Clinical Trial: NCT02610777 - My Cancer Genome

NCT02610777

Description:

The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.

Related Conditions:

Acute Myeloid Leukemia

Recruiting Status:

Completed

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT02610777

Trial Eligibility

Document

Title

Brief Title: An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)
Official Title: A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Low-Blast Acute Myelogenous Leukemia

Clinical Trial IDs

ORG STUDY ID: Pevonedistat-2001
SECONDARY ID: U1111-1169-6540
SECONDARY ID: 2015-000221-37
SECONDARY ID: REec-2016-2145
SECONDARY ID: Pevonedistat-2001CTID
NCT ID: NCT02610777

Conditions

Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Acute

Interventions

Drug	Synonyms	Arms
Azacitidine		Azacitidine
Pevonedistat		Azacitidine + Pevonedistat

Purpose

The purpose of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.

Detailed Description

      The drug being tested in this study is called pevonedistat. Pevonedistat is being tested to
      treat people with MDS or CMML, or low-blast AML as a combination treatment with azacitidine.
      This study will look at the overall survival, event free survival and response to treatment
      in people who take pevonedistat and azacitidine when compared to people who take single-agent
      azacitidine.

      The study will enroll 120 participants. Once enrolled, participants will be randomly assigned
      (by chance, like flipping a coin) to one of the two treatment groups in 28-day treatment
      cycles:

        -  Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination

        -  Single-agent azacitidine 75 mg/m^2

      All participants will receive azacitidine via intravenous or subcutaneous route. Participants
      randomized to the combination arm will also receive pevonedistat intravenous infusion.

      This multi-center trial will be conducted worldwide. The overall time to participate in this
      study is approximately 44 months. Participants will attend the end-of-treatment visit 30 days
      after the last dose of study drug or before the start of subsequent anti-neoplastic therapy
      if that occurs sooner. Participants will enter event-free survival follow-up or response
      follow-up (study visits every 3 months) if their disease has not transformed to AML (for
      participants with HR MDS or CMML) or progressed (for participants with low-blast AML), and
      they have not started subsequent therapy. Participants will also enter overall survival
      follow-up (contacted every 3 months to document subsequent therapies and survival status).

Trial Arms

Name	Type	Description	Interventions
Azacitidine	Active Comparator	Azacitidine 75 milligram per square meter (mg/m^2), intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 in 28-day treatment cycles.	Azacitidine
Azacitidine + Pevonedistat	Experimental	Azacitidine 75 mg/m^2, intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2, 60-minute (+ or - 10) infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles.	Azacitidine Pevonedistat

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female participants 18 years or older.

          2. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with
             white blood cells [WBC] <20,000 per microliter [/mcL]) or low blast AML based on 1 of
             the following:

             French American British (FAB) Classifications:

               -  Refractory anemia with excess blasts (RAEB) - defined as having 5% to 20%
                  myeloblasts in the bone marrow.

               -  CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in
                  the blood.

             OR

             WHO Classifications:

               -  RAEB 1 - defined as having 5% to 9% myeloblasts in the bone marrow.

               -  RAEB 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to
                  19% blasts in the blood.

               -  CMML 2 - defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to
                  19% blasts in the blood.

               -  CMML 1 (Although CMML 1 is defined as having <10% myeloblasts in the bone marrow
                  and/or <5% blasts in the blood, these participants may enroll only if bone marrow
                  blasts >=5%.

               -  WHO defined AML with 20% to 30% myeloblasts in the bone marrow and <30%
                  myeloblasts in peripheral blood who are deemed by the investigator to be
                  appropriate for azacitidine based therapy.

          3. For MDS and CMML participants, prognostic risk category, based on the Revised
             International Prognostic Scoring System (IPSS R), of:

               -  Very high (>6 points),

               -  High (>4.5 to 6 points), or

               -  Intermediate (>3 to 4.5 points): a participant determined to be in the
                  Intermediate Prognostic Risk Category is only allowable in the setting of >=5%
                  bone marrow myeloblasts.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

          5. Clinical laboratory values within the following parameters (repeat within 3 days
             before the first dose of study drug if laboratory values used for randomization were
             obtained more than 3 days before the first dose of study drug):

               -  Albumin >2.7 g/dL.

               -  Total bilirubin <upper limit of normal (ULN) except in participants with
                  Gilbert's syndrome. Participants with Gilbert's syndrome may enroll if direct
                  bilirubin <=1.5*ULN of the direct bilirubin.

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5*ULN.

               -  Creatinine clearance >=50 milliliter per minutes (mL/min).

               -  Hb >8 g/dL. Participants may be transfused to achieve this value. Elevated
                  indirect bilirubin due to post transfusion hemolysis is allowed.

          6. For CMML participants: WBC count <20,000/mcL before administration of the first dose
             of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at
             least 1 week prior to WBC count assessment.

          7. Ability to undergo the study required bone marrow sample collection procedures.

          8. Suitable venous access for the study required blood sampling (that is, including
             pharmacokinetic (PK) and biomarker sampling).

          9. Female participants who:

               -  Are postmenopausal for at least 1 year before the Screening visit , or

               -  Are surgically sterile, or

               -  If they are of childbearing potential, agree to practice 1 highly effective
                  method and 1 additional effective (barrier) method of contraception at the same
                  time, from the time of signing the informed consent through 4 months after the
                  last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [example, calendar,
                  ovulation, symptothermal, postovulation methods] withdrawal, spermicides only,
                  and lactational amenorrhea are not acceptable methods of contraception. Female
                  and male condoms should not be used together).

             Male participants, even if surgically sterilized (that is, status postvasectomy), who:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 4 months after the last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [example, calendar,
                  ovulation, symptothermal, postovulation methods for the female partner]
                  withdrawal, spermicides only, and lactational amenorrhea are not acceptable
                  methods of contraception. Female and male condoms should not be used together).

         10. Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the participant at any time without prejudice to future medical care.

        Exclusion Criteria:

          1. Previous treatment with decitabine or azacitidine or other hypomethylating agent.

          2. Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow,
             by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone
             marrow, or by other accepted analysis.

          3. Eligible for allogenic stem cell transplantation.

          4. Participants with MDS, CMML, or low blast AML, whose only site of disease is
             extramedullary, example, the skin.

          5. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of study procedures or could limit
             participant expected survival to less than 6 months.

          6. Treatment with any anti leukemic/anti MDS therapies (example, lenalidomide,
             cytarabine, anthracyclines, purine analogs) or with any investigational products
             within 14 days before the first dose of any study drug.

          7. Known hypersensitivity to mannitol.

          8. Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
             meningitis, or septicemia.

          9. Major surgery within 14 days before first dose or a scheduled surgery during study
             period; insertion of a venous access device (example, catheter, port) is not
             considered major surgery.

         10. Diagnosed or treated for another malignancy within 2 years before randomization or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type
             are not excluded if they have undergone resection.

         11. Life threatening illness unrelated to cancer.

         12. Prothrombin time (PT) or prolongation of the activated thromboplastin time (aPTT) >1.5
             ULN or active uncontrolled coagulopathy or bleeding disorder.

         13. Known human immunodeficiency virus (HIV) seropositive.

         14. Known hepatitis B surface antigen seropositive, or known or suspected active hepatitis
             C infection. Note: Participants who have isolated positive hepatitis B core antibody
             (that is, in the setting of negative hepatitis B surface antigen and negative
             hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

         15. Known hepatic cirrhosis or severe pre-existing hepatic impairment.

         16. Known cardiopulmonary disease defined as unstable angina, clinically significant
             arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or
             IV) and/or myocardial infarction within 6 months prior to first dose, or severe
             pulmonary hypertension. As an example, well controlled atrial fibrillation would not
             be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.

         17. Treatment with strong cytochrome P450 (CYP) 3A inhibitors or inducers within 14 days
             before the first dose of study drug.

         18. Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
             12 months before the first dose of any study drug, except for hydroxyurea.

         19. Female participants who are lactating and breast feeding or have a positive serum
             pregnancy test during the Screening period or a positive urine pregnancy test on Day 1
             before first dose of study drug.

         20. Female participants who intend to donate eggs (ova) during the course of this study or
             4 months after receiving their last dose of study drug(s).

         21. Male participants who intend to donate sperm during the course of this study or 4
             months after receiving their last dose of study drug(s).

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Overall Survival (OS)
Time Frame:	From date of randomization until death (up to 3 years and 5 months)
Safety Issue:
Description:	OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive.

Secondary Outcome Measures

Measure:	Event-Free Survival (EFS)
Time Frame:	From date of randomization until transformation to AML, or death due to any cause (up to 5 years and 9 months)
Safety Issue:
Description:	EFS is defined as the time from the date of randomization to the date of the occurrence of an event. An event is defined as death or transformation to AML for HR MDS/CMML participants, whichever occurs first, or defined as death for low-blast AML participants. HR MDS/CMML participants without documented EFS event will be censored at the date of the last response assessment. HR MDS/CMML participants with no response assessment and no death will be censored at the date of randomization. Low-blast AML participants without documentation of death will be censored at the date the participant was last known to be alive. HR MDS/CMML participants who received alternative antineoplastic therapy before death or transformation to AML will be censored at the date of last adequate assessment prior to starting alternate antineoplastic therapy. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Six-month Survival Rate
Time Frame:	Month 6
Safety Issue:
Description:	Six-month survival rate (at 6 months) was defined as the Kaplan-Meier estimate of survival rate at 6 months. OS was defined as the time from the date of randomization to the date of death due to any cause. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	One-year Survival Rate
Time Frame:	Month 12
Safety Issue:
Description:	One-year survival rate (at 12 months) was defined as the Kaplan-Meier estimate of survival rate at 12 months. OS was defined as the time from the date of randomization to the date of death due to any cause. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Time to AML Transformation in HR MDS or CMML Participants
Time Frame:	From date of randomization until transformation to AML (up to 5 years and 9 months)
Safety Issue:
Description:	Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants who died before progression to AML will be censored. Transformation to AML is defined, according to World Health Organization (WHO) classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With Complete Remission (CR)
Time Frame:	From date of randomization until CR (up to 5 years and 9 months)
Safety Issue:
Description:	Disease responses for HR MDS or CMML is based on the modified International Working Group (IWG) response criteria for MDS and for low-blast AML on the revised IWG response criteria for AML. CR for HR MDS or CMML: less than or equal to (<=) 5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to (>=) 11 gram/deciliter (g/dL) hemoglobin (Hb), >=10010^9/liter (/L) platelets (plt), >=1.010^9/L absolute neutrophil count (ANC) and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.010^9/L and plt of >=1.010^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.010^9/L) or thrombocytopenia (TTP) (<10010^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With CR and Partial Remission (PR)
Time Frame:	From date of randomization until CR and PR (up to 5 years and 9 months)
Safety Issue:
Description:	Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow ,>=11 g/dL Hb;>=10010^9/L plt; >=1.010^9/L ANC and 0% blasts in peripheral blood. PR for HR MDS/CMML:considered achieved if all CR criteria is met except for bone marrow blasts decreased by >=50%over pretreatment but still >5%. CR for low-blast AML: morphologic leukemia-free state, ANC of >1.010^9/L and plt of >=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML:fulfill all criteria for CR except for residual neutropenia (<10010^9/L)/TTP(<10010^9/L). PR for low-blast AML:all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With Overall Response
Time Frame:	From date of randomization until CR, PR, or hematologic improvement (HI) (up to 5 years and 9 months)
Safety Issue:
Description:	Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=10010^9/L plt,>=1.010^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=3010^9/L if baseline>2010^9/L/Inc. from <2010^9/L->2010^9/L, ANC inc. by 100%;absolute inc. of>0.510^9/L if baseline<10010^9/L. LB AML-CR:morphologic leukemia-freestate>1.010^9ANC,>=10010^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.010^9/L/TTP<10010^9/L;PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With CR in Low-blast AML
Time Frame:	From date of randomization until CR (up to 5 years and 9 months)
Safety Issue:
Description:	Disease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.010^9/L and plt of >=1.010^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.010^9/L) or thrombocytopenia (TTP) (<10010^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With CR by Cycle 4
Time Frame:	From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)
Safety Issue:
Description:	Disease responses for HR MDS or CMML were based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=10010^9/L plt, ANC >=1.010^9/L and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.010^9/L and plt of >=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.010^9/L)/TTP (<10010^9/L).Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With CR and PR by Cycle 4
Time Frame:	From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)
Safety Issue:
Description:	Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, >=11 g/dL Hb; >=10010^9/L plt; >=1.010^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML: considered achieved if all CR criteria is met except for bone marrow blasts decreased by>=50% over pretreatment but still>5%.CR for low-blast AML: morphologic leukemia-free state, ANC of>1.010^9/L and plt of>=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: fulfill all criteria for CR except for residual neutropenia (<10010^9/L)/TTP (<10010^9/L). PR for low-blast AML: all hematological values for CR but with decrease of >=50% in percentage of blasts to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With Overall Response by Cycle 4
Time Frame:	From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)
Safety Issue:
Description:	Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of bone marrow (BM) cell lines,>=11g/dL Hb,>=10010^9/L plt,>=1.010^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts>=50%less over pretreatment but still>5%; HI:hb increase (inc)>=1.5g/dL if baseline<11g/dL;plt inc>=3010^9/L if baseline>2010^9/L/Inc. from <2010^9/L->2010^9/L, ANC inc. by 100%;absolute inc. of>0.510^9/L if baseline<10010^9/L. LB AML-CR:morphologic leukemia-freestate>1.010^9ANC,>=10010^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.010^9/L/TTP<10010^9/L;PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With CR in Low-blast AML by Cycle 4
Time Frame:	From the date of randomization until CR by Cycle 4 (cycle length=28 days)
Safety Issue:
Description:	Disease response for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.010^9/L and ptl of >=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.010^9/L)/TTP (<10010^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Duration of CR
Time Frame:	From date of randomization until CR (up to 5 years and 9 months)
Safety Issue:
Description:	Duration of CR will be analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for HR MDS or CMML are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=10010^9/L plt, >=1.010^9/L ANC and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.010^9/L and plt of >=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.010^9/L)/TTP (<10010^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Duration of CR and PR
Time Frame:	From date of randomization until CR or PR (up to 5 years and 9 months)
Safety Issue:
Description:	Duration of CR and PR will be analyzed by standard survival analysis techniques based on Kaplan Meier estimates. Disease responses (HR MDS/CMML) are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. For HR MDS/CMML-CR:<=5%myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=10010^9/L plt,>=1.010^9/L neutrophils, 0% blasts in peripheral blood;PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still >5%; low-blast AML-CR: morphologic leukemia-free state, >1.010^9/L ANC ,plt >=10010^9/L,transfusion independence, no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia <1.010^9/L/TTP <10010^9/L;PR:all CR hematological values but with a decrease of >=50% in blasts percentage to 5%-25% in bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Duration of Overall Response
Time Frame:	From date of randomization until CR, PR or HI (up to 5 years and 9 months)
Safety Issue:
Description:	Disease responses(HR MDS/CMML): modified IWG criteria for MDS;low-blast(LB)AML: revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+CR with incomplete blood count recovery(Cri)+PR.HR MDS/CMML-CR: <=5%myeloblasts with normal maturation of bone marrow (BM) cell lines, >=11g/dL Hb,>=10010^9/L plt, >=1.010^9/L ANC,0%blasts in peripheral blood; PR:CR criteria met except BM blasts >=50%less over pretreatment but still>5%; HI:hb increase(inc) >=1.5g/dL if baseline<11g/dL; plt inc>=3010^9/L if baseline >2010^9/L inc from<2010^9/L->2010^9/L,ANC inc by100%; absolute inc of >0.510^9/L if baseline <10010^9/L.LB AML-CR: morphologic leukemia-freestate >1.010^9 ANC, >=1001 ^9/Lplt, transfusion independence, no residual evidence of extramedullary leukemia; CRi:fulfill CR criteria except residual neutropenia<1.010^9/L/TTP<10010^9/L; PR:all CR hematological values but>=50%less in BM aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Duration of CR in Low-blast AML
Time Frame:	From date of randomization until CR (up to 5 years and 9 months)
Safety Issue:
Description:	Duration of CR was analyzed using standard survival analysis techniques based on Kaplan Meier estimates. Disease responses for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.010^9/L and plt of >=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.010^9/L)/TTP (<10010^9/L). Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Time to First CR or PR
Time Frame:	From date of randomization until CR or PR (up to 5 years and 9 months)
Safety Issue:
Description:	Time to first CR or PR: time from randomization to first documented CR or PR, whichever occurs first. Disease responses (HR MDS/CMML) based on modified IWG response criteria for MDS; low-blast AML on revised IWG response criteria for AML. HR MDS/CMML-CR: <=5% myeloblasts with normal maturation of all bone marrow cell lines, >=11 g/dL Hb, >=10010^9/L plt,>=1.010^9/L ANC, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts >=50% decrease over pretreatment but still >5%; For low-blast AML-CR: morphologic leukemia-free state, >1.010^9/L ANC, plt >=10010^9/L, transfusion independence, no residual evidence of extramedullary leukemia; CR with incomplete blood count recovery: fulfill CR criteria except residual neutropenia <1.010^9/L/TTP <10010^9/L; PR: all CR hematological values but with a decrease of >=50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate. Data will be reported after study completion (which is planned for 2022).

Measure:	Time to Subsequent Therapy
Time Frame:	From date of randomization up to 5 year 9 months
Safety Issue:
Description:	Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study will not be counted as receiving subsequent therapy. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence
Time Frame:	8 weeks before randomization through 30 days after last dose of any study drug (up to 5 years and 9 months)
Safety Issue:
Description:	A participant was defined as RBC or platelet-transfusion independent if he/she receives no RBC or platelet transfusions for a period of at least 8 weeks before randomization through 30 days after the last dose of any study drug. Rate of transfusion independence is defined as number of participants who become transfusion independent divided by the number of participants who are transfusion dependent at Baseline. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Percentage of Participants With at Least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
Time Frame:	From date of randomization until transformation to AML or until initiation of subsequent therapy (up to 5 years and 9 months)
Safety Issue:
Description:	Inpatient hospital admission data will be collected through transformation to AML (HR MDS/CMML participants) or disease progression (low-blast AML participants) or until initiation of subsequent therapy (all participants), whichever occurs first. Transformation to AML is defined, according to WHO Classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Time to Progressive Disease (PD), Relapse, or Death
Time Frame:	From date of randomization until PD, relapse or death (up to 5 years and 9 months)
Safety Issue:
Description:	Time from randomization until PD/transformation to AML/relapse/death due to any cause, whichever occurs first. Relapse after CR or PR in MDS/CMML: return to pretreatment bone marrow blast % or decrement of >=50% from maximum remission levels in ANC or plt, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence. PD: at least 50% decrement from maximum remission in ANC or plt, or reduction in Hb by>=2g/dL or transfusion dependence;participants with <5% blasts: >=50% increase (inc) in blasts to >5%; 5%-10%: >=50% inc to >10%; 10%-20%: >=50% inc to>20%;20%-30%:>=50% inc to >30%. Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy). If there are no circulating blasts, bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later. Data will be reported after study completion (which is planned for 2022).

Measure:	Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame:	From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)
Safety Issue:
Description:	Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Number of Participants With Markedly Abnormal Clinical Laboratory Values
Time Frame:	From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)
Safety Issue:
Description:	Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status
Time Frame:	From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)
Safety Issue:
Description:	Number of participants with change from Baseline in ECOG performance status was measured on 6 point scale to assess participant's performance status, where: Grade 0(Normal activity. Fully active, able to carry on all pre-disease activities without restriction); Grade 1(Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); Grade 2(In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours); Grade 3(In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours); Grade 4(100% bedridden. Completely disabled, cannot carry on any self-care, totally confined to bed or chair); Grade 5(Dead). Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) Values
Time Frame:	From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)
Safety Issue:
Description:	Data for this outcome measure will be reported after study completion (which is planned for 2022).

Measure:	Number of Participants With Clinically Significant Change From Baseline Values in Vital Signs
Time Frame:	From date of randomization up to 30 days after administration of the last dose of any study drug (up to 5 years and 9 months)
Safety Issue:
Description:	Data for this outcome measure will be reported after study completion (which is planned for 2022).

Details

Phase:	Phase 2
Primary Purpose:	Interventional
Overall Status:	Completed
Lead Sponsor:	Millennium Pharmaceuticals, Inc.

Trial Keywords

Drug Therapy

Last Updated

August 12, 2021

Clinical Trials /

An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)