040
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tretinoin and Arsenic Trioxide
Arm Type
Experimental
Arm Description
This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission.
Intervention Type
Drug
Intervention Name(s)
Tretinoin and Arsenic Trioxide
Intervention Description
See Detailed Description
Primary Outcome Measure Information:
Title
To Determine the Rate of Molecular Remission
Description
after induction with combined tretinoin and ATO (along with idarubicin in patients with high-risk disease or who develop leukocytosis) in APL.
Time Frame
4 years
Secondary Outcome Measure Information:
Title
Participants Who Experienced a Complete Remission
Description
after induction with tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop leukocytosis).
Time Frame
4 years
Title
To Determine the Proportion of Patients in Molecular Remission
Description
after each course of postremission therapy.
Time Frame
4 years
Title
To Determine the Disease-free and Event-free Survival of Patients
Description
treated with this program.
Time Frame
4 years
Title
To Determine the Toxicity of This Treatment Program
Description
including the early death rate (within 30 days), the incidence of APL differentiation syndrome, the number and length of hospitalizations, the incidence of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the effects of treatment on left ventricular ejection fraction (LVEF) Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be tabulated.
Time Frame
4 years
Title
To Characterize the Differentiation of APL Cells During Treatment
Description
with combined tretinoin and ATO using serial immunophenotyping studies of peripheral blood
Time Frame
4 years
Title
Explore the in Vivo Induction of Telomerase-dependent Cell Death
Description
by ATRA (Tretinoin) and ATO (Arsenic Trioxide). Bone marrow samples will be analyzed at baseline and at the time of clinical CR for telomerase activity, telomere length and TERT expression
Time Frame
4 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Previously untreated patients with a morphologic diagnosis of APL, confirmed by demonstration of t(15;17) using conventional cytogenetics OR florescence in situ hybridization (FISH), OR a positive RT-PCR assay for PML-RAR at the subject's local institution.
Age ≥18 years. Karnofsky performance status of ≥ 60%.
Adequate renal function as demonstrated by a serum creatinine ≤ 2.0 mg/dl or a creatinine clearance of > 60 ml/min.
Adequate hepatic function as demonstrated by a bilirubin < 2.0 mg/dl (unless attributable to Gilbert's disease) and an alkaline phosphatase, AST, and ALT ≤ 2.5 times the upper limit of normal.
Normal cardiac function as demonstrated by a left ventricular ejection fraction ≥ 50% on echocardiogram or MUGA scan.
QTc ≤ 500 msec on baseline ECG.
Negative serum pregnancy test in women of childbearing potential.
Ability to swallow oral medication.
Men and women of child-bearing potential must be willing to practice an effective method of birth control during treatment and at least 4 months after treatment is finished.
Patients with central nervous system involvement by APL are eligible and may receive concomitant treatment with radiation therapy and/or intrathecal chemotherapy in accordance with standard medical practice.
Exclusion Criteria:
Previous treatment for APL, except tretinoin, which may be given for up to 7 days prior to study entry.
Active serious infections not controlled by antibiotics.
Pregnant women or women who are breast-feeding.
Concurrent active malignancy requiring immediate therapy.
Clinically significant cardiac disease (NY Heart Association Class III or IV), including chronic arrhythmias, or pulmonary disease.
Other serious or life-threatening conditions deemed unacceptable by the principal investigator.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jae Park, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Southern California
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Northwestern University
City
Evanston
State/Province
Illinois
ZIP/Postal Code
60208
Country
United States
Facility Name
National Heart, Lung, and Blood Institute (NIH)
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20824
Country
United States
Facility Name
Memorial Sloan Kettering at Basking Ridge
City
Basking Ridge
State/Province
New Jersey
ZIP/Postal Code
07920
Country
United States
Facility Name
Memorial Sloan Kettering Monmouth
City
Middletown
State/Province
New Jersey
ZIP/Postal Code
07748
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center @ Suffolk
City
Commack
State/Province
New York
ZIP/Postal Code
11725
Country
United States
Facility Name
Memorial Sloan Kettering Westchester
City
Harrison
State/Province
New York
ZIP/Postal Code
10604
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
New York Presbyterian Hospital-Weill Medical College of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Memorial Sloan Kettering at Mercy Medical Center
City
Rockville Centre
State/Province
New York
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Princess Margaret Hospital/Ontario Cancer Institute
City
Toronto
State/Province
Ontario
Country
Canada
12. IPD Sharing Statement
Links:
URL
http://www.mskcc.org/mskcc/html/44.cfm
Description
Memorial Sloan Kettering Cancer Center
Learn more about this trial
Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy
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