Nivolumab With Chemotherapy in Refractory MDS

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

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.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Nivolumab; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: all trans retinoic acid; Drug: Sildenafil; Drug: Melphalan; Drug: Azacitidine

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Saint-Petersburg, Russian Federation, 197089
    • First Pavlov State Medical University of St. Petersburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / 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: Vidaza; 5-azacitidine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2017
• Primary Completion (Actual): December 25, 2018
• Study Completion (Actual): December 25, 2018

Study Registration Dates

• First Submitted: August 22, 2017
• First Submitted That Met QC Criteria: August 22, 2017
• First Posted (Actual): August 23, 2017

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: April 3, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: nivolumab; cytarabine; myelodysplastic syndrome; melphalan; all-trans retinoic acid; 5-azacitidine; lymphodepletion
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Anti-Infective Agents; Urological Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Immune Checkpoint Inhibitors; Keratolytic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Cyclophosphamide; Nivolumab; Melphalan; Azacitidine; Fludarabine; Cytarabine; Sildenafil Citrate; Tretinoin
• Other Study ID Numbers: 18/17-n

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No