Myelodysplastic SyndromesPhase 1/2NCT03259516
Nivolumab With Chemotherapy in Refractory MDS
A Phase 1/2 study testing Nivolumab, Azacitidine and Fludarabine in people with Myelodysplastic Syndromes, run by St. Petersburg State Pavlov Medical University at 1 site in Russia.
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Myelodysplastic Syndromes
- What is being tested?
- Nivolumab, Azacitidine and Fludarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteRussia
- Study dates
- 25 May 2017to 25 Dec 2018
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Russia1 site
First Pavlov State Medical University of St. Petersburg
Saint Petersburg, 197089
About this study
Official title: 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.
- Conditions
- Myelodysplastic Syndromes
- Being tested
- Nivolumab, Azacitidine, Fludarabine, Cyclophosphamide, Cytarabine
- Keywords
- myelodysplastic syndrome, nivolumab, 5-azacitidine, cytarabine, melphalan, all-trans retinoic acid, lymphodepletion
- Medical subject headings
- Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabDrug
Also called Opdivo
1 mg/kg by vein on Days 1 and 15 of a 28 day cycle
AzacitidineDrug
Also called 5-azacitidine, Vidaza
75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle
FludarabineDrug
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.
CyclophosphamideDrug
300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle.
CytarabineDrug
Also called Ara-C, LDAC
10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle
all trans retinoic acidDrug
Also called ATRA
45 mg/m2 per os daily during the whole course of treatment
SildenafilDrug
20 mg per os three times a day during the whole course of treatment
MelphalanDrug
2 mg per os daily during the whole course of treatment
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: Drug: Nivolumab; Drug: Azacitidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6 months
Secondary outcomes (2)
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).
Measured: 6 months
Infectious complications
Incidence of severe bacterial, fungal and viral infections incidence based on laboratory confirmation and attending physician assessment
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Aug 2017
- Study start25 May 2017
- Primary completion25 Dec 2018
- Study completion25 Dec 2018
Why it stopped: Slow recruitment rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Myelodysplastic SyndromesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- St. Petersburg State Pavlov Medical University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ivan S Moiseev, St. Petersburg State Pavlov Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03259516
- Sponsor's protocol ID
- 18/17-n
- Status last verified
- Apr 2019
- First submitted
- 22 Aug 2017
- Last updated
- 5 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Open-label Trial of Nivolumab Combined With Chemotherapy in Refractory Myelodysplastic Syndromes.
- ClinicalTrials.gov ID
- NCT03259516
- Acronym / sponsor ID
- 18/17-n
- Conditions
- Myelodysplastic Syndromes
- Keywords
- myelodysplastic syndrome, nivolumab, 5-azacitidine, cytarabine, melphalan, all-trans retinoic acid, lymphodepletion
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Slow recruitment rate
- Enrolment
- 2 participants (actual)
- Lead sponsor
- St. Petersburg State Pavlov Medical UniversityUniversity, hospital or other
- Study start
- 25 May 2017 (actual)
- Primary completion
- 25 Dec 2018 (actual)
- Study completion
- 25 Dec 2018 (actual)
- First posted
- 23 Aug 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Nivo + FC | Experimental | Drug: Nivolumab, Drug: Fludarabine, Drug: CyclophosphamideNivolumab 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 |
| Nivo + LDAC + ATRA | Experimental | Drug: Nivolumab, Drug: Cytarabine, Drug: all trans retinoic acidNivolumab 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 |
| Nivo + LDAC + Sildenafil | Experimental | Drug: Nivolumab, Drug: Cytarabine, Drug: SildenafilNivolumab 1 mg/kg days 1,15 iv q28days Cytarabine 10 mg/m2 bid days 1-10 sc q28days Sildenafil 20 mg tid |
| Nivo + Melphalan | Experimental | Drug: Nivolumab, Drug: MelphalanNivolumab 1 mg/kg days 1,15 iv q28days Melphalan 2 mg qd days 1-10 q28days |
| Nivo + 5-aza | Experimental | Drug: Nivolumab, Drug: AzacitidineNivolumab 1 mg/kg days 1,15 iv q28days 5-azacitidine 75 mg/m2 days 1-7 q28days |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NivolumabAlso: Opdivo1 mg/kg by vein on Days 1 and 15 of a 28 day cycle | Drug | Nivo + 5-aza, Nivo + FC, Nivo + LDAC + ATRA, Nivo + LDAC + Sildenafil, Nivo + Melphalan |
| AzacitidineAlso: 5-azacitidine, Vidaza75 mg/m2 subcutaneously on Days 1-7 of a 28 day cycle | Drug | Nivo + 5-aza |
| Fludarabine25 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 | Nivo + FC |
| Cyclophosphamide300 mg/m2 by vein on Days 1, 2 and 3 of a 28 day cycle. | Drug | Nivo + FC |
| CytarabineAlso: Ara-C, LDAC10 mg/m2 subcutaneously two times a day on Days 1-10 of a 28 day cycle | Drug | Nivo + LDAC + ATRA, Nivo + LDAC + Sildenafil |
| all trans retinoic acidAlso: ATRA45 mg/m2 per os daily during the whole course of treatment | Drug | Nivo + LDAC + ATRA |
| Sildenafil20 mg per os three times a day during the whole course of treatment | Drug | Nivo + LDAC + Sildenafil |
| Melphalan2 mg per os daily during the whole course of treatment | Drug | Nivo + Melphalan |
Primary outcome
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.
2 secondary outcomes
Treatment-related adverse events as assessed by CTCAE v4.03
Time frame: 6 months
Infectious complications
Time frame: 6 months
Results and safety
The study was stopped early (reason given: Slow recruitment rate). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2019.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nivolumab, Azacitidine and Fludarabine in people with Myelodysplastic Syndromes, run by St. Petersburg State Pavlov Medical University at 1 site in Russia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 5 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Russia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Slow recruitment rate). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall response rate (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2019.