Nivolumab With Chemotherapy in Refractory MDS

NCT03259516 | Terminated Phase 1

• 1 other identifier: 18/17-n
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Myelodysplastic Syndromes

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

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

  6 months

• Infectious complications

  6 months

Study Arms (5)

Nivo + FC

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cyclophosphamide

Nivo + LDAC + ATRA

EXPERIMENTAL

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; Drug: Cytarabine; Drug: all trans retinoic acid

Nivo + LDAC + Sildenafil

EXPERIMENTAL

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; Drug: Cytarabine; Drug: Sildenafil

Nivo + Melphalan

EXPERIMENTAL

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

Drug: Nivolumab; Drug: Melphalan

Nivo + 5-aza

EXPERIMENTAL

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

Drug: Nivolumab; Drug: Azacitidine

Interventions

Nivolumab DRUG

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

Also known as: Opdivo

Nivo + 5-aza; Nivo + FC; Nivo + LDAC + ATRA; Nivo + LDAC + Sildenafil; Nivo + Melphalan

Azacitidine DRUG

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

Also known as: 5-azacitidine, Vidaza

Nivo + 5-aza

Fludarabine DRUG

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.

Nivo + FC

Cyclophosphamide DRUG

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

Nivo + FC

Cytarabine DRUG

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

Also known as: Ara-C, LDAC

Nivo + LDAC + ATRA; Nivo + LDAC + Sildenafil

all trans retinoic acid DRUG

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

Also known as: ATRA

Nivo + LDAC + ATRA

Sildenafil DRUG

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

Nivo + LDAC + Sildenafil

Melphalan DRUG

2 mg per os daily during the whole course of treatment

Nivo + Melphalan

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• St. Petersburg State Pavlov Medical University: lead

Study Sites (1)

First Pavlov State Medical University of St. Petersburg

Saint Petersburg, 197089, Russia

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Nivolumab; Azacitidine; fludarabine; Cyclophosphamide; Cytarabine; Tretinoin; Sildenafil Citrate; Melphalan

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Arabinonucleosides; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Piperazines; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice-director for science, R.M. Gorbacheva memorial institute

Study Record Dates

• First Submitted: August 22, 2017
• First Posted: August 23, 2017
• Study Start: May 25, 2017
• Primary Completion: December 25, 2018
• Study Completion: December 25, 2018
• Last Updated: April 5, 2019

Record last verified: 2019-04

Locations

RU (1)