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Nivolumab With Chemotherapy in Refractory MDS

Primary Purpose

Myelodysplastic Syndromes

Status

Terminated

Phase

Phase 1

Locations

Russian Federation

Study Type

Interventional

Intervention

Nivolumab

Azacitidine

Fludarabine

Cyclophosphamide

Cytarabine

all trans retinoic acid

Sildenafil

Melphalan

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring myelodysplastic syndrome, nivolumab, 5-azacitidine, cytarabine, melphalan, all-trans retinoic acid, lymphodepletion

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

First Pavlov State Medical University of St. Petersburg

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Nivo + FC

Nivo + LDAC + ATRA

Nivo + LDAC + Sildenafil

Nivo + Melphalan

Nivo + 5-aza

Arm 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

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

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

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).

Infectious complications

Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment

Full Information

NCT ID

NCT03259516

First Posted

August 22, 2017

Last Updated

April 3, 2019

Sponsor

St. Petersburg State Pavlov Medical University

1. Study Identification

Unique Protocol Identification Number

NCT03259516

Brief Title

Nivolumab With Chemotherapy in Refractory MDS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Terminated

Why Stopped

Slow recruitment rate

Study Start Date

May 25, 2017 (Actual)

Primary Completion Date

December 25, 2018 (Actual)

Study Completion Date

December 25, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

St. Petersburg State Pavlov Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nivo + FC

Arm Type

Experimental

Arm 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

Arm Title

Nivo + LDAC + ATRA

Arm Type

Experimental

Arm 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

Arm Title

Nivo + LDAC + Sildenafil

Arm Type

Experimental

Arm Description

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

Arm Title

Nivo + Melphalan

Arm Type

Experimental

Arm Description

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

Arm Title

Nivo + 5-aza

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Other Intervention Name(s)

Opdivo

Intervention Description

1 mg/kg by vein on Days 1 and 15 of a 28 day cycle

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Other Intervention Name(s)

5-azacitidine, Vidaza

Intervention Description

75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Intervention Description

300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Other Intervention Name(s)

Ara-C, LDAC

Intervention Description

10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle

Intervention Type

Drug

Intervention Name(s)

all trans retinoic acid

Other Intervention Name(s)

ATRA

Intervention Description

45 mg/m2 per os daily during the whole course of treatment

Intervention Type

Drug

Intervention Name(s)

Sildenafil

Intervention Description

20 mg per os three times a day during the whole course of treatment

Intervention Type

Drug

Intervention Name(s)

Melphalan

Intervention Description

2 mg per os daily during the whole course of treatment

Primary Outcome Measure Information:

Title

Overall response rate

Description

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.

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Treatment-related adverse events as assessed by CTCAE v4.03

Description

Time Frame

6 months

Title

Infectious complications

Description

Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility 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

Facility Information:

Facility Name

First Pavlov State Medical University of St. Petersburg

City

Saint-Petersburg

ZIP/Postal Code

197089

Country

Russian Federation

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Nivolumab With Chemotherapy in Refractory MDS

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