Myelodysplastic SyndromesPhase 2NCT04044209
A Study of the IDH1 Inhibitor AG-120 in Combination With the Checkpoint Blockade Inhibitor, Nivolumab, for Patients With IDH1 Mutated Relapsed/Refractory AML and High Risk MDS
A Phase 2 study testing AG-120 and Nivolumab in people with Myelodysplastic Syndromes and Acute Myeloid Leukemia, run by Yale University at 1 site in United States.
Trial summary
In this trial the investigators aim to evaluate safety and efficacy of combination Ivosidenib (AG-120) and nivolumab in the context of adult patients with Isocitrate dehydrogenase-1 (IDH1) mutated acute myeloid leukemias (AML) or Myelodysplastic syndromes (MDS). Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Myelodysplastic Syndromes, Acute Myeloid Leukemia
- What is being tested?
- AG-120 and Nivolumab
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Feb 2020to Sep 2023
- Phase
- Phase 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 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of Myelodysplastic Syndrome with Excess Blast 2 (MDS-EB2) or AML according to World Health Organization (WHO) 2016 classification
- Documented IDH1 mutation within 2 months of the screening
- IDH1 mutation must be confirmed by the local laboratory during the screening period.
- Age over 18 years
- Patient must have been treated with at least 1 prior line of therapy. Hydrea is not considered as 1 line of therapy.
- Patient may have been previously treated with allogeneic transplantation if the transplant was more than 6 months ago, that the patient is not with active Graft vs. Host Disease (GVHD), and provided that the patient is not at the time of inclusion on immunosuppressant
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- Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2
- The patient must have recovered from toxicities of any prior treatment regimen (no CTCAE grading over 1 or return to baseline)
- Adequate hepatic and renal function:
- Hepatic Total bilirubin 1.5 x the ULN unless considered due to Gilbert's syndrome, Alanine aminotransferase (ALT) (SGPT), or aspartate aminotransferase (AST) (SGOT) 2.5 x the ULN unless considered due to organ leukemic involvement
- Renal: Serum creatinine 2 x the institutional upper limit of normal (ULN)
- The patient is able to understand and sign an informed consent form
- Females of reproductive potential and fertile males with partners who are females of reproductive potential must agree to use of 2 effective forms of contraception, one being a barrier method, or must be abstinent as part of their usual lifestyle.
- The patient is willing to participate to the study, able to adhere to the study visit schedule and other protocol procedures, and has the ability to understand and sign an inform consent form
Who cannot join
- Prior exposure to IDH targeted agents
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- Acute Promyelocytic leukemias
- Active Central Nervous System (CNS) disease
- Participants who have received a live/ attenuated vaccine within 30 days of first treatment. Any live vaccine (ex: varicella, zoster, yellow fever, rotavirus, oral polio and measles mumps, rubella (MMR) are strictly prohibited during and for a 100 days post last treatment.
- Autoimmune disease: Patients with active, known or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
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- Medical history of Progressive multifocal leukoencephalopathy
- Patients who are unable to take PO regularly, with active gastroparesis, short gut syndrome or other malabsorption syndrome.
- Any significant medical/social condition that could limit the understanding of the study or the compliance to the protocol including but not limited to uncontrolled infection, severe or uncontrolled psychiatric illness, platelet refractoriness
- Use of strong cytochrome P-450 3A4 (CYP3A) inducers or inhibitors that cannot be safely replaced by other medications. This includes: alfentanil, aprepitant, budesonide, buspirone, conivaptan, darifenacin, darunavir, dronedarone, eletriptan, eplerenone, felodipine, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, tolvaptan, tipranavir, triazolam, ticagrelor, vardenafil and/or the CYP2B6 substrates: bupropion, efavirenz. Posaconazole and voriconazole are not strictly prohibited, but all alternatives much be explored and use of these agents must be discussed with the Sponsor PI.
- Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of nivolumab. Corticosteroids with minimal systemic absorption (for example, topical or inhalational and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease). Use of steroids to treat toxicities acceptable is acceptable based on the local investigators standard of care).
- Prior malignancies: Any malignancy less than 1 year after end of treatment. Any malignancy presenting signs of active disease. Basal cell carcinoma and superficial cervix cancer can be included.
- History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association. Patients with heart-rate corrected QT interval using Fridericia's method (QTcF) >=450 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF interval in the setting of bundle branch block or pacemaker should be considered with documented consultation of a cardiologist.
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- Any known history of a positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection
- Supplemental oxygen dependency or clinically significant interstitial lung disease.
- Pregnant or nursing women
- Active alcohol or drug abuse
- Patient suitable for allogeneic transplantation and with an identified allogeneic donor at the time of screening.
- Patients post allogeneic transplantation may be included on the trial if they are:
- 6 months from transplantation
- not actively on any immunosuppressive therapy
- without evidence of acute or chronic GVHD.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase II of the IDH1 Inhibitor AG-120 in Combination With the Checkpoint Blockade Inhibitor, Nivolumab, for Patients With IDH1 Mutated Relapsed/Refractory AML and High Risk MDS
In this trial the investigators aim to evaluate safety and efficacy of combination Ivosidenib (AG-120) and nivolumab in the context of adult patients with Isocitrate dehydrogenase-1 (IDH1) mutated acute myeloid leukemias (AML) or Myelodysplastic syndromes (MDS).
Read the detailed description
Primary objectives:
- To determine the overall response rate of (CR/CRi) of combination ivosidenib (AG-120) and nivolumab in patients with high risk MDS and relapsed/ refractory AML
- To determine the duration of response of combination ivosidenib (AG-120) and nivolumab in patients with high risk MDS and relapsed/ refractory AML 2.2 Secondary Objectives
- To determine the progression free survival of patients treated with combination ivosidenib (AG- 120) and nivolumab. 2) To determine the overall survival of patients treated with combination ivosidenib (AG-120) and nivolumab. 3) To determine hematological response rate of patients treated with combination ivosidenib (AG- 120) and nivolumab. 4) To establish the duration of response to treatment of patients treated with combination ivosidenib (AG-120) and nivolumab. 5) To evaluate the safety and tolerability of combination ivosidenib (AG-120) and nivolumab.
Exploratory objectives:
- To assess the relationship between treatment response and correlative studies such as plasma and bone marrow 2-HG levels, and IDH variant allele frequency.
- Genomic characterization by assaying specimens obtained from patients using an MDS/AML specific panel through the duration of therapy to longitudinally assess mutational burden before and during therapy, and correlating this mutational data with patient outcomes
- Correlate exploratory biomarkers including PD-L1 expression, circulating myeloid-derived suppressor cells and interferon gamma signatures to response
- Conditions
- Myelodysplastic Syndromes, Acute Myeloid Leukemia
- Being tested
- AG-120, Nivolumab
- Medical subject headings
- Myelodysplastic Syndromes, Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AG-120Drug
The IDH1 inhibitor ivosidenib (AG-120) that will be administered orally on a continuous basis at the dose of 500 mg/day starting at day 1 of each cycle. A cycle will be defined as a 28-day period.
NivolumabDrug
On Cycle 2 day 1 the patient will receive nivolumab 480mg once. This will be repeated on Day 1 of every subsequent cycle.
| Study group | Role | What they receive |
|---|---|---|
| Patients receiving nivolumab and ivosidenib | Experimental | Patients who meet eligibility criteria will initiate therapy with the IDH1 inhibitor ivosidenib (AG-120) that will be administered orally on a continuous basis at the dose of 500 mg/day starting at day 1 of each cycle. A cycle will be defined as a 28-day period.
On Cycle 2 day 1 the patient will receive nivolumab 480mg once. This will be repeated on Day 1 of every subsequent cycle. Patient will be treated until progression, transplant or unacceptable toxicity. The patient will be continually monitored on therapy and will undergo scheduled response assessments to evaluate response. Receives: Drug: AG-120; Drug: Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall response rate
- Overall response rate (ORR) of 60%, i.e., a 20% ORR improvement (historical control ORR = 40% with Ivosidenib[AG-120] monotherapy after 2 lines of therapy20) after 6 cycles of treatment based on MDS International Working Group 2006 criteria and AML MDS International Working group MDS/AML criteria33, 34Cumulative ORR will include complete remission (CR), morphologic complete remission with incomplete blood count recovery (CRi), CR with incomplete platelet recovery (CRp) and Partial response (PR).
Measured: 168 days
Change in duration of response
- In the patients who respond, Improvement in duration of response to 12 months (compared to single agent ivosidenib [AG-120] 8.2 months with ivosidenib [AG-120] monotherapy)
Measured: 12 months
Secondary outcomes (3)
Overall survival rate
Overall survival will be defined from the time of treatment initiation to the time of last follow up or death. Survival with censoring patients at the time of transplantation will also be evaluated.
Measured: Up to 4 years
Progression free survival rate
Progression free survival will be defined from the time of documentation of response to the time of relapse or death or censored at the time of last follow-up. Survival with censoring patients at the time of transplantation will also be evaluated.
Measured: Up to 4 years
Amount of Allogeneic hematopoietic stem cell transplant (HSCT) patients
Percentage of patients bridged to HSCT
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Aug 2019
- Study start12 Feb 2020
- Primary completionSep 2021 (estimated)
- Study completionSep 2023 (estimated)
Why it stopped: No patients were able to be screened nor enrolled.
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.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The study is a single arm phase II trial with a safety cohort
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas Prebet, PhD, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04044209
- Sponsor's protocol ID
- 2000024263
- Status last verified
- Jan 2022
- First submitted
- 25 Jul 2019
- Last updated
- 20 Jan 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II of the IDH1 Inhibitor AG-120 in Combination With the Checkpoint Blockade Inhibitor, Nivolumab, for Patients With IDH1 Mutated Relapsed/Refractory AML and High Risk MDS
- ClinicalTrials.gov ID
- NCT04044209
- Acronym / sponsor ID
- 2000024263
- Conditions
- Myelodysplastic Syndromes, Acute Myeloid Leukemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: No patients were able to be screened nor enrolled.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- 12 Feb 2020 (actual)
- Primary completion
- Sep 2021 (estimated)
- Study completion
- Sep 2023 (estimated)
- First posted
- 5 Aug 2019 (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.
In this trial the investigators aim to evaluate safety and efficacy of combination Ivosidenib (AG-120) and nivolumab in the context of adult patients with Isocitrate dehydrogenase-1 (IDH1) mutated acute myeloid leukemias (AML) or Myelodysplastic syndromes (MDS).
Detailed description
Primary objectives:
- To determine the overall response rate of (CR/CRi) of combination ivosidenib (AG-120) and nivolumab in patients with high risk MDS and relapsed/ refractory AML
- To determine the duration of response of combination ivosidenib (AG-120) and nivolumab in patients with high risk MDS and relapsed/ refractory AML 2.2 Secondary Objectives
- To determine the progression free survival of patients treated with combination ivosidenib (AG- 120) and nivolumab. 2) To determine the overall survival of patients treated with combination ivosidenib (AG-120) and nivolumab. 3) To determine hematological response rate of patients treated with combination ivosidenib (AG- 120) and nivolumab. 4) To establish the duration of response to treatment of patients treated with combination ivosidenib (AG-120) and nivolumab. 5) To evaluate the safety and tolerability of combination ivosidenib (AG-120) and nivolumab.
Exploratory objectives:
- To assess the relationship between treatment response and correlative studies such as plasma and bone marrow 2-HG levels, and IDH variant allele frequency.
- Genomic characterization by assaying specimens obtained from patients using an MDS/AML specific panel through the duration of therapy to longitudinally assess mutational burden before and during therapy, and correlating this mutational data with patient outcomes
- Correlate exploratory biomarkers including PD-L1 expression, circulating myeloid-derived suppressor cells and interferon gamma signatures to response
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The study is a single arm phase II trial with a safety cohort
| Arm | Type | Receives |
|---|---|---|
| Patients receiving nivolumab and ivosidenib | Experimental | Drug: AG-120, Drug: NivolumabPatients who meet eligibility criteria will initiate therapy with the IDH1 inhibitor ivosidenib (AG-120) that will be administered orally on a continuous basis at the dose of 500 mg/day starting at day 1 of each cycle. A cycle will be defined as a 28-day period. On Cycle 2 day 1 the patient will receive nivolumab 480mg once. This will be repeated on Day 1 of every subsequent cycle. Patient will be treated until progression, transplant or unacceptable toxicity. The patient will be continually monitored on therapy and will undergo scheduled response assessments to evaluate response. |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Diagnosis of Myelodysplastic Syndrome with Excess Blast 2 (MDS-EB2) or AML according to World Health Organization (WHO) 2016 classification
- Documented IDH1 mutation within 2 months of the screening
- IDH1 mutation must be confirmed by the local laboratory during the screening period.
- Age over 18 years
- Patient must have been treated with at least 1 prior line of therapy. Hydrea is not considered as 1 line of therapy.
Key exclusion criteria (23 listed)
- Prior exposure to IDH targeted agents
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- Acute Promyelocytic leukemias
- Active Central Nervous System (CNS) disease
- Participants who have received a live/ attenuated vaccine within 30 days of first treatment. Any live vaccine (ex: varicella, zoster, yellow fever, rotavirus, oral polio and measles mumps, rubella (MMR) are strictly prohibited during and for a 100 days post last treatment.
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 |
|---|---|---|
| AG-120The IDH1 inhibitor ivosidenib (AG-120) that will be administered orally on a continuous basis at the dose of 500 mg/day starting at day 1 of each cycle. A cycle will be defined as a 28-day period. | Drug | Patients receiving nivolumab and ivosidenib |
| NivolumabOn Cycle 2 day 1 the patient will receive nivolumab 480mg once. This will be repeated on Day 1 of every subsequent cycle. | Drug | Patients receiving nivolumab and ivosidenib |
Primary outcome
Overall response rate
Time frame: 168 days
1) Overall response rate (ORR) of 60%, i.e., a 20% ORR improvement (historical control ORR = 40% with Ivosidenib[AG-120] monotherapy after 2 lines of therapy20) after 6 cycles of treatment based on MDS International Working Group 2006 criteria and AML MDS International Working group MDS/AML criteria33, 34Cumulative ORR will include complete remission (CR), morphologic complete remission with incomplete blood count recovery (CRi), CR with incomplete platelet recovery (CRp) and Partial response (PR).
Change in duration of response
Time frame: 12 months
2) In the patients who respond, Improvement in duration of response to 12 months (compared to single agent ivosidenib [AG-120] 8.2 months with ivosidenib [AG-120] monotherapy)
3 secondary outcomes
Overall survival rate
Time frame: Up to 4 years
Progression free survival rate
Time frame: Up to 4 years
Amount of Allogeneic hematopoietic stem cell transplant (HSCT) patients
Time frame: 2 years
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jan 2022.
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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.
Thomas Prebet, PhD, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AG-120 and Nivolumab in people with Myelodysplastic Syndromes and Acute Myeloid Leukemia, run by Yale University at 1 site in United States.
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 14 inclusion and 23 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: withdrawn, as of the sponsor's last update on 20 Jan 2022. 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 United States. 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 phase mean?
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 withdrawn before enrolling participants, so there are no results.
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: 168 days). The study lists 2 primary outcomes in all. 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 20 Jan 2022.