Nivolumab With Chemotherapy in Refractory MDS

Sponsor

St. Petersburg State Pavlov Medical University (Other)

Overall Status

Terminated

CT.gov ID

NCT03259516

Collaborator

(none)

Enrollment

Location

Arms

Actual Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Nivolumab Drug: Azacitidine Drug: Fludarabine Drug: Cyclophosphamide Drug: Cytarabine Drug: all trans retinoic acid Drug: Sildenafil Drug: Melphalan	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

2 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 25, 2017

Actual Primary Completion Date :

Dec 25, 2018

Actual Study Completion Date :

Dec 25, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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).
Infectious complications [6 months]
Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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