Ruxolitinib in Combination With Venetoclax With and Without Azacitidine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Phase I Study to Evaluate Safety of Ruxolitinib in Combination With Azacitidine + Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia

This phase I trial studies the side effects and best dose of ruxolitinib when given together with venetoclax and compares the effect of ruxolitinib in combination with venetoclax to venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back (relapsed) or has not responded to treatment (refractory). Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Azacitidine stops cells from making deoxyribonucleic acid and may kill cancer cells. It is a type of antimetabolite. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving ruxolitinib in combination with venetoclax and azacitidine may be safe, tolerable, and/or effective compare to ruxolitinib with venetoclax in treating patients with relapsed or refractory AML.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Recurrent Secondary Acute Myeloid Leukemia; Refractory Secondary Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Azacitidine; Other: Questionnaire Administration; Procedure: Biospecimen Collection; Drug: Venetoclax; Procedure: Punch Biopsy; Drug: Ruxolitinib; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Echocardiography Test

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate an maximum-tolerated dose (MTD) for ruxolitinib in combination with Ia. Venetoclax (Arm 1); Ib. Venetoclax and azacitidine (Arm 2).

SECONDARY OBJECTIVES:

I. To assess the efficacy of the study treatment. II. To assess the duration of clinical response. III. To assess the duration of clinical benefit. IV. To assess survival in the absence of treatment failure, hematologic relapse, or progressive disease.

V. To assess overall survival. VI. To assess overall acute toxicity and tolerability. VII. To assess the effect of ruxolitinib in combination with azacitidine + venetoclax on quality of life (QOL).

EXPLORATORY OBJECTIVES:

I. To assess in vitro kinase inhibitor sensitivity using participants' bone marrow (or peripheral blood).

II. To characterize changes in disease using molecular techniques (potentially including next-generation sequencing and/or BH3 profiling).

III. To assess the impact of changes in molecular disease features. IV. To determine the in vivo pharmacokinetics (PK)/pharmacodynamics (PD) parameters of the study drugs (Arm 1 only).

OUTLINE: This is a dose-escalation study of ruxolitinib in combination with fixed dose venetoclax with and without azacitidine. Patients are assigned to 1 of 2 arms.

ARM 1 (COMPLETE 04/04/2025): Patients receive ruxolitinib orally (PO) twice daily (BID) and venetoclax PO once daily (QD) on days 1-28 of each cycle. Cycles repeat 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 the discretion of the sponsor-investigator. Patients also undergo a skin punch biopsy and echocardiography (ECHO) at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study.

ARM 2: Patients receive ruxolitinib PO BID, venetoclax PO QD, and azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study.

After completion of study treatment, patients are followed up every 6 months for up to 2 years.

• Study Type: Interventional
• Enrollment (Estimated): 51
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Suspended
      • Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • OHSU Knight Cancer Institute
      • Contact: Jennifer N. Saultz, MD; Phone Number: 503-494-5566; Email: saultzje@ohsu.edu
      • Principal Investigator: Jennifer N. Saultz, MD
  • Texas
    • Dallas, Texas, United States, 75390
      • Suspended
      • UT Southwestern/Simmons Cancer Center-Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent document
• Age >= 18 years at time of informed consent. Persons of all genders and gender identities, and members of all races and ethnic groups will be included

• Morphologically documented relapsed/refractory (R/R) AML or R/R secondary AML (sAML) that has progressed after at least 1 prior therapy for AML

  • Prior treatment with venetoclax and azacitidine is allowed
  • Treatment with hydroxyurea will not be considered a line of therapy

  • Patients with morphologically documented myelodysplastic syndrome (MDS) that has progressed on hypomethylating agent (HMA) therapy also will be considered if the patient is ineligible for induction with intensive chemotherapy (IC), defined for this study as meeting one or more of the following criteria:

    • Severe cardiac disorder (e.g., congestive heart failure requiring treatment, left ventricular ejection fraction (LVEF) of ≤ 50%, or chronic stable angina)
    • Severe pulmonary disorder, certified by the managing physician
    • Creatinine clearance of < 45 ml/min or
    • Hepatic disorder with total bilirubin > 1.5 x upper limit of normal (ULN)
    • Eastern Cooperative Oncology Group (ECOG) equal to 2
    • Other comorbidity(ies) judged to be incompatible with high dose chemotherapy by the managing physician will be considered, at the discretion of the principal investigator (PI)
• ECOG performance status 0 to 2
• Persons of childbearing potential (PCBP) must have a negative serum or urine pregnancy test within 14 days prior to start of study drug administration
• Patients must agree to use an adequate method of contraception while on study treatment and for 120 days after the last dose of ruxolitinib for Arm 1 and 6 months after the last dose of azacitidine for Arm 2
• Must be able to take and absorb oral medications
• Creatinine clearance ≥ 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hour urine collection
• Total serum bilirubin ≤ 1.5 x ULN unless thought to be due to leukemic involvement
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3.0 x 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
• Chemotherapy or therapy with a non-investigational agent other than a biologic intended to within 1 week of the planned start of study therapy, with the exception of hydroxyurea for cytoreduction of proliferative disease, or at the discretion of the principal investigator (PI)
• Therapy with a non-biologic investigational agent within 14 days or 5 half lives, whichever is longer, of the planned start of study therapy, or for the period recommended by the institution's research pharmacy service, or at the discretion of the PI
• Therapy with a biologic investigational or non-investigational agent (e.g., monoclonal antibody) within 30 days of the planned start of study therapy, or for the period recommended by the institution's research pharmacy service, or at the discretion of the PI
• Concurrent active malignancy with expected survival of less than 1 year, at the discretion of the investigator. 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
• 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
• Documented cardiac insufficiency (e.g., symptomatic heart failure, left ventricular ejection fraction of ≤ 40%)
• Symptomatic shortness of breath or patient requires supplemental oxygen support
• Clinically significant coagulation abnormality, such as disseminated intravascular coagulation
• Known history of cerebrovascular accident, myocardial infarction, or intracranial hemorrhage within 2 months of enrollment
• Known clinically significant liver disease defined as ongoing drug-induced liver injury, chronic active hepatitis C (hepatitis C virus [HCV]), chronic active hepatitis B (hepatitis B virus [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 polymerase chain reaction (PCR), or chronic hepatitis B (patients positive for hepatitis B core antibody who are receiving intravenous immunoglobulin therapy [IVIG] are eligible if hepatitis B [HepB] PCR is negative)

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

  *Patients with a 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)

• Clinically significant surgery within 2 weeks of enrollment
• Unwillingness to receive infusion of blood products

• Requires use of medications interact with study drug and that cannot be terminated or adjusted. Use of the following therapies requires review by the sponsor investigator:

  • Strong and moderate CYP3A inhibitors
  • Strong and Moderate CYP3A inducers
• Patients with uncontrolled white blood cell count (defined as > 50 K/mm^3 and not controlled with hydroxyurea)
• Patients with known sensitivity to ruxolitinib, venetoclax, or azacitidine
• Since it is unknown whether ruxolitinib, venetoclax, or azacitidine (or their metabolites) are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant, breastfeeding concurrent with study participation is prohibited

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (ruxolitinib, venetoclax); Patients receive ruxolitinib PO BID and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat 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 the discretion of the sponsor-investigator. Patients also undergo a skin punch biopsy and ECHO at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study. (COMPLETE 04/04/2025)	Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; ABT 199; GDC 0199; GDC0199; Procedure: Punch Biopsy; Undergo skin punch biopsy; Other Names: BIOPSY, PUNCH; Punch Biopsy of Skin; Drug: Ruxolitinib; Given PO; Other Names: INCB-18424; INCB18424; Oral JAK Inhibitor INCB18424; INCB-018424; INCB 018424; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration and biopsy; Procedure: Bone Marrow Biopsy; Undergo bone marrow aspiration and biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC
Experimental: Arm 2 (ruxolitinib,venetoclax, azacitidine); Patients receive ruxolitinib PO BID, venetoclax PO QD, and azacitidine IV or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study.	Drug: Azacitidine; Given IV or SC; Other Names: 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; 5-Azacitidine; Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; ABT 199; GDC 0199; GDC0199; Procedure: Punch Biopsy; Undergo skin punch biopsy; Other Names: BIOPSY, PUNCH; Punch Biopsy of Skin; Drug: Ruxolitinib; Given PO; Other Names: INCB-18424; INCB18424; Oral JAK Inhibitor INCB18424; INCB-018424; INCB 018424; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration and biopsy; Procedure: Bone Marrow Biopsy; Undergo bone marrow aspiration and biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicities (DLT) for each arm-specific combination	Within each arm, patient-level toxicity events will be summarized by dose level, major organ category, and grade.	Up to day 56 (of cycle 1 [cycle length = 28 days]) for non-hematologic DLT and up to day 42 (of cycle 1 [cycle length = 28 days]) for hematologic DLTs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite complete remission rate	Will be estimated, along with 95% confidence intervals (CIs).	From first dose to end of cycle 2 (cycle length = 28 days)
Clinical response rate	Will be estimated, along with 95% CIs.	From first dose to end of cycle 2 (cycle length = 28 days)
Clinical benefit rate (CBR)	CBR will be defined as the proportion of evaluable subjects obtaining stable disease (SD), partial remission, or composite complete remission during the first 2 cycles of therapy. Will be estimated, along with 95% CIs.	From first dose to end of cycle 2 (up to 36 days)
Duration of clinical response		From first morphologic leukemia-free state or better to bone marrow blasts >= 5%, circulating blasts, or EMD, or date of last disease assessment, assessed up to 2 years
Duration of clinical benefit		From first SD or better to evidence of progressive disease, or date of last disease assessment, assessed up to 2 years
Event-free survival (EFS)	Will be estimated using the Kaplan-Meier method, with median and survival rate estimates at common landmark times reported with 95% log-log CIs. Univariable Cox models will be fit to EFS to assess the impact of baseline patient and disease features; model results such as unadjusted hazard ratios and associated Wald test p-values will be considered hypothesis-generating.	From first occurrence of treatment failure, disease progression, or death due to any cause, or date of last exam, assessed up to 2 years
Overall survival (OS)	Will be estimated using the Kaplan-Meier method, with median and survival rate estimates at common landmark times reported with 95% log-log CIs. Univariable Cox models will be fit to OS to assess the impact of baseline patient and disease features; model results such as unadjusted hazard ratios and associated Wald test p-values will be considered hypothesis-generating. Median follow-up (and 95% log-log CI) will utilize a patient's OS time and censoring status and be estimated using the reverse Kaplan-Meier method.	From date of first dose to death due to any cause or date of last known alive, assessed up to 2 years
Overall incidence of treatment-related and non-treatment related toxicity	The overall incidence of treatment- related and non-treatment- related toxicity will be determined using the safety-evaluable population. The point estimate and 95% CI for the proportion of patients with each of these toxicity types will be reported. adverse event and abnormal concerning laboratory values will be tabulated by patient and by toxicity event (there can be > 1 event patient) will be tabulated overall and within dose level and summarized by major organ site and severity according to the Common Terminology Criteria for Adverse Events version 5.0.	From first dose to 30 days after last dose of study agent
Changes in patient reported quality of life (QOL) outcomes (Arm 2)	Will be assessed using European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 and Patient Reported Outcomes Measurement Information System-Fatigue-Short Form 7A. Will be reported with descriptive statistics (e.g., sample size, median, and range) for each survey time point during the treatment period and for (within-patient) changes from baseline. The QOL summary statistics from each survey will be compared to other studies conducted in relapsed/refractory acute myeloid leukemia patients.	From first dose of study treatment to date of last completed survey, assessed up to 2 years

Collaborators and Investigators

• Sponsor: Jennifer Saultz
• Collaborators: AbbVie; Oregon Health and Science University; Incyte Corporation
• Investigators: Principal Investigator: Jennifer N. Saultz, MD, OHSU Knight Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2019
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: January 10, 2019
• First Submitted That Met QC Criteria: March 11, 2019
• First Posted (Actual): March 14, 2019

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 20, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Nucleic Acids, Nucleotides, and Nucleosides; Cytodiagnosis; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Diagnostic Techniques, Surgical; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; Biopsy; Specimen Handling; venetoclax; ruxolitinib
• Other Study ID Numbers: STUDY00018238 (Other Identifier: OHSU Knight Cancer Institute); NCI-2019-03272 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No