Acute Myeloid Leukemia, Myeloid and Monocytic Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
AML, MDS
Brief summary
This is a multi-center, single-arm, open-label, phase II trial for the frontline treatment of relapsed AML or MDS following allo-HCT. Eligible subjects will receive up to 4 cycles of combined modality treatment. The number of cycles depends on response, toxicity, and the remaining cell dose.
Interventions
DRUGDecitabine
10 days of decitabine 20 mg/m2 IV daily; or, alternatively, per institution, physician, or patient preference on a 5-2-5 schedule with no weekend infusion. If a CR is achieved after 2 cycles using the 10-day schedule, subsequent cycles will change to a 5-day schedule.
DRUGRuxolitinib
Starting with day 1 of cycle 1 and continuing for up to 6 months after the end of the last cycle, patients will receive ruxolitinib 5 mg twice daily orally. Dose may be increased to 10 mg twice daily in cycles 2 through 4 if platelets improve to \>100 x 10\^9/L.
DLI from the original donor will be infused within 10 days after the last dose of decitabine in each cycle.
Sponsors
Incyte Corporation
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patient Inclusion Criteria: * Age ≥12 years * Have undergone first allo-HCT from a 6/6 matched sibling donor, 8/8 matched unrelated donor, or an HLA haploidentical donor. * History of AML or MDS for which allo-HCT was performed. Overlap MPN/MDS is included. * Untreated relapse of the underlying malignancy as defined by \>5% of malignant blasts (by morphology and/or flow cytometry) in the bone marrow, or myeloid sarcoma. * Additional cells sufficient for the first DLI available from the same donor, or the donor must be willing to donate. Both G-CSF mobilized and unmobilized products are allowed and the choice is at the discretion of the treating physician. * Partial (or better) engraftment from the bone marrow showing relapse, defined as \>50% donor chimerism on non-split RFLP. Patients with chimerism of 25-50% may be enrolled with approval of the site PI and Sponsor/Investigator * Karnofsky performance status ≥ 50% * Adequate organ function within 14 days of study registration defined as: * Total bilirubin \< 1.5 x upper limit of institutional normal, unless a diagnosis of Gilbert's disease * AST/ALT \< 2.5 x upper limit of institutional normal * Creatinine clearance ≥40 mL/minute as calculated by the Cockcroft-Gault formula. Cockcroft-Gault CrCl = (140-age) \* (Wt in kg) \* (0.85 if female) / (72 \* Cr). * Peripheral white blood cell count \<50 x 10\^9/L. The use of hydroxyurea for cytoreduction is allowed and may continue until cycle 2 day 1 * Subjects and spouse/partner who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method) starting at Screening and continuing through the entire study (for at least 3 months after the last dose of ruxolitinib if study treatment is stopped early or subject withdraws consent). Highly effective contraception is defined as: * Established use of oral, injected or implanted hormonal methods of contraception. * Placement of an intrauterine device or intrauterine system. * Double barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (double barrier method will count as 2 forms of contraception). * Male subjects must not donate sperm during the Screening and Treatment Periods, and for at least 3 months after the last dose of ruxolitinib. * Subjects are willing and able to give written informed consent and to comply with all study visits and procedures. Parents or legal guardians will consent for minors and minors will be asked to assent. Patient
Exclusion criteria
* Active uncontrolled infection at the time of consent. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without signs or symptoms of infection will not be interpreted as an active uncontrolled infection. Subjects with a controlled infection receiving definitive therapy for 72 hours prior to enrollment are eligible. * History of infection with human immunodeficiency virus (HIV), unresolved hepatitis B, or hepatitis C. * Untreated CNS leukemia * Untreated or active GVHD (acute or chronic) * History of grade III-IV acute GVHD at any point in time * Any form of iatrogenic immunosuppression except \<0.5 mg/kg/day of prednisone or equivalent at the time of consent. * Unresolved veno-occlusive disease of the liver, defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction (renal, ascites). * Subjects who are pregnant, breast feeding or sexually active and unwilling to use effective birth control for the duration of the study, as agents in this study are in pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, and category D: there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans. * Radiation therapy within 14 days prior to consent. * Any prior therapy for relapse after allo-HCT. * Prior DLI. CD34-selected boost is allowed * Exposure to any other investigational agent, device or procedure within 14 days prior to consent * Patients or donors with any medical or psychological condition that, in the opinion of the Investigator, might interfere with the subject's participation in the trial, pose any additional risk for the patient/donor, or confounds the assessments of the subject. * Subjects with known allergies, hypersensitivity or intolerance to ruxolitinib or similar compounds.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS) | 6 Months | Rate of Overall Survival (OS) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV) | 3 Months | Percentage of Participants with Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV) |
| Progression Free Survival (PFS) | 6 Months | Rate of Progression Free Survival (PFS) |
| Relapse | 6 Months | Cumulative Incidence of Relapse |
| Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS) | 1 Year | Rate of Overall Survival (OS) |
| Non-Relapse Mortality (NRM) | 6 Months | Cumulative Incidence of Non-Relapse Mortality (NRM) |
| Best Response | 1 Year | Best response until next line of treatment, death, or last follow up, whichever occurs sooner |
| Complete Remission (CR) | 6 Months | Rate of Complete Remission (CR) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Decitabine + Ruxolitinib + DLI Eligible subjects will receive up to 4 cycles of combined modality treatment. The number of cycles depends on response, toxicity, and the remaining cell dose.
Decitabine: 10 days of decitabine 20 mg/m2 IV daily; or, alternatively, per institution, physician, or patient preference on a 5-2-5 schedule with no weekend infusion. If a CR is achieved after 2 cycles using the 10-day schedule, subsequent cycles will change to a 5-day schedule.
Ruxolitinib: Starting with day 1 of cycle 1 and continuing for up to 6 months after the end of the last cycle, patients will receive ruxolitinib 5 mg twice daily orally. Dose may be increased to 10 mg twice daily in cycles 2 through 4 if platelets improve to \>100 x 10\^9/L.
Donor Lymphocyte Infusion (DLI): DLI from the original donor will be infused within 10 days after the last dose of decitabine in each cycle. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Death | 1 |
| Overall Study | Poor Performance | 1 |
Baseline characteristics
| Characteristic | Decitabine + Ruxolitinib + DLI |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 3 / 14 |
Outcome results
Primary
Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS)
Rate of Overall Survival (OS)
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS) | 36 Percentage of participants |
Secondary
Best Response
Best response until next line of treatment, death, or last follow up, whichever occurs sooner
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Best Response | 14 Percentage of participants |
Secondary
Complete Remission (CR)
Rate of Complete Remission (CR)
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Complete Remission (CR) | 14 Percentage of participants |
Secondary
Complete Remission (CR)
Rate of Complete Remission (CR)
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Complete Remission (CR) | 7 Percentage of participants |
Secondary
Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS)
Rate of Overall Survival (OS)
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS) | 14 Percentage of participants |
Secondary
Non-Relapse Mortality (NRM)
Cumulative Incidence of Non-Relapse Mortality (NRM)
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Non-Relapse Mortality (NRM) | 14 Percentage of participants |
Secondary
Non-Relapse Mortality (NRM)
Cumulative Incidence of Non-Relapse Mortality (NRM)
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Non-Relapse Mortality (NRM) | 14 Percentage of participants |
Secondary
Percentage of Participants With Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV)
Percentage of Participants with Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV)
Time frame: 3 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Percentage of Participants With Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV) | 43 Percentage of participants |
Secondary
Progression Free Survival (PFS)
Rate of Progression Free Survival (PFS)
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Progression Free Survival (PFS) | 14 Percentage of participants with PFS |
Secondary
Progression Free Survival (PFS)
Rate of Progression Free Survival (PFS)
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Progression Free Survival (PFS) | 7 Percentage of participants |
Secondary
Relapse
Cumulative Incidence of Relapse
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Relapse | 71 Percentage of participants |
Secondary
Relapse
Cumulative Incidence of Relapse
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Ruxolitinib + DLI | Relapse | 79 Percentage of participants |