Relapsed/Refractory Acute Myeloid LeukemiaPhase 2NCT02665143
A Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia
A Phase 2 study testing Nintedanib and AML induction in people with Relapsed/Refractory Acute Myeloid Leukemia, run by Yale University at 2 sites in United States.
Trial summary
The purpose of this study is to determine if a combination of nintedanib+ induction chemotherapy can be an effective strategy for patients where outcome of relapse/refractory acute myeloid leukemia (AML) is poor. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Relapsed/Refractory Acute Myeloid Leukemia
- What is being tested?
- Nintedanib and AML induction
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 2 sitesUnited States
- Study dates
- 21 Jul 2016to 30 Mar 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of AML according to WHO 2008 criteria. Therapy related AML may be included if off treatment for their prior malignancy for more than 2 years and in complete remission. AML arising after documented MPD is excluded.
- Patient must meet one of the following criteria: a/ patient refractory to one or two standard induction regimens b/ patients with a first untreated relapse within 2 years of documentation of complete remission. Patients relapsing after allogeneic stem cell transplantation are eligible if more than 6 months after transplantation and without signs of active GVHD.
- Patient may have been pre treated with intermediate to high dose cytarabine if the day of the last infusion was at least 90 days before the inclusion.
- ECOG performance status of 2 or less
- Patient is willing to participate to the study, has the ability to adhere to the study visit schedule and other protocol procedures, and has the ability to understand and sign an inform consent form.
- Women of childbearing potential must agree to use effective contraception without interruption throughout the study and for 3 months after the end of treatment;
- Men must agree to not conceive during the treatment and to use effective contraception during the treatment period (including periods of dose reduction or temporary suspension) and for 3 months after the end of treatment if their partner is of childbearing potential.
Who cannot join
- Patient with documented acute promyelocytic leukemia and/or PML-RAR transcript.
- Patient relapsing more than 2 years after initial remission.
- Use of any active treatment for relapse including but not restricted to chemotherapy, targeted agents, hypomethylating agents or investigational drugs. Use of hydroxyurea up to 6g per day for cytoreduction is allowed for a maximum of 30 days prior treatment.
- Patients with clinical evidence of active CNS disease at enrollment
- LVEF below 45% or lifetime exposure to anthracyclines over 350mg/m2 of daunorubicin equivalent
- Liver function tests: ASAT ALAT above 2.5 ULN, total bilirubin above 2.5 ULN in the absence of Hemolysis or diagnosis of Gilbert's syndrome
Show all 18Show fewer
- Serum creatinine above 2.0mg/dl
- Any sign of active uncontrolled disease including but not restricted to cardiac disease, infections, hepatitis. Any severe chronic disease potentially interfering with the protocol including HIV infection, active hepatitis B or C. It includes major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
- Documented platelet refractoriness
- Patient has a history of GI surgery, procedures or conditions that might interfere with the absorption or swallowing of the study drugs .
- Women who are or pregnant, or who are currently breastfeeding
- Prior treatment with nintedanib or any other VEGFR inhibitor
- Known hypersensitivity to nintedanib, any other trial drug, or their excipients
- Persistence of any clinically relevant (CTCAE grade 2 or above) non-hematological toxicities from previous AML therapy
- Active alcohol or drug abuse
- Any other condition that, according to the investigator, may forbid the administration of the idarubicin+cytarabine regimen
- Therapeutic anticoagulation with INR modifying drug of or use of antiplatelet therapy (with the exception of low dose aspirin<325mg/d)
- Any other malignancies requiring an active treatment within the past year other than basal cell skin cancer or carcinoma in situ of the cervix. Patients actively treated with hormonotherapy for prostate cancer or breast cancer are eligible.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Vanderbilt Ingram Cancer Center
Nashville, Tennessee, 37232
Yale University
New Haven, Connecticut, 06520
About this study
Official title: A Phase I-II Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia
The purpose of this study is to determine if a combination of nintedanib+ induction chemotherapy can be an effective strategy for patients where outcome of relapse/refractory acute myeloid leukemia (AML) is poor.
Read the detailed description
This study will conducted as a Phase 1/Phase 2 trial.
The primary objective of Phase 1 is to determine the safety and tolerability of a combination of Nintedanib + induction chemotherapy in patients with acute myeloid leukemia.
The primary objective of Phase 2 is to determine the efficacy (rate of CR/CRp/CRi) of Nintedanib+ induction vs Placebo+ induction.
The secondary objectives of this study include: determining the overall response rate according to IWG AML 2003 criteria, the toxicity profile and safety of the combination, the percentage of patients bridging to transplantation, the overall survival, leukemia free survival including analysis with censoring at HSCT and rates of haematological improvement according to IWG MDS 2006 criteria. In addition, exploratory correlative studies will be conducted.
- Being tested
- Nintedanib and AML induction
- Keywords
- acute myeloid leukemia
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nintedanib and AML inductionDrug
Also called Phase II Open Label
The AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. In the phase I part, all patients will receive the combination with Nintedanib 200mg bid begun at day 8 and continued until end of cycle. If a significant incidence of dose limiting toxicities is demonstrated, Nintedanib will be given at a lower dose level (150mg bid).
| Study group | Role | What they receive |
|---|---|---|
| Nintedanib and AML induction | Experimental | The AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. Based on the phase I dose, in the randomized phase II, the combination will be compared with chemotherapy+placebo. Nintedanib or placebo will be added at day 8 and continued until end of cycle . Receives: Drug: Nintedanib and AML induction |
What is being measured
The primary outcome is the main question the study is designed to answer.
Count of Patients With Treatment-Emergent Adverse Events (Phase 1)
In the Phase 1 portion of the study, safety will be assessed after the inclusion of the first 6 patients, to analyze tolerance and adverse events occurring during this trial and will decide on any action to be taken. Safety will be evaluated according to NCI CTCAE V4 criteria. TEAE's were considered adverse events that occurred within 60 days of treatment initiation. The title of this outcome measure was adjusted when results were entered.
Measured: 60 days
Complete Remission Rate (Phase 2)
In Phase 2, the primary endpoint of complete remission rate will be based on IWG 2003 AML response criteria.
This construct is an overall response composite and it will be assessed using the following metrics:
Morphologic complete remission (CR): ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% bone marrow blasts, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration).
Morphologic complete remission with incomplete blood count recovery (CRi): Same as CR but ANC may be < 1,000/mcl but >500 mcl and/or platelet count < 100,000/mcl but >20,000/mcl
Partial remission (PR): ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods.
Marrow Leukemia Free State: < 5% bone marrow blasts, no Auer rods, no extra medullary disease. No requirement on cytopenias.
Measured: Up to 2 years
Secondary outcomes (1)
Incidence of Hematological Improvement (Phase 2)
Evaluation of hematological improvement will be assessed based on IWG MDS 2006 criteria. Due to differing pretreatment conditions of participants, response to treatment in this construct will be assessed in the following manner:
Erythroid response (pretreatment <11 g/dL) : Hgb increase at least by 1.5 g/dL. Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk. Only RBC transfusions given for a Hgb of below or equal to 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation.
Platelet response (pretreatment 100x109/L): Absolute increase of at least 30x109/L for patients starting with more than 20x109/L platelets. Increase from less than 20x109/L to more than 20x109/L and by at least 100%.
Neutrophil response (pretreatment, <1.0x109/L) At least 100% increase and an absolute increase of at least 0.5x109/L.
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2016 (estimated)
- Study start21 Jul 2016
- Primary completion8 Mar 2021
- Study completion30 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Relapsed/Refractory Acute Myeloid LeukemiaStudies 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
- Masking
- None (open label)
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- Vanderbilt University
- Responsible party
- Sponsor
- Investigators
- Thomas Prebet, MD,PhD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02665143
- Sponsor's protocol ID
- 1507016193
- Status last verified
- Apr 2022
- First submitted
- 20 Jan 2016
- Last updated
- 8 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I-II Randomized Trial of a Combination of Nintedanib/Placebo in Combination With Induction Chemotherapy for Patients With Refractory or First Relapse Acute Myeloid Leukemia
- ClinicalTrials.gov ID
- NCT02665143
- Acronym / sponsor ID
- 1507016193
- Keywords
- acute myeloid leukemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- Vanderbilt University
- Study start
- 21 Jul 2016 (actual)
- Primary completion
- 8 Mar 2021 (actual)
- Study completion
- 30 Mar 2021 (actual)
- First posted
- 27 Jan 2016 (estimated)
- Results
- Posted 8 Apr 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine if a combination of nintedanib+ induction chemotherapy can be an effective strategy for patients where outcome of relapse/refractory acute myeloid leukemia (AML) is poor.
Detailed description
This study will conducted as a Phase 1/Phase 2 trial.
The primary objective of Phase 1 is to determine the safety and tolerability of a combination of Nintedanib + induction chemotherapy in patients with acute myeloid leukemia.
The primary objective of Phase 2 is to determine the efficacy (rate of CR/CRp/CRi) of Nintedanib+ induction vs Placebo+ induction.
The secondary objectives of this study include: determining the overall response rate according to IWG AML 2003 criteria, the toxicity profile and safety of the combination, the percentage of patients bridging to transplantation, the overall survival, leukemia free survival including analysis with censoring at HSCT and rates of haematological improvement according to IWG MDS 2006 criteria. In addition, exploratory correlative studies will be conducted.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nintedanib and AML induction | Experimental | Drug: Nintedanib and AML inductionThe AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. Based on the phase I dose, in the randomized phase II, the combination will be compared with chemotherapy+placebo. Nintedanib or placebo will be added at day 8 and continued until end of cycle . |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Diagnosis of AML according to WHO 2008 criteria. Therapy related AML may be included if off treatment for their prior malignancy for more than 2 years and in complete remission. AML arising after documented MPD is excluded.
- Patient must meet one of the following criteria: a/ patient refractory to one or two standard induction regimens b/ patients with a first untreated relapse within 2 years of documentation of complete remission. Patients relapsing after allogeneic stem cell transplantation are eligible if more than 6 months after transplantation and without signs of active GVHD.
- Patient may have been pre treated with intermediate to high dose cytarabine if the day of the last infusion was at least 90 days before the inclusion.
- ECOG performance status of 2 or less
- Patient is willing to participate to the study, has the ability to adhere to the study visit schedule and other protocol procedures, and has the ability to understand and sign an inform consent form.
Key exclusion criteria (18 listed)
- Patient with documented acute promyelocytic leukemia and/or PML-RAR transcript.
- Patient relapsing more than 2 years after initial remission.
- Use of any active treatment for relapse including but not restricted to chemotherapy, targeted agents, hypomethylating agents or investigational drugs. Use of hydroxyurea up to 6g per day for cytoreduction is allowed for a maximum of 30 days prior treatment.
- Patients with clinical evidence of active CNS disease at enrollment
- LVEF below 45% or lifetime exposure to anthracyclines over 350mg/m2 of daunorubicin equivalent
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 |
|---|---|---|
| Nintedanib and AML inductionAlso: Phase II Open LabelThe AML induction regimen combines Idarubicin 12mg/m2/d day 1 to 3 and Cytarabine 0.667g/m2/d CIV day 1 to 3. In the phase I part, all patients will receive the combination with Nintedanib 200mg bid begun at day 8 and continued until end of cycle. If a significant incidence of dose limiting toxicities is demonstrated, Nintedanib will be given at a lower dose level (150mg bid). | Drug | Nintedanib and AML induction |
Primary outcome
Count of Patients With Treatment-Emergent Adverse Events (Phase 1)
Time frame: 60 days
In the Phase 1 portion of the study, safety will be assessed after the inclusion of the first 6 patients, to analyze tolerance and adverse events occurring during this trial and will decide on any action to be taken. Safety will be evaluated according to NCI CTCAE V4 criteria. TEAE's were considered adverse events that occurred within 60 days of treatment initiation. The title of this outcome measure was adjusted when results were entered.
Complete Remission Rate (Phase 2)
Time frame: Up to 2 years
In Phase 2, the primary endpoint of complete remission rate will be based on IWG 2003 AML response criteria. This construct is an overall response composite and it will be assessed using the following metrics: Morphologic complete remission (CR): ANC ≥ 1,000/mcl, platelet count ≥ 100,000/mcl, < 5% bone marrow blasts, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). Morphologic complete remission with incomplete blood count recovery (CRi): Same as CR but ANC may be < 1,000/mcl but >500 mcl and/or platelet count < 100,000/mcl but >20,000/mcl Partial remission (PR): ANC ≥ 1,000/mcl, platelet count > 100,000/mcl, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts < 5% with persistent Auer rods. Marrow Leukemia Free State: < 5% bone marrow blasts, no Auer rods, no extra medullary disease. No requirement on cytopenias.
1 secondary outcome
Incidence of Hematological Improvement (Phase 2)
Time frame: Up to 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
Related trials for Relapsed/Refractory Acute Myeloid Leukemia
RecruitingPhase 1
A Study of CHM-029 in Participants With NPM1 Mutated, KMT2A or NUP98 Rearranged AML
AML (Acute Myeloid Leukemia)
Not yet recruitingPhase 1
A Study to Assess the Pharmacokinetics and Safety of Revumenib in Participants With Advanced Cancer and Hepatic or Renal Impairment
Relapsed/Refractory (R/R) Hematologic Malignancies, Acute Leukemia
Active, not recruitingPhase 3
Venetoclax in Children With Relapsed Acute Myeloid Leukemia (AML)
Acute Myeloid Leukemia
RecruitingPhase 1
First-in-human (FIH) Trial of GEN3018 in Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) or Higher-risk Myelodysplastic Syndrome (HR-MDS)
R/R AML, R/R HR-MDS
RecruitingPhase 2
Olutasidenib in Relapsed IDH1 Mutated AML Patients Who Have Previously Received Venetoclax
IDH1 Mutation, Relapsed / Refractory AML
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, MD,PhD principal investigator
Yale University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nintedanib and AML induction in people with Relapsed/Refractory Acute Myeloid Leukemia, run by Yale University at 2 sites 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 7 inclusion and 18 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: finished, as of the sponsor's last update on 8 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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?
Yes. Results are posted in the registry (first posted 8 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Count of Patients With Treatment-Emergent Adverse Events (Phase 1) (time frame: 60 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 8 Apr 2022.