Clinical Trials /

Cytarabine and Daunorubicin in Combination With Ruxolitinib for the Treatment of Secondary Acute Myeloid Leukemia Transformed From Myeloproliferative Neoplasms.

NCT03878199

Description:

This phase I/II studies the safety and efficacy of ruxolitinib in combination with liposomal formulation of cytarabine and daunorubicin (CPX-351) for treatment of secondary acute myelogenous leukemia (AML) transformed from myeloproliferative neoplasms (MPNs). The phase I portion of the study will establish the maximum tolerated dose (MTD) for ruxolitinib in combination with a fixed dose of CPX-351. The modified Toxicity Probability Interval (mTPI) design will be used to determine the optimal dose of ruxolitinib in combination with CPX-351. Once the MTD is established and phase I objectives completed, the study will open for enrollment in the phase II portion of the trial. The phase II portion of the trial will assess the efficacy of the ruxolitinib and CPX-351 combination. Prior publications highlight the important role of the janus kinase inhibitor, ruxolitinib in the treatment of MPNs and its preliminary efficacy in combination with hypomethylating agents for the treatment of secondary AML.

Related Conditions:
  • Secondary Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cytarabine and Daunorubicin in Combination With Ruxolitinib for the Treatment of Secondary Acute Myeloid Leukemia Transformed From Myeloproliferative Neoplasms.
  • Official Title: A Phase I/II, Open-label, Multi-center Study Evaluating the Safety and Efficacy of Ruxolitinib and CPX-351 in Combination for the Treatment of Secondary Acute Myeloid Leukemia Transformed From Myeloproliferative Neoplasms.

Clinical Trial IDs

  • ORG STUDY ID: STUDY00018059
  • NCT ID: NCT03878199

Conditions

  • Acute Myeloid Leukemia
  • Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
RuxolitinibINCB-18424 Phosphate, JakafiRuxolitinib in combination with CPX-351
CPX-351Cytarabine, DaunorubicinRuxolitinib in combination with CPX-351

Purpose

This phase I/II studies the safety and efficacy of ruxolitinib in combination with liposomal formulation of cytarabine and daunorubicin (CPX-351) for treatment of secondary acute myelogenous leukemia (AML) transformed from myeloproliferative neoplasms (MPNs). The phase I portion of the study will establish the maximum tolerated dose (MTD) for ruxolitinib in combination with a fixed dose of CPX-351. The modified Toxicity Probability Interval (mTPI) design will be used to determine the optimal dose of ruxolitinib in combination with CPX-351. Once the MTD is established and phase I objectives completed, the study will open for enrollment in the phase II portion of the trial. The phase II portion of the trial will assess the efficacy of the ruxolitinib and CPX-351 combination. Prior publications highlight the important role of the janus kinase inhibitor, ruxolitinib in the treatment of MPNs and its preliminary efficacy in combination with hypomethylating agents for the treatment of secondary AML.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Phase I: To evaluate the MTD of ruxolitinib in combination with CPX-351 for treatment of
      post-MPN AML.

      II. Phase II. To evaluate the rate of composite complete remission in patients with secondary
      AML transformed from MPNs (PV, ET and MF) following treatment with the combination of
      Ruxolitinib and CPX-351 (8 weeks at end of induction or re-induction). The composite complete
      remission (CRc) includes complete remission (morphologic CR) and complete remission with
      incomplete count recovery (CRi).

      SECONDARY OBJECTIVES:

      I. Phase I: To evaluate the safety and tolerability of ruxolitinib in combination with
      CPX-351 for treatment of post-MPN AML II. Phase II: Assess survival outcomes and proportion
      of patients receiving transplant associated with ruxolitinib in combination with CPX-351.

      III. Phase II: Assess safety and incidence of adverse events as assessed by CTCAE v5.0.

      EXPLORATORY OBJECTIVES:

      I. Phase II: Assess the proportion of treated (completion of induction or re-induction)
      participants with sub-clinical levels of AML (i.e., minimal residual disease, MRD) as
      measured by flow cytometry and/or next generation sequencing of known mutations (e.g., JAK-2,
      CALR and other disease-specific mutations) at the end of 6 months. Cytogenetic and molecular
      remission will be measured.

      OUTLINE:

      Phase I. Eligible participants will first receive induction therapy consisting of intravenous
      CPX-351 (65 u/m2) administered on day 1, 3, and 5, which will be followed by a 23 day course
      of ruxolitinib (days 6 to 28) that will be given at a starting dose of 20 mg BID and will
      increase according to the mTPI dose escalation/de-escalation rule (up to the maximum dose of
      25 mg BID). A bone marrow aspirate/biopsy will be performed between D14-D22 to assess disease
      status and possible need for re-induction. A recovery bone marrow aspirate/biopsy to assess
      response to induction will be performed between D35-D42 or when ANC>500 and platelet count >
      50,000 per microliter; depend on which events occurs first. An enrollment of up to 24
      participants is planned for the phase I portion of this study.

      Phase II. Once the MTD is established and phase I objectives completed, the study will open
      for enrollment in the phase II portion of the trial. The phase II portion of the trial will
      assess the efficacy of the ruxolitinib and CPX-351 combination by evaluating the rate of
      composite complete remission in participants using a Simon's two-stage minimax design.
      Enrollment in phase II is planned for a total of 26 participants. The combination treatment
      regimen will be the same as described for phase I except that ruxolitinib dose will also be
      fixed per the recommended phase 2 dose (RP2D)(i.e., established MTD).

      Participants are eligible to proceed to allogeneic hematopoietic stem cell transplantation
      (allo-HSCT) at any time after achieving complete remission (CR/CRi) if they have a suitable
      donor. In this case, participants will come off treatment and be followed for disease status
      and survival outcomes, including peri-transplant data
    

Trial Arms

NameTypeDescriptionInterventions
Ruxolitinib in combination with CPX-351ExperimentalPhase I, participants start with induction therapy consisting of intravenous CPX-351 (65 u/m2) administered on day 1, 3, and 5, which will be followed by a 23 day course of ruxolitinib (days 6 to 28) that will be given at a starting dose of 20 mg BID and will increase according dose escalation/de-escalation rule. A bone marrow aspirate/biopsy will be performed between day 14-22 and potentially again on day 35-42 to assess disease status and possible need for re-induction. Those with CR/CRi after induction will receive 1-2 cycles of consolidation therapy. Participants who completed consolidation therapy with CR/CRi and have not undergone allo-HSCT will complete 12 months of maintenance therapy with ruxolitinib according to established dose derived during phase I. For Phase II, drug regimen, schedule and assessments will remain the same as phase I except that ruxolitinib will be administered at the MTD or recommended phase II dose (RP2D).
  • Ruxolitinib
  • CPX-351

Eligibility Criteria

        Inclusion Criteria:

          1. Ability to understand and the willingness to sign a written informed consent document.

          2. Age ≥18 years at time of informed consent. Both men and women and members of all races
             and ethnic groups will be included.

          3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

          4. Newly diagnosed secondary AML patients (including transformed AML).

               1. Diagnosis of essential thrombocythemia, polycythemia vera, or myelofibrosis
                  (based on prior bone marrow biopsy or presence of known MPN-associated mutations
                  [e.g., JAK2, CALR and MPL]) that has transformed to AML after receiving
                  one/multiple of the treatments listed below :Hydroxyurea, HMA therapy,

               2. JAK2 inhibitors including ruxolitinib , and/or

               3. Anti-platelet therapies, including hydroxyurea and anagrelide are allowable.

          5. Female patients of childbearing potential must agree to use adequate contraception (2
             forms of contraception or abstinence) from the screening visit until 30 days following
             the last dose of study treatment. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

          6. Male patients of childbearing potential having intercourse with females of
             childbearing potential must agree to abstain from heterosexual intercourse or have
             their partner use 2 forms of contraception from the screening visit until 90 days
             until the last dose of study treatment. They must also refrain from sperm donation
             from the screening visit until 90 days following the last dose of study treatment.

          7. Left ventricular ejection fraction at >/= 50% above the lower limit of institutional
             normal by echocardiogram (ECHO) or multigated acquisition (MUGA) scan (14 days prior).

          8. Candidate for cytotoxic-intensive induction chemotherapy.

          9. Must be able to take oral medication.

         10. Adequate organ function as defined by the following:

               1. Serum creatinine ≤2× the upper limit of normal (ULN), or glomerular filtration
                  rate >20ml/h as calculated by Cockgroft-Gault formula.

               2. Serum potassium, magnesium, and calcium (corrected for albumin) within
                  institutional normal limits or can be corrected with supplementation.

               3. Total serum bilirubin ≤2.5× ULN.

               4. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN.

        Exclusion Criteria:

          1. Ongoing participation in another clinical trial.

          2. Isolated myeloid sarcoma (i.e., participants must have blood or marrow involvement
             with AML to enter the study).

          3. Acute promyelocytic leukemia (FAB M3 Classification)

          4. Active central nervous system (CNS) involvement by AML.

          5. Any unresolved toxicity equal to or greater than Grade 2 from previous anticancer
             therapy, except for stable chronic toxicities not expected to resolve, such as
             peripheral neurotoxicity.

          6. Incomplete recovery from any prior surgical procedures or had surgery within 4 weeks
             prior to study entry, excluding the placement of vascular access.Disseminated
             intravascular coagulopathy with active bleeding or signs of thrombosis.

          7. Participants with rapidly progressive disease or organ dysfunction that would prevent
             them from receiving these agents.

          8. Participants with uncontrolled infection will not be enrolled until infection is
             treated and symptoms controlled.

             a. Participants with an infection receiving treatment (antibiotic, antifungal or
             antiviral treatment) may be entered into the study but must be afebrile and
             hemodynamically stable for ≥72 hrs.

          9. Known hypersensitivity to ruxolitinib, cytarabine, daunorubicin, or liposomal
             products.

         10. History of Wilson's disease or other copper metabolism disorder.

         11. Uncontrolled intercurrent illness or any concurrent condition that, in the
             Investigator's opinion, would jeopardize the safety of the patient or compliance with
             the protocol per investigator's discretion. Including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia,
             myocardial infarction within 6 months prior to enrollment, New York Heart Association
             (NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias.

         12. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2
             daunorubicin (or equivalent).

         13. All patients must discontinue anti-platelet agents or anticoagulants prior to
             initiation of study drug, including aspirin and clopidogrel.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity (DLT) of ruxolitinib given in combination with CPX-351.
Time Frame:Day 1 to end of first induction (Day 28)
Safety Issue:
Description:DLT of ruxolitinib given in combination with CPX-351. DLT is defined as treatment related ≥ Grade 3 non-hematological or ≥ Grade 4 hematological toxicity.

Secondary Outcome Measures

Measure:Incidence of adverse events as assessed by CTCAE version 4.03
Time Frame:Up to 30 days after last on-study dose
Safety Issue:
Description:The incidence of treatment-related toxicity and the exact confidence interval will be measured. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE v4.03.
Measure:Progression Free Survival (PFS)
Time Frame:1 year post treatment
Safety Issue:
Description:Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate event-free and overall survival. A point estimate and confidence interval will be computed for the proportion of participants who undergo an allo-SCT.
Measure:Overall Survival (OS)
Time Frame:1 year post treatment
Safety Issue:
Description:Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate overall survival.
Measure:Proportion of patients proceeding to transplant
Time Frame:Date of enrollment to time of transplant or end of follow-up (if no transplant), up to 2 years
Safety Issue:
Description:A point estimate and 95% confidence interval will be computed for the proportion of participants who undergo an allo-SCT (stem cell transplant).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Last Updated