Clinical trial NCT03874052: Ruxolitinib in Combination With Venetoclax With and Without Azacitidine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official title: Phase I Study to Evaluate Safety of Ruxolitinib in Combination With Azacitidine + Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Recurrent Acute Myeloid Leukemia
Recurrent Secondary Acute Myeloid Leukemia
Refractory Acute Myeloid Leukemia
Refractory Secondary Acute Myeloid Leukemia
Lead sponsor: OHSU Knight Cancer Institute
Sponsor class: OTHER
Collaborators: name: AbbVie
name: Incyte Corporation
name: Oregon Health and Science University
First posted: 2019-03-14
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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 azacitdine. 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.

Eligibility criteria: 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
* Currently receiving chemotherapy or investigational agents within or 5 half lives, or less of the planned start of treatment, with the exception of hydroxyurea for cytoreduction of proliferative disease
* 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

  * 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)
* Clinically significant surgery within 2 weeks of enrollment
* 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

Primary outcomes:
measure: Dose-limiting toxicities (DLT) for each arm-specific combination
timeFrame: 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 outcomes:
measure: Composite complete remission rate
timeFrame: From first dose to end of cycle 2 (cycle length = 28 days)
measure: Clinical response rate
timeFrame: From first dose to end of cycle 2 (cycle length = 28 days)
measure: Clinical benefit rate (CBR)
timeFrame: From first dose to end of cycle 2 (up to 36 days)
measure: Duration of clinical response
timeFrame: 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
measure: Duration of clinical benefit
timeFrame: From first SD or better to evidence of progressive disease, or date of last disease assessment, assessed up to 2 years
measure: Event-free survival (EFS)
timeFrame: From first occurrence of treatment failure, disease progression, or death due to any cause, or date of last exam, assessed up to 2 years
measure: Overall survival (OS)
timeFrame: From date of first dose to death due to any cause or date of last known alive, assessed up to 2 years
measure: Overall incidence of treatment-related and non-treatment related toxicity
timeFrame: From first dose to 30 days after last dose of study agent
measure: Changes in patient reported quality of life (QOL) outcomes (Arm 2)
timeFrame: From first dose of study treatment to date of last completed survey, assessed up to 2 years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
Study officials:
affiliation: OHSU Knight Cancer Institute
name: Jennifer N. Saultz, MD
role: PRINCIPAL_INVESTIGATOR
References: