Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy

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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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

To determine the rate of molecular remission

Secondary Outcome

 To determine the rate of clinical complete remission (CR) and the time to remission

Condition

Acute Promyelocytic Leukemia

Intervention

Tretinoin and Arsenic Trioxide

Study Arms / Comparison Groups

 Tretinoin and Arsenic Trioxide
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

39

Start Date

July 2011

Completion Date

July 2021

Primary Completion Date

July 2021

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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jae Park, MD, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT01404949

Organization ID

11-040


Responsible Party

Sponsor

Study Sponsor

Memorial Sloan Kettering Cancer Center

Collaborators

 Northwestern University

Study Sponsor

Jae Park, MD, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

March 2020