Clinical Trials /

Ruxolitinib and Venetoclax in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT03874052

Description:

This phase I trial studies the side effects and best dose of ruxolitinib when given together with venetoclax in treating patients with acute myeloid leukemia that has come back or has not responded to treatment. Ruxolitinib and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study is being done to see if the combination of ruxolitinib and venetoclax works better in treating patients with acute myeloid leukemia compared to standard of care chemotherapy.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ruxolitinib and Venetoclax in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: Phase I Study to Evaluate Safety of Ruxolitinib in Combination With Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: STUDY00018238
  • SECONDARY ID: NCI-2019-03272
  • NCT ID: NCT03874052

Conditions

  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
RuxolitinibINCB018424, Jakafi, INCB18424, (3R)-3-cyclopentyl-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)pyrazol-1-yl)propanenitrile, INCB-18424, Oral JAK Inhibitor INCB18424, 941678-49-5Treatment (ruxolitinib, venetoclax)
VenetoclaxABT-199, GDC-0199, Venclexta, ABT-0199, 4-(4-((2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide, 1257044-40-8, ABT199, RG7601, VenclyxtoTreatment (ruxolitinib, venetoclax)

Purpose

This phase I trial studies the side effects and best dose of ruxolitinib when given together with venetoclax in treating patients with acute myeloid leukemia that has come back or has not responded to treatment. Ruxolitinib and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study is being done to see if the combination of ruxolitinib and venetoclax works better in treating patients with acute myeloid leukemia compared to standard of care chemotherapy.

Detailed Description

      PRIMARY OBJECTIVES:

      To evaluate the maximum tolerated dose (MTD) of ruxolitinib in combination with venetoclax.

      SECONDARY OBJECTIVES:

      I. To assess the preliminary efficacy of the ruxolitinib and venetoclax combination.

      II. To estimate overall and event-free survival.

      EXPLORATORY OBJECTIVES:

      I. To assess in vitro kinase inhibitor sensitivity using patients' bone marrow in response to
      ruxolitinib and venetoclax combination.

      II. Use molecular techniques (potentially including next-generation sequencing and/or BH3
      profiling) to examine the mechanisms of response vs. no response

      III. To correlate molecular features with the patient response and resistance to venetoclax
      combination therapies.

      OUTLINE:

      Patients receive ruxolitinib orally (PO) twice daily (BID) and venetoclax PO once daily (QD)
      on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease
      progression or unacceptable toxicity. Patients may receive additional cycles of ruxolitinib
      and venetoclax at physician's discretion.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ruxolitinib, venetoclax)ExperimentalPatients receive ruxolitinib PO BID and venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of ruxolitinib and venetoclax at physician's discretion.
  • Ruxolitinib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

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

          -  Morphologically documented relapsed/refractory AML as defined by World Health
             organization (WHO) criteria after at least 2 prior therapies for AML with the
             exception of hydroxyurea.

          -  ECOG performance status 0 to 2

          -  Women must not be pregnant or breastfeeding. Women of childbearing potential must have
             a negative serum or urine pregnancy test within 14 days prior to start of study drug
             administration.

          -  Participants must agree to use an adequate method of contraception.

          -  Must be able to take oral medications.

          -  Creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or
             measured by 24 hours urine collection.

          -  Total serum bilirubin ≤2× ULN unless thought to be due to leukemic involvement.

          -  Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN unless
             thought to be due to leukemic involvement.

        Exclusion Criteria:

          -  Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype)

          -  Active central nervous system involvement with AML

          -  Concurrent active malignancy with expected survival of less than 1 year. For example,
             candidates with treated skin cancers, prostate cancer, breast cancer, etc. without
             metastatic disease are candidates for therapy since their expected survival exceeds
             that of relapsed or refractory AML. All subjects with concurrent malignancies will be
             reviewed by the PI prior to enrollment.

          -  Clinically significant graft versus host disease (GVHD) or active GVHD requiring
             initiation or escalation of treatment within 28 day screening period

          -  Participants with rapidly progressive disease (defined by blast count doubles within
             48 hours) or organ dysfunction.

          -  Clinically significant coagulation abnormality, such as disseminated intravascular
             coagulation.

          -  Participants who are currently receiving any other investigational agents.

          -  Known clinically significant liver disease defined as ongoing drug-induced liver
             injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic
             liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic
             obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or
             history of autoimmune hepatitis.

          -  Untreated HIV or active hepatitis C detectable by PCR, or chronic hepatitis B
             (patients positive for hepatitis B core antibody who are receiving IVIG are eligible
             if HepB PCR is negative).

          -  Known history of cerebrovascular accident, myocardial infarction, or intracranial
             hemorrhage within 2 months of enrollment.

          -  Clinically significant surgery within 2 weeks of enrollment.

          -  Per PI discretion, active infection that is not well controlled by antibacterial or
             antiviral therapy.

             a. Participants with known history of tuberculosis (TB; Mycobacterium tuberculosis)
             are not eligible for participation. At investigator discretion, latent TB test should
             be performed for individuals considered to be at high-risk (e.g., immune compromised,
             persons that have traveled to, or emigrated from, regions with high rates of TB)

          -  Cancer-directed therapy within 1 week prior to starting treatment, with the exception
             of hydroxyurea, which is allowed to control white blood cell count.

          -  Unwillingness to receive infusion of blood products.

          -  Participant on any of the following therapies need to be on an alternative therapy
             within 7 days prior to the first dose of study drug:

               1. Steroid therapy for anti-neoplastic intent;

               2. Strong and moderate CYP3A inhibitors

               3. Strong and Moderate CYP3A inducers

          -  Patients with uncontrolled white blood cell count (defined as >50 K/mm3 not controlled
             with hydroxyurea).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLT) of ruxolitinib and venetoclax in combination.
Time Frame:Up to Day 28
Safety Issue:
Description:The maximum tolerated dose (MTD) of ruxolitinib and venetoclax combination will be determined according to the hierarchical Bayesian model of the BOIN design.42 The MTD of ruxolitinib and venetoclax in combination is the dose corresponding to a DLT probability of 30%. The study will start with dose level 0 with escalation/de-escalation of the dose level) occurring in a cohort of 3 participants according to the BOIN rule until a total of 30 participants or the maximum of 15 patients at a dose level are evaluated.

Secondary Outcome Measures

Measure:Composite complete remission rate
Time Frame:From first dose to Cycle 2 (up to 36 days)
Safety Issue:
Description:
Measure:Clinical benefit rate (CBR)
Time Frame:From first dose to Cycle 2 (up to 36 days)
Safety Issue:
Description:The clinical benefit rate (CBR) is defined as the proportion of evaluable subjects obtaining stable disease (SD), PR, or CCR during the first 2 cycles of therapy.
Measure:Overall Survival at 12 months
Time Frame:From date of first dose to date of death or last contact, whichever came first, assessed up to 12 months
Safety Issue:
Description:Kaplan-Meier method will be used to estimate overall survival.
Measure:Overall incidence of treatment-related and non-treatment related toxicity
Time Frame:From first PR/CR to 30 days after last dose
Safety Issue:
Description:Overall incidence of treatment and non-treatment related toxicity will be estimated, and 95% confidence intervals will be provided.
Measure:Duration of response.
Time Frame:From first PR/CR to 30 days after last dose
Safety Issue:
Description:For patients that achieve >= PR, how long do they maintain this response before progression.
Measure:Event-free survival
Time Frame:From first dose to 24 months post treatment
Safety Issue:
Description:Kaplan-Meier method will be used to estimate event-free survival.

Details

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

Last Updated

October 28, 2019