Nivolumab With Chemotherapy in Refractory MDS

St. Petersburg State Pavlov Medical University

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Myelodysplastic Syndromes

Treatments: Drug: Sildenafil; Drug: all trans retinoic acid; Drug: Melphalan; Drug: Cytarabine; Drug: Azacitidine; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Nivolumab

Study type: Interventional

Funder types: Other

Identifiers

NCT03259516

18/17-n

Details and patient eligibility

About

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.

Enrollment: 2 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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2 participants in 5 patient groups

Nivo + FC

Experimental group

Description:

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

Treatment:

Drug: Fludarabine

Drug: Nivolumab

Drug: Cyclophosphamide

Nivo + LDAC + ATRA

Experimental group

Description:

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

Treatment:

Drug: Nivolumab

Drug: Cytarabine

Drug: all trans retinoic acid

Nivo + LDAC + Sildenafil

Experimental group

Description:

Nivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days Sildenafil 20 mg tid

Treatment:

Drug: Nivolumab

Drug: Sildenafil

Drug: Cytarabine

Nivo + Melphalan

Experimental group

Description:

Nivolumab 1 mg/kg days 1,15 iv q28days Melphalan 2 mg qd days 1-10 q28days

Treatment:

Drug: Nivolumab

Drug: Melphalan

Nivo + 5-aza

Experimental group

Description:

Nivolumab 1 mg/kg days 1,15 iv q28days 5-azacitidine 75 mg/m2 days 1-7 q28days

Treatment:

Drug: Nivolumab

Drug: Azacitidine