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Ruxolitinib in Combination With Venetoclax for the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03874052
Recruitment Status : Not yet recruiting
First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Collaborators:
Incyte Corporation
AbbVie
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Uma Borate, OHSU Knight Cancer Institute

Brief Summary:
This Phase I trial assesses the safety and tolerability of ruxolitinib and venetoclax in combination for the treatment of patients with relapse or refractory Acute Myeloid Leukemia (AML). This study is designed to evaluate the maximum tolerated dose (MTD) of the ruxolitinib and venetoclax combination treatment. Developing successful therapeutic approaches for patients with relapsed and refractory AML remains challenging; however, targeted inhibition of several critical signaling pathways may provide a novel avenue of treatment. The emergence of subclones with discrete genotypes leading to relapse may necessitate the use of drug combinations that target distinct pathways. Preliminary ex vivo assays have shown myeloid leukemias were extremely sensitive to combinations of ruxolitinib with BCL-2 inhibitors (e.g., venetoclax).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia, in Relapse Drug: Ruxolitinib Drug: Venetoclax Phase 1

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.

TERTIARY 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:

The study will start at dose level 0 and the dose is escalated/de-escalated according to the Bayesian Optimal Interval Design (BOIN) rule in a cohort of 3 participants until the total of 30 participants are evaluated or the maximum of 15 patients at one dose level. The rule is based on a target dose limiting toxicity (DLT) of 0.30. Participants, on Day 1, will receive a starting dose (i.e., dose level 0) of ruxolitinib (20 mg PO, b.i.d) and venetoclax (200 mg, PO, qd). Per BOIN, a cohort of 3 participants will be treated at the same dose level, or higher or lower dose level, depending on the cumulative number of participants experiencing DLT and number of individuals treated at that dose level.

Participants will be followed in subsequent cycles for safety and will be assessed for status of their disease in every second cycle or as otherwise specified. Treatment cycles will be repeated until intolerability or disease progression.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study to Evaluate Safety of Ruxolitinib in Combination With Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Estimated Study Start Date : March 15, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Experimental: Combination Ruxolitinib and Venetoclax
Participants, on Day 1, will receive a starting dose (i.e., dose level 0) of ruxolitinib (20 mg PO, b.i.d) and venetoclax (200 mg, PO, qd). A cohort of 3 participants will be treated at the same dose level, or higher or lower dose level, depending on the cumulative number of participants experiencing DLT and number of individuals treated at that dose level. Treatment cycles will be repeated until intolerability or disease progression.
Drug: Ruxolitinib
Administered orally (PO), twice daily at assigned dose levels ranging from 5 mg - 50mg.
Other Names:
  • INCB018424
  • Jakafi
  • INCB18424

Drug: Venetoclax
Administered orally (PO), twice daily at assigned dose levels ranging from 100 mg - 600mg.
Other Names:
  • ABT-199
  • GDC-0199
  • Venclexta
  • ABT-0199




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Composite complete remission rate [ Time Frame: From first dose to Cycle 2 (up to 36 days) ]
  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. Event-free survival [ Time Frame: From first dose to 24 months post treatment ]
    Kaplan-Meier method will be used to estimate event-free survival.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Morphologically documented relapsed/refractory AML as defined by World Health organization (WHO) criteria after at least 1 prior therapy for AML with the exception of hydroxyurea.
  4. ECOG performance status 0 to 2
  5. 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.
  6. Participants must agree to use an adequate method of contraception.
  7. Must be able to take oral medications.
  8. Adequate organ function as defined by the following:

    1. Creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection.
    2. Total serum bilirubin ≤2× ULN unless thought to be due to leukemic involvement.
    3. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN unless thought to be due to leukemic involvement.

Exclusion Criteria:

  1. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype)
  2. Active central nervous system involvement with AML
  3. 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.
  4. Clinically significant graft versus host disease (GVHD) or active GVHD requiring initiation or escalation of treatment within 28 day screening period
  5. Participants with rapidly progressive disease (defined by blast count doubles within 48 hours) or organ dysfunction.
  6. Clinically significant coagulation abnormality, such as disseminated intravascular coagulation.
  7. Participants who are currently receiving any other investigational agents.
  8. 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.
  9. 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).
  10. Known history of cerebrovascular accident, myocardial infarction, or intracranial hemorrhage within 2 months of enrollment.
  11. Clinically significant surgery within 2 weeks of enrollment.
  12. Per PI discretion, active infection that is not well controlled by antibacterial or antiviral therapy.
  13. Cancer-directed therapy within 1 week prior to starting treatment, with the exception of hydroxyurea, which is allowed to control white blood cell count.
  14. Unwillingness to receive infusion of blood products.
  15. 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
  16. Patients with uncontrolled white blood cell count (defined as >50 K/mm3 not controlled with hydroxyurea).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03874052


Contacts
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Contact: Tara Macey 503-494-3835 maceyt@ohsu.edu

Locations
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United States, Oregon
OHSU Knight Cancer Institute Not yet recruiting
Portland, Oregon, United States, 97239
Contact: Tara Macey       maceyt@ohsu.edu   
Principal Investigator: Uma Borate, MD         
Sponsors and Collaborators
OHSU Knight Cancer Institute
Incyte Corporation
AbbVie
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Uma Borate, MD OHSU Knight Cancer Institute

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Responsible Party: Uma Borate, Principal Investigator, OHSU Knight Cancer Institute
ClinicalTrials.gov Identifier: NCT03874052     History of Changes
Other Study ID Numbers: STUDY00018238
First Posted: March 14, 2019    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Venetoclax
Antineoplastic Agents