Ruxolitinib With Azacitidine Maintenance for the Treatment of Patients With Acute Myeloid Leukemia Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of Rux monotherapy (part A) and Rux plus AZA maintenance therapy (part B) following alloHSCT in AML patients.

SECONDARY OBJECTIVES:

I. To evaluate the feasibility of Rux plus AZA maintenance. II. To evaluate the effect on measurable residual disease (MRD) of Rux plus AZA maintenance.

III. To evaluate the impact of post-alloHSCT Rux on neutrophil engraftment. IV. To evaluate the impact of post-alloHSCT Rux on platelet engraftment. V. To evaluate the frequency and timing of disease relapse after alloHSCT when treated with Rux +/- AZA maintenance.

VI. To evaluate risk of post alloHSCT acute graft versus host disease (aGVHD) when treated with Rux +/- AZA maintenance.

VII. To evaluate risk of post alloHSCT chronic graft versus host disease (cGVHD) when treated with Rux +/- AZA maintenance.

VIII. To evaluate post alloHSCT survival in the absence of GVHD and disease relapse when treated with Rux +/- AZA maintenance.

IX. To evaluate the rate of post alloHSCT early infection when treated with Rux +/- AZA maintenance.

X. To evaluate overall survival after alloHSCT and treatment with Rux +/- AZA maintenance.

XI. To overall the effect on quality of life (QoL) of post alloHSCT Rux +/- AZA maintenance.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of pre transplant disease characteristics on treatment outcomes.

II. To evaluate the impact of MRD on treatment outcomes. III. To explore biomarkers associated with treatment outcomes.

OUTLINE: This is a dose-escalation study of azacitidine in combination with fixed-dose cyclophosphamide, tacrolimus, mycophenolate mofetil, and ruxolitinib.

PART A: Patients undergo standard of care (SOC) reduced intensity conditioning (RIC) or non-myeloablative (NMA) conditioning followed by alloHSCT on day 0 and receive cyclophosphamide intravenously (IV) over 1-2 hours on days +3 and +4, tacrolimus orally (PO) or IV daily on day + 5 and tapered per institutional protocol through day +180, and mycophenolate mofetil PO or IV three times daily (TID) on days +5 to +35 in the absence of disease progression or unacceptable toxicity. Staring on day +5, patients also receive ruxolitinib PO twice daily (BID) continuously and tapered through post-treatment day 28. Treatment with ruxolitinib continues through screening of part B in the absence of disease progression or unacceptable toxicity. Patients not eligible for Part B have ruxolitinib tapered starting no later than day +100.

PART B: Starting no earlier than day +35 and no later than day +100, patients receive ruxolitinib PO BID continuously and tapered through post-treatment day 28, as well as azacitidine IV on days 1-5 of each cycle. Cycles repeat every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients also undergo blood sample collection and bone marrow aspiration and biopsy throughout the study.

After completion of study treatment, patients are followed up every 3 months for the first year and every 6 months until 2 years.

• Allogeneic Hematopoietic Stem Cell Transplantation (Procedure), also known as Allogeneic, Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT, Stem Cell Transplantation, Allogeneic: Undergo alloHSCT
• Azacitidine (Drug), also known as 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza: Given IV
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo blood sample collection
• Bone Marrow Aspiration (Procedure): Undergo bone marrow aspiration
• Bone Marrow Biopsy (Procedure), also known as Biopsy of Bone Marrow, Biopsy, Bone Marrow: Undergo bone marrow biopsy
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518, B-518, B518, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Frindovyx, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR 138719, WR- 138719, WR-138719, WR138719: Given IV
• Echocardiography Test (Procedure), also known as EC, Echocardiography: Undergo ECHO
• Electronic Health Record Review (Other): Ancillary studies
• Multigated Acquisition Scan (Procedure), also known as Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning: Undergo MUGA
• Mycophenolate Mofetil (Drug), also known as CellCept, MMF, Myhibbin: Given PO or IV
• Reduced-Intensity Transplant Conditioning Procedure (Other), also known as Non-Myeloablative Conditioning, Reduced Intensity Conditioning, Reduced Intensity Conditioning/Reduced Toxicity Conditioning: Undergo SOC RIC or NMA conditioning
• Ruxolitinib (Drug), also known as INCB 018424, INCB-018424, INCB-18424, INCB18424, Oral JAK Inhibitor INCB18424: Given PO
• Survey Administration (Other): Ancillary studies
• Tacrolimus (Drug), also known as FK 506, FK-506, FK506, Fujimycin, Hecoria, Prograf, Protopic, Tacforius: Given PO or IV

Primary outcomes

• Incidence of dose limiting toxicities (DLTs) [From cycle 1 day 1 (i.e., day +5 post-transplant) to end of cycle 2 (Cycle length = 28 days)]: Will determine the safety and tolerability of ruxolitinib monotherapy (part A) and ruxolitinib plus azacitidine therapy (part B). DLTs will be used to identify a maximum tolerated dose. Dose levels will either be de-escalated, escalated, or retained-according to pre calculated Bayesian Optimal Interval decision rules.
• Incidence of grade 3+ treatment-related adverse events (TRAEs) (Part B) [Up to 30 days after the end of cycle 9]: TRAEs of grade 3 and higher experienced during treatment with the doublet of ruxolitinib + azacitidine will be reported (with frequencies and percentages) as a co-primary endpoint. TRAEs are defined as adverse events that are definitely or possibly attributable to study treatment. Will be assessed using Common Terminology Criteria for Adverse Events version 5.0, where adverse events are assessed on a scale of 1-5, with higher scores indicating worse outcomes.

Secondary outcomes

• Graft versus host disease (GVHD)-free, relapse-free survival [From date of transplant to disease relapse, grade III-IV acute (a) GVHD, chronic (c) GVHD requiring systemic immunosuppressive therapy, or death from any cause or last known alive (censored), whichever occurs earlier, assessed up to 2 years]: Will be estimated by the Kaplan-Meier method, with estimates provided for the median time-to-event (with 95% log-log confidence interval \[CI\]) and event rates (and 95% log-log CIs) at landmark times like 3-, 6-, 12-, and 24-months post-allogeneic hematopoietic stem cell transplant (HSCT).
• Overall survival [From date of transplant to last known alive (censored) or death date, assessed up to 2 years]: Will be estimated by the Kaplan-Meier method, with estimates provided for the median time-to-event (with 95% log-log CI) and event rates (and 95% log-log CIs) at landmark times like 3-, 6-, 12-, and 24-months post-allogeneic HSCT.
• Cumulative incidence of neutrophil engraftment [From date of transplant to 30 days post-HSCT]: Deaths in the absence of the event of interest will be considered as a competing risk. Cumulative incidence function (CIF) estimates will be provided with 95% CIs at landmark times (e.g., day +30, day +60, day +100) for each time-to-event endpoint with a competing risk.
• Cumulative incidence of platelet engraftment [From date of transplant to 100 days post-HSCT but prior to Part B]: Deaths in the absence of the event of interest will be considered as a competing risk. CIF estimates will be provided with 95% CIs at landmark times (e.g., day +30, day +60, day +100) for each time-to-event endpoint with a competing risk.
• Cumulative incidence of Blood and Marrow Transplant Clinical Trials Network grade 2-3 infections [From date of transplant to 100 days post-HSCT]: Deaths in the absence of the event of interest will be considered as a competing risk. CIF estimates will be provided with 95% CIs at landmark times (e.g., day +30, day +60, day +100) for each time-to-event endpoint with a competing risk.
• Cumulative incidence of grade ≥ II aGVHD [From date of transplant to end of study, assessed up to 2 years]: Will be assessed using Mount Sinai Acute Graft Versus Host Disease International Consortium criteria. Deaths in the absence of the event of interest will be considered as a competing risk. CIF estimates will be provided with 95% CIs at landmark times (e.g., day +30, day +60, day +100) for each time-to-event endpoint with a competing risk.
• Cumulative incidence of cGVHD requiring systemic immunosuppressive therapy [From day +100 post-HSCT to end of study, assessed up to 2 years]: Deaths in the absence of the event of interest will be considered as a competing risk. CIF estimates will be provided with 95% CIs at landmark times (e.g., day +30, day +60, day +100) for each time-to-event endpoint with a competing risk.
• Cumulative incidence of relapse [From date of transplant to end of study, assessed up to 2 years]: Deaths in the absence of the event of interest will be considered as a competing risk. CIF estimates will be provided with 95% CIs at landmark times (e.g., day +30, day +60, day +100) for each time-to-event endpoint with a competing risk.
• Percentage of part A participants enrolled on part B (Feasibility) [From part A screening (day -28 to day -5 pre-transplant) to part B screening (day +35 post-HSCT to day +100 post-HSCT) assessed up to 128 days]: Descriptive summaries of discrete data will present the sample size and the incidence as frequency count and percentage, with exact binomial 95% CI.
• Median time from transplant to part B enrollment (Feasibility) [From part A screening (day -28 to day -5 pre-transplant) to part B screening (day +35 post-HSCT to day +100 post-HSCT) assessed up to 128 days]: Descriptive summaries of continuous data will present mean and standard deviation, or median, interquartile range, and range, depending on the sample distribution of the continuous variable.
• Patient reported quality of life outcome measurements, using the FACT-BMT patient reported outcome questionnaires [From time of part A screening to 365 days post-HSCT]: Descriptive summaries of discrete data will present the sample size and the incidence as frequency count and percentage, with exact binomial 95% CI.
• Conversion rate of pre-transplant measurable residual disease (MRD) positive to negative [From pre-transplant MRD assessment date to 1 year on study treatment or end of therapy, whichever occurs later, assessed up to 2 years]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* PART A: Willingness to provide written informed consent before any study-specific procedures or interventions are performed. For participants unable to independently provide consent, a legally authorized representative (LAR) must provide consent
* PART A: Age ≥ 18 years, at the time of consent
* PART A: All types and categories of AML, as defined by World Health Organization (WHO) 2022, excluding acute promyelocytic leukemia (APL)
* PART A: In complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after induction of remission for transition to transplant by European LeukemiaNet 2022 Risk Stratification (ELN 2022)
* PART A: Planned alloHSCT with granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSCs) and pre transplant conditioning disease status assessment of CR or CRi, as defined by ELN 2022 criteria
* PART A: Patient is at high risk for relapse based on cytogenetics, MRD by next generation sequencing (NGS), and/or ELN 2022 definition of adverse risk disease per the opinion of the treating physician
* PART A: Patients must have an unrelated PBSC donor meeting study donor selection requirements
* PART A: Only RIC or NMA conditioning must be plan and patient is not a candidate for myeloablative conditioning (MAC). Post-transplant cyclophosphamide / tacrolimus / mycophenolate mofetil (PTCy/Tac/MMF) GVHD prophylaxis is planned with PTCy at 25 mg/kg/day on Day +3 and Day +4 post-HSCT

  * Permitted conditioning regimens (per institutional protocol)

    * Reduced-intensity conditioning:

      * Fludarabine/ melphalan

        * Dose reduction of melphalan to 100 mg/m\^2 rather than 140 mg/m\^2 are permitted at discretion of treating physician
    * Non-Myeloablative Conditioning:

      * Fludarabine/ busulfan/ total-body irradiation (TBI)
      * Fludarabine/ TBI
* PART A: Backup graft donor (meeting study donor selection requirements) identified and ready for cases of graft failure
* PART A: Eastern Cooperative Oncology Group (ECOG) performance status (ECOG PS) ≤ 2
* PART A: Direct bilirubin ≤ 3 × upper limit of normal (ULN) within 7 days prior to start of conditioning. Patients with leukemic involvement or Gilbert's Syndrome must have a direct bilirubin of ≤ 2 x ULN within 7 days of start of conditioning
* PART A: Creatinine clearance > 30 mL/min, calculated by the Cockcroft-Gault formula or measured by 24-hour urine collection
* PART A: Willingness to receive infusion of SOC blood products
* PART A: Evidence of chronic hepatitis B virus (HBV) infection (i.e., hepatitis B virus surface antigen \[HBsAg\]-positive with undetectable or low HBV deoxyribonucleic acid \[DNA\]) in the absence of HBV therapy, or serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and hepatitis B virus core antibody \[anti-HBc-positive\]) is permitted but patient must agree to appropriate institutional guideline prophylaxis
* PART A: History of hepatitis C virus (HCV) infection is permitted given prior curative treatment or undetectable HCV viral load by serology or polymerase chain reaction (PCR) testing

  * Patients who are HCV antibody (Ab) seropositive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution are eligible
* PART A: For persons of child-bearing potential (PCBP), a negative pregnancy test within ≤ 7 days of start of conditioning
* PART A: Ruxolitinib may have adverse effects on a fetus in utero. Furthermore, it is not known if either drug agent has transient adverse effects on the composition of sperm. PCBP and participants who produce viable sperm must be willing to comply with study requirements for contraception starting at start of conditioning through 120 days after discontinuation of study treatment. Should a participant or participant's sexual partner become pregnant or suspect a pregnancy while participating in this study, the individual should inform their treating physician immediately
* PART A: It is unknown whether ruxolitinib, or its metabolites, are excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, patients must agree to not breast-feed for the entire 3 years of the study to be eligible for enrollment
* PART B: Absolute neutrophil count (ANC) ≥ 1,000/μL, measured twice approximately 48 hours apart, within 7 days prior to C2D1, in the absence of granulocyte colony-stimulating factor (G-CSF) treatment during this 7-day period
* PART B: Platelet count ≥ 50,000/μL, measured twice approximately 48 hours apart, within 7 days prior to C2D1, in the absence of platelet transfusions or growth factor therapies that increase platelet counts during this 7 day period
* PART B: Hemoglobin > 8 g/L within the 7 days prior to C2D1, regardless of transfusion support
* PART B: Day +30 (+/- 5 days) chimerism of ≥ 70% donor CD3+ cells and 100% donor CD33+ cells
* DONOR: Donor is willing and able to donate
* DONOR: Unrelated donor with a 7/8 or 8/8 match at human leukocyte antigen (HLA)-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Unrelated donor must be willing to donate peripheral blood stem cells
* DONOR: Age 18-35 at the time of workup request for PBSC donation
* DONOR: Meet the donor registries' medical suitability requirements for PBSC donation
* DONOR: Must undergo screening, testing, and determination of eligibility according to current Food and Drug Administration (FDA) requirements as defined in 21 Code of Federal Regulations (CFR) 1271 Subpart C and applicable guidance documents. Donors will be tested using kits that are FDA licensed, approved, or cleared for human cell and tissue/tissue-product donor screening. Sample testing will be performed at Clinical Laboratory Improvement Amendments (CLIA) certified laboratories
* DONOR: Must agree to donate PBSC
* DONOR: Must have the ability to give informed consent according to standard (non study) informed consent according to applicable donor regulatory requirements

Exclusion Criteria:

* PART A: Patients with active central nervous system (CNS) involvement with AML. Prior diagnosis of CNS involvement of AML will be allowed if curatively treated
* PART A: Patients with malabsorption syndrome or other condition that precludes oral route of drug administration
* PART A: Patients with prior intolerance to any of the interventional study drugs or component of the formulations
* PART A: Patients with prior failure of treatment with ruxolitinib
* PART A: Patients with history of any other malignancy within the 5 years prior to screening, with the exception of the following:

  * Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
  * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  * Previous non-hematologic malignancy that has been successfully treated with curative intent (i.e., confined and surgically resected or treated with other modalities);
  * Myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (only allowed if it transformed to AML and AML should be the indication for marrow transplantation)
* PART A: Patients with ejection fraction (EF) < 40% and patients with New York Heart Association (NYHA) grade III or IV heart failure
* PART A: Patients with history of pulmonary embolism (PE) or myocardial infarction (MI) within the 6 months prior to cycle 1 day 1 (C1D1). Treated deep vein thromboses (DVTs) are allowed
* PART A: Patients with known history of stroke (including intracranial hemorrhage) within 60 days prior to start of conditioning
* PART A: Patients administered therapy with an investigational agent, a known JAK1/2 inhibitor (with the exception of ruxolitinib), or a SOC anti-cancer therapy, including chemotherapy and radiotherapy, within 5 half lives prior to C1D1, or per institutional practice
* PART A: Patients administered therapy with a biologic agent (e.g., a monoclonal antibody) for anti-neoplastic intent within 30 days prior to C1D1, or per the institutional practice
* PART A: Patients administered moderate or strong CYP3A4 inhibitors or inducers without full washout (5 half-lives) prior to start of study intervention, or at the discretion of pharmacy services and the principal investigator (PI)
* PART A: Patients with known clinically significant liver disease defined as ongoing drug-induced liver injury, 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
* PART A: Patients with known human immunodeficiency virus (HIV) infection. HIV infection, even when controlled with combination antiretroviral therapy, is not allowed due to increased risk of lethal infections associated with marrow-suppressive therapy. Studies in participants under combination antiretroviral therapy may be undertaken at a later date
* PART A: Patients with history of active tuberculosis (TB)
* PART A: Patients with known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

  * Subjects with confirmed SARS-CoV-2 infection must be screen failed and may only rescreen after they meet institutional SARS-CoV-2 infection viral clearance criteria
* PART A: Patients with evidence of clinically significant systemic infection
* PART A: Patients with clinically significant coagulation abnormality defined by international normalized ratio (INR) > 1.5
* PART A: Patients with recent significant medical interventions, such as major surgery within 28 days of C1D1. Standard of care procedures for patients with hematologic malignancies, such as biopsies and lumbar punctures, are allowed
* PART A: Patients with psychiatric illness/social situation that would limit compliance with the study
* PART A: Patients with history of clinically significant medical condition(s) (including comorbidities) and no other reason, per the determination of the investigator, which could interfere with the patient's adherence to the study protocol or would make the patient an unsuitable candidate to receive study drugs
* PART B: Patients with evidence of primary graft failure (PGF) or secondary graft failure (SGF) while enrolled on Part A or SGF during screening for Part B
* PART B: Patients who experienced a dose limiting toxicity (DLT) in Part A
* PART B: Patients administered an investigational agent, a known JAK1/2 inhibitor (with the exception of ruxolitinib), or SOC chemotherapy or radiotherapy within 5 half-lives of C2D1, or per institutional practice
* PART B: Patients administered a biologic of anti-neoplastic intent within 30 days of C2D1, or per institutional practice
* PART B: Patients with a plan for other maintenance therapy outside of this trial, including a FLT3-ITD inhibitor
* PART B: Patients with evidence of clinically significant, uncontrolled systemic infection
* PART B: Patients with Mount Sinai Acute Graft Versus Host Disease International Consortium (MAGIC) grade II or greater active aGVHD
* PART B: Patients with ongoing or planned therapy with prednisone equivalent of ≥ 10 mg daily for GVHD treatment or other illness
* PART B: Patients with newly diagnosed psychiatric illness or new social situation that would limit compliance with the study
* PART B: Patients with new or recent history of clinically significant medical condition(s) (including comorbidities) or any other reason, per the determination of the investigator, which could interfere with the patient's adherence to the study protocol or would make the patient an unsuitable candidate to receive study drugs
* DONOR: Recipient has evidence of donor-specific HLA antibody (DSA). If recipient is positive for HLA antibodies against a mismatched HLA in the selected donor, defined as the presence of DSA to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, -DRB1, DRB3, DRB4, DRB5, -DQA1, - DQB1, -DPA1, -DPB1) with mean fluorescence intensity (MFI) > 3000 by microarray-based single antigen bead testing, the donor will be excluded. In patients receiving red blood cell or platelet transfusions, DSA evaluation should be performed prior to donor mobilization and initiation of recipient preparative regimen whenever possible
* DONOR: Donors with positive coronavirus disease 2019 (COVID-19) testing results (confirmed by PCR) within 72 hours (hr) of stem cell collection

• Jennifer N Saultz, Principal investigator, OHSU Knight Cancer Institute