Nivolumab With Chemotherapy in Refractory MDS

Myelodysplastic Syndromes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03259516
• Other study ID #: 18/17-n
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: May 25, 2017
• Est. completion date: December 25, 2018

Study information

• Verified date: April 2019
• Source: St. Petersburg State Pavlov Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: December 25, 2018
• Est. primary completion date: December 25, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Nivolumab
1 mg/kg by vein on Days 1 and 15 of a 28 day cycle
• Azacitidine
75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle
• 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.
• Cyclophosphamide
300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.
• Cytarabine
10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle
• all trans retinoic acid
45 mg/m2 per os daily during the whole course of treatment
• Sildenafil
20 mg per os three times a day during the whole course of treatment
• Melphalan
2 mg per os daily during the whole course of treatment

Locations

Country	Name	City	State
Russian Federation	First Pavlov State Medical University of St. Petersburg	Saint-Petersburg

Sponsors (1)

Lead Sponsor	Collaborator
St. Petersburg State Pavlov Medical University

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Infectious complications	Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment	6 months