Nivolumab With Chemotherapy in Refractory MDS

• Sponsor: St. Petersburg State Pavlov Medical University
• Information provided by (Responsible Party): Ivan S Moiseev, St. Petersburg State Pavlov Medical University

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

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Study Type :	Interventional (Clinical Trial)
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 :	December 25, 2018
Actual Study Completion Date :	December 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 Name: 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 Name: Opdivo; Drug: Cytarabine; 10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle; Other Name: Ara-C, LDAC; Drug: all trans retinoic acid; 45 mg/m2 per os daily during the whole course of treatment; Other Name: 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 Name: Opdivo; Drug: Cytarabine; 10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle; Other Name: 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 Name: 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 Name: 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 :

1. Overall response rate [ Time Frame: 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 :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

St. Petersburg State Pavlov Medical University

More Information

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Responsible Party:	Ivan S Moiseev, Vice-director for science, R.M. Gorbacheva memorial institute, St. Petersburg State Pavlov Medical University
ClinicalTrials.gov Identifier:	NCT03259516 History of Changes
Other Study ID Numbers:	18/17-n
First Posted:	August 23, 2017
Last Update Posted:	April 5, 2019
Last Verified:	April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Ivan S Moiseev, St. Petersburg State Pavlov Medical University:

myelodysplastic syndrome; nivolumab; 5-azacitidine; cytarabine	melphalan; all-trans retinoic acid; lymphodepletion

Additional relevant MeSH terms:

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Myelodysplastic Syndromes; Preleukemia; Nivolumab; Syndrome; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Cyclophosphamide; Fludarabine phosphate; Cytarabine; Melphalan; Fludarabine	Azacitidine; Tretinoin; Sildenafil Citrate; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Antimetabolites, Antineoplastic; Antimetabolites