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

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ClinicalTrials.gov Identifier: NCT03874052
Recruitment Status : Recruiting
First Posted : March 14, 2019
Last Update Posted : October 30, 2019
Sponsor:
Collaborators:
Incyte Corporation
AbbVie
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Uma Borate, OHSU Knight Cancer Institute

Tracking Information
First Submitted Date  ICMJE January 10, 2019
First Posted Date  ICMJE March 14, 2019
Last Update Posted Date October 30, 2019
Actual Study Start Date  ICMJE August 16, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2019)
Dose limiting toxicities (DLT) of ruxolitinib and venetoclax in combination. [ Time Frame: Up to Day 28 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 11, 2019)
DLT of Ruxolitinib and Venetoclax in combination. [ Time Frame: Up to Day 28 ]
The 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.
Change History Complete list of historical versions of study NCT03874052 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2019)
  • Composite complete remission rate [ Time Frame: From first dose to Cycle 2 (up to 36 days) ]
  • Clinical benefit rate (CBR) [ Time Frame: From first dose to Cycle 2 (up to 36 days) ]
    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.
  • 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 ]
    Kaplan-Meier method will be used to estimate overall survival.
  • Overall incidence of treatment-related and non-treatment related toxicity [ Time Frame: From first PR/CR to 30 days after last dose ]
    Overall incidence of treatment and non-treatment related toxicity will be estimated, and 95% confidence intervals will be provided.
  • Duration of response. [ Time Frame: From first PR/CR to 30 days after last dose ]
    For patients that achieve >= PR, how long do they maintain this response before progression.
  • Event-free survival [ Time Frame: From first dose to 24 months post treatment ]
    Kaplan-Meier method will be used to estimate event-free survival.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ruxolitinib and Venetoclax in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official Title  ICMJE Phase I Study to Evaluate Safety of Ruxolitinib in Combination With Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Ruxolitinib
    Given PO
    Other Names:
    • INCB018424
    • 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
    • 941678-49-5
  • Drug: Venetoclax
    Given PO
    Other Names:
    • ABT-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
    • Venclyxto
Study Arms  ICMJE Experimental: Treatment (ruxolitinib, venetoclax)
Patients 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.
Interventions:
  • Drug: Ruxolitinib
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 11, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Madison Hayes 503-494-3835 hayema@ohsu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03874052
Other Study ID Numbers  ICMJE STUDY00018238
NCI-2019-03272 ( Registry Identifier: NCI CTRP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Uma Borate, OHSU Knight Cancer Institute
Study Sponsor  ICMJE OHSU Knight Cancer Institute
Collaborators  ICMJE
  • Incyte Corporation
  • AbbVie
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Uma Borate, MD OHSU Knight Cancer Institute
PRS Account OHSU Knight Cancer Institute
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP