Nivolumab With Chemotherapy in Refractory MDS

Study Overview
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Brief Summary
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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.

Official Title
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Pilot Open-label Trial of Nivolumab Combined With Chemotherapy in Refractory Myelodysplastic Syndromes.

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Azacitidine
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: all trans retinoic acid
* Drug: Sildenafil
* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivo + FC<br>Nivolumab 1 mg/kg days 1,15 iv q28days Fludarabine 25 mg/m2 days 1-3 iv q28days Cyclophosphamide 300 mg/m2 days 1-3 iv q28days | Drug: Nivolumab<br>* 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle<br>* Other names: Opdivo;Drug: Fludarabine<br>* 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.<br>Drug: Cyclophosphamide<br>* 300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.<br>|
| Experimental: Nivo + LDAC + ATRA<br>Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days All-trans retinoic acid (ATRA) 45 mg/m2 po qd | Drug: Nivolumab<br>* 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle<br>* Other names: Opdivo;Drug: Cytarabine<br>* 10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle<br>* Other names: Ara-C, LDAC;Drug: all trans retinoic acid<br>* 45 mg/m2 per os daily during the whole course of treatment<br>* Other names: ATRA;|
| Experimental: Nivo + LDAC + Sildenafil<br>Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days Sildenafil 20 mg tid | Drug: Nivolumab<br>* 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle<br>* Other names: Opdivo;Drug: Cytarabine<br>* 10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle<br>* Other names: Ara-C, LDAC;Drug: Sildenafil<br>* 20 mg per os three times a day during the whole course of treatment<br>|
| Experimental: Nivo + Melphalan<br>Nivolumab 1 mg/kg days 1,15 iv q28days Melphalan 2 mg qd days 1-10 q28days | Drug: Nivolumab<br>* 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle<br>* Other names: Opdivo;Drug: Melphalan<br>* 2 mg per os daily during the whole course of treatment<br>|
| Experimental: Nivo + 5-aza<br>Nivolumab 1 mg/kg days 1,15 iv q28days 5-azacitidine 75 mg/m2 days 1-7 q28days | Drug: Nivolumab<br>* 1 mg/kg by vein on Days 1 and 15 of a 28 day cycle<br>* Other names: Opdivo;Drug: Azacitidine<br>* 75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related adverse events as assessed by CTCAE v4.03 | 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). | 6 months | 
| Infectious complications | Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myelodysplastic syndrome, nivolumab, 5-azacitidine, cytarabine, melphalan, all-trans retinoic acid, lymphodepletion