This phase I trial studies the side effects and best dose of ruxolitinib (Rux) therapy alone (monotherapy) followed by Rux plus azacitidine (AZA) maintenance therapy and to see how well it works in treating patients with acute myeloid leukemia (AML) who are undergoing reduced intensity allogeneic hematopoietic stem cell transplantation (alloHSCT). AlloHSCT provides the only chance for cure for many patients with AML. AlloHSCT is a procedure in which a person receives blood-forming stem cells (cells from which all blood cells develop) from a genetically similar, but not identical, donor. This is often a sister or brother, but could be an unrelated donor. One of the common reasons for death after an alloHSCT is graft versus host disease (GVHD), which occurs when the transplanted cells from the donor attacks the recipient's normal cells. Ruxolitinib is in a class of medications called kinase inhibitors. It works to treat GVHD by blocking the signals of the cells that cause GVHD. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. Giving Rux after the transplant may stop GVHD from occurring. Maintenance therapy with AZA, may help prevent or delay cancer from coming back. Giving Rux monotherapy followed by Rux plus AZA maintenance therapy may be safe, tolerable, and/or effective in treating patients with AML who are undergoing alloHSCT.
PRIMARY OBJECTIVE: I. To determine the safety and tolerability of Rux monotherapy (part A) and Rux plus AZA therapy (part B) following alloHSCT in AML patients. SECONDARY OBJECTIVES: I. To determine the feasibility of Rux plus AZA maintenance. II. To determine the effect on measurable residual disease (MRD) of Rux plus AZA maintenance. III. To determine the impact on neutrophil engraftment of study treatment. IV. To determine the impact on platelet engraftment of study treatment. V. To determine the frequency and timing of disease relapse after alloHSCT when treated with Rux plus AZA maintenance. VI. To determine risk of post alloHSCT acute graft versus host disease (aGVHD) when treated with Rux plus AZA maintenance. VII. To determine risk of post alloHSCT chronic graft versus host disease (cGVHD) when treated with Rux plus AZA maintenance. VIII. To determine post alloHSCT survival in the absence of GVHD or disease relapse when treated with Rux plus AZA maintenance. IX. To determine the rate of post alloHSCT early infection in context of Rux plus AZA maintenance. X. To determine overall survival after alloHSCT and treatment with Rux plus AZA maintenance. XI. To determine the effect on quality of life (QoL) of post alloHSCT Rux plus AZA maintenance. EXPLORATORY OBJECTIVES: I. To evaluate the impact of pre transplant disease characteristics on treatment outcomes. II. To determine the impact of MRD on treatment outcomes. III. To explore biomarkers predictive of patient outcomes while on treatment. 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. 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 at 30-35 days and then as per institutional practice for up to 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Undergo alloHSCT
Given IV
Undergo blood sample collection
Undergo bone marrow aspiration
Undergo bone marrow biopsy
Given IV
Undergo ECHO
Ancillary studies
Undergo MUGA
Given PO or IV
Undergo SOC RIC or NMA conditioning
Given PO
Ancillary studies
Given PO or IV
OHSU Knight Cancer Institute
Portland, Oregon, United States
RECRUITINGIncidence of dose limiting toxicities (DLTs)
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.
Time frame: From cycle 1 day 1 (day +5 post-transplant) to end of cycle 2 (Cycle length = 28 days)
Incidence of grade 3+ treatment-related adverse events (TRAEs) (Part B)
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.
Time frame: Up to 30 days after last dose of study drug
Graft versus host disease (GVHD)-free, relapse-free survival
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).
Time frame: 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
Overall survival
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.
Time frame: From date of transplant to last known alive (censored) or death date, assessed up to 2 years
Cumulative incidence of neutrophil engraftment
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.
Time frame: From date of transplant to 30 days post-HSCT
Cumulative incidence of platelet engraftment
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.
Time frame: From date of transplant to 100 days post-HSCT
Cumulative incidence of Blood and Marrow Transplant Clinical Trials Network grade 2-3 infections
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.
Time frame: From date of transplant to 100 days post-HSCT
Cumulative incidence of grade ≥ II aGVHD
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.
Time frame: From date of transplant to end of study, assessed up to 2 years
Cumulative incidence of cGVHD requiring systemic immunosuppressive therapy
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.
Time frame: From day +100 post-HSCT to end of study, assessed up to 2 years
Cumulative incidence of relapse
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.
Time frame: From date of transplant to end of study, assessed up to 2 years
Percentage of part A participants enrolled on part B (Feasibility)
Descriptive summaries of discrete data will present the sample size and the incidence as frequency count and percentage, with exact binomial 95% CI.
Time frame: 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
Median time from transplant to part B enrollment (Feasibility)
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.
Time frame: 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
Patient reported quality of life outcome measurements, using the FACT-BMT patient reported outcome questionnaires
Descriptive summaries of discrete data will present the sample size and the incidence as frequency count and percentage, with exact binomial 95% CI.
Time frame: From time of part A screening to 365 days post-HSCT
Conversion rate of pre-transplant measurable residual disease (MRD) positive to negative
Time frame: From pre-transplant MRD assessment date to 1 year on study treatment or end of therapy, whichever occurs later, assessed up to 2 years
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