Myelodysplastic Syndromes
Conditions
Keywords
myelodysplastic syndrome, nivolumab, 5-azacitidine, cytarabine, melphalan, all-trans retinoic acid, lymphodepletion
Brief summary
There is evidence of involvement of checkpoint pathways, including PD-1, in the pathogenesis and resistance of myelodysplastic syndrome (MDS). However monotherapy with checkpoint inhibitors was ineffective in a number of studies, indicating the presence of several mechanisms of resistance. This pilot study evaluates the safety and preliminary efficacy of nivolumab combination with currently existing treatments in MDS patients who failed at least one line of therapy. The study evaluates if there is a combination which induces objective responses.
Interventions
DRUGNivolumab
1 mg/kg by vein on Days 1 and 15 of a 28 day cycle
DRUGAzacitidine
75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle
DRUGFludarabine
25 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle. Dose reduction to 15 mg/m2 is permitted in cases of grade 4 hematological toxicity after first cycle.
DRUGCyclophosphamide
300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.
DRUGCytarabine
10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle
45 mg/m2 per os daily during the whole course of treatment
DRUGSildenafil
20 mg per os three times a day during the whole course of treatment
DRUGMelphalan
2 mg per os daily during the whole course of treatment
Sponsors
St. Petersburg State Pavlov Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with myelodysplastic syndrome (MDS) (up to 20% blasts) of any risk. Patients with lower risk MDS (low and int-1 by IPSS) should have failed prior non-hypomethylating agent therapy (ie growth factors or lenalidomide). Patients with higher risk MDS (int-2 or high by IPSS) should have failed prior at least one therapy with a hypomethylating agent or Ara-C. * Age 18 years or older. * No severe organ dysfunction: creatinine \<=2.5 x ULN; serum bilirubin \<=2.5 x ULN; AST and ALT \<=5 x ULN. * Karnofsky index \>=70% * Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 24 hours prior to the first dose of treatment and must agree to use an effective contraception to avoid pregnancy for 24 weeks * Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 24 weeks after the last dose of nivolumab.
Exclusion criteria
* Another malignancy requiring treatment at the time of inclusion * History of interstitial lung disease or pneumonitis * Patients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure NYHA Class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the study * Active, known or suspected autoimmune disease requiring treatment at the time of inclusion * Pregnancy or breastfeeding * Patients unwilling or unable to comply with the protocol * Somatic or psychiatric disorder making the patient unable to sign informed consent * Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA4 therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate | 6 months | Overall response rate (ORR) defined as complete response plus partial response (CR + PR) and hematological improvement (HI). MDS International Working Group criteria will be used to assess response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Infectious complications | 6 months | Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment |
| Treatment-related adverse events as assessed by CTCAE v4.03 | 6 months | Toxicity parameters based on NCI CTCAE 4.03 grades: hematological toxicity (CBC), hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), fatigue (attending physician assessment), rash (attending physician assessment), colitis (attending physician assessment), pneumonitis (attending physician assessment), autoimmune disorders (level of hormones, presence of autoimmune antibodies, attending physician assessment). |
Countries
Russia
Outcome results
None listed