IVOSIDENIB for Acute myeloid leukemia (AML) | IDH1-mutated AML | IDH2-mutated AML

Inclusion criteria

• {"criterion_text":"- 1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).\n- 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.\n- 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.\n- 4. Subject has newly diagnosed, primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapyrelated) AML according to the WHO classification (Appendix B) with ≥ 20% leukemic blasts in the bone marrow: a. Have an IDH1 or IDH2 gene mutation (R132, R140, or R172) - IDH mutational status will be assessed locally; for sites without local testing capabilities, a referral lab will be identified. b. By the investigator's assessment who are not candidates to receive intensive IC.\n- 5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D).\n- 6. Subject has adequate organ function defined as: - Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to leukemic organ involvement. - Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, ≤3 times the upper limit of normal for Gilbert's syndrome (eg, a gene mutation in UGT1A1), or leukemic organ involvement. - Serum creatinine < 2 x ULN or creatinine clearance > 30 mL/min based on the Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR): GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)\n- 7. Agree to serial bone marrow aspirate/biopsies.\n- 8. Females of childbearing potential (FCBP)* may participate, providing they meet the following conditions: - Agree to practice true abstinence ** from sexual intercourse or to use highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intrauterine device intrauterine hormone-releasing system; or male partner sterilization [note that a vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that a vasectomized partner has received medical assessment of the surgical success]) at screening and throughout the study, and for at least 4 months following the last study treatment; and - Have a negative serum β-subunit of human chorionic gonadotropin (βhCG) pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and - Have a negative serum or urine (investigator's discretion under local regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Period (note that the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Period if it is performed within the 72-hour timeframe).\n- 9. Male subjects must agree to practice true abstinence from sexual intercourse or agree to the use of highly effective contraceptive methods (as described above) with non-pregnant female partners of child bearing potential at screening and throughout the course of the study and should avoid conception with their partners during the course of the study and for at least 4 months following the last study treatment (6 months following last dose of azacitidine in Canada). Furthermore, the male subject must agree to use a condom while treated with azacitidine and for at least 4 months following the last azacitidine dose."}

Exclusion criteria

• {"criterion_text":"- 1. Subject is suspected or proven to have acute promyelocytic leukemia based onmorphology, immunophenotype, molecular assay, or karyotype (Appendix B).\n- 2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C).\n- 3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.\n- 4. Subject has received prior systemic anticancer therapy, HSCT, or radiotherapy for AML. Note: Hydroxyurea is allowed prior to enrollment for the control of peripheral leukemic blasts in subjects with leukocytosis. (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine). For subjects with secondary AML (eg, MDS or MPN) treatment for prior cancer is not exclusionary; full treatment information will be collected within the CRF. The use of all trans retinoic acid (ATRA) for suspected APL is not exclusionary provided it is discontinued prior to initiation of treatment in the protocol.\n- 5. Subject has received more than 1 cycle of prior treatment with azacitidine, or subject has received any prior treatment with decitabine for MDS.\n- 6. Subject has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening.\n- 7. Subject has immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.\n- 8. Subject has significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment.\n- 9. Subject has prior history of malignancy, other than MDS, MPN, or AML, unless the subject has been free of the disease for ≥ 1 year prior to the start of study treatment. However, subjects with the following history/concurrent conditions are allowed: -Basal or squamous cell carcinoma of the skin -Carcinoma in situ of the cervix -Carcinoma in situ of the breast -Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system)\n- 10. Subject is known seropositive for or has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis Bvirus (HBV) or hepatitis C virus (HCV)\n- 11. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally\n- 12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)\n- 13. Subject is taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment: phenytoin(CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2) (Appendix K).\n- 14. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive substrate rosuvastatin; subject should be excluded from the study unless he/she can be transferred to other medications at least 5 half-lives prior to the start of study treatment (Appendix L).\n- 15. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).\n- 16. Subject has known or suspected hypersensitivity to any of the components of study therapy.\n- 17. Subject is taking medications that are known to prolong the QT interval (Appendix M) unless he/she can be transferred to other medications within ≥ 5 halflives prior to the start of study treatment. (If equivalent medication is not available, QTc will be closely monitored as defined in Section 8.1.)\n- 18. Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome) at screening.\n- 19. Female subject who is pregnant or lactating.\n- 20. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.\n- 21. Subject has any condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he/she were to participate in the study.\n- 22. Subject has any condition that confounds the ability to interpret data from the study."}

Primary endpoints

• {"endpoint_text":"- Ph Ib Dose Finding and AG-120 Expansion: 1. Recommended Combination Dose - Review of dose-limiting toxicities (DLTs), safety, PK / pharmacodynamic, biomarker, and preliminary efficacy data by DRT.\n- 2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.\n- 3. Overall Response Rate (as assessed by the investigator)- Rate of CR + CRi + CRp + MLFS + PR according to modified IWG AML response criteria (Appendix F).","definition_or_measurement_approach":"1. Determination of Recommended Combination Dose based on review of DLTs, safety, PK/pharmacodynamic, biomarker, and preliminary efficacy data by the Dose Review Team (DRT). 2. Safety/tolerability measured by type, frequency, seriousness and severity of adverse events and their relationship to study treatment. 3. Overall Response Rate defined as rate of CR + CRi + CRp + MLFS + PR assessed by investigator according to modified IWG AML response criteria (Appendix F)."}

Secondary endpoints

• {"endpoint_text":"- Ph Ib Dose Finding and AG-120 Expansion: 1. Overall Response Rate (as assessed by the investigator) - Rate of CR + CRi + CRp + MLFS + PR according to modified IWG AML response criteria (Appendix F).\n- 2. Sponsor Derived CR and CRh - Rate of CR/ CRh and CR + CRh based on laboratory data\n- 3. Pharmacodynamics (Exploratory) - To evaluate the pharmacodynamics of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when administered in combination in this population.\n- 4. Event-Free Survival - Time from randomization to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death from any cause, whichever occurs first.\n- 5. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.\n- 6. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).\n- 7. Sponsor Derived CR - Rate of CR based on laboratory data\n- 8. Sponsor Derived CR and CRh - Rate of CR +CRh based on laboratory data\n- 9. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).\n- 10. Duration of Response - Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death due to any cause, whichever occurs first\n- 11. Time to response - Time from first dose of study drug to first documented CR/CRi/CRp/MLFS/PR according to modified IWG AML response criteria (Appendix F)\n- 12. Time to sponsored assessed CR and CRh - Time from first dose of study drug to first documented CR / CRh\n- 13. Duration of sponsor assessed CR and CRh - Time from the first documented CR/CRh to documented morphologic relapse, progression\n- 14. Overall Survival - Time from randomization to death due to any cause.\n- 15. One-year survival - The probability of survival at 1 year from randomization\n- 16. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.\n- 17. HRQoL outcomes - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) (Appendix N) and EuroQoL Group EQ-5D-5L instrument (Appendix O)\n- 18. Healthcare resource utilization (Exploratory) - Information about all resource use (eg, hospitalization)\n- 19. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization\n- 20. Pharmacodynamics (Exploratory) - Evaluation of 2-HG and α-KG levels in plasma and/or bone marrow. Evaluate methylation in PB and/or transcription in BM.\n- 21. Correlative studies (Exploratory) - Evaluation of molecular, cellular and metabolic markers which may be predictive of antitumor activity and/or resistance. Evaluation of minimal residual disease (MRD) by flow cytometry and by IDH2 variant allele fraction (VAF) in blood and bone marrow cells. Evaluation of changes in cellular differentiation and changes in histone and deoxyribonucleic acid (DNA) methylation profiles of IDH2 mutated leukemic cells.\n- 22. Correlative studies continuation - Evaluation of changes in cellular differentiation and changes in histone and DNA methylation profiles of IDH2 mutated leukemic cells.","definition_or_measurement_approach":"Endpoints use modified IWG AML response criteria (Appendix F) where specified for response endpoints. Safety/tolerability assessed by AE type/frequency/seriousness/severity and relationship to treatment. Event-free survival, duration of response, time to response and overall survival defined by time-to-event measures as specified. PK parameters measured by plasma concentrations. HRQoL measured by EORTC QLQ-C30 and EQ-5D-5L. Hematologic improvement per IWG MDS HI criteria (Appendix G). Correlative and pharmacodynamic studies measure 2-HG/α-KG, methylation, MRD by flow cytometry and IDH2 VAF as specified."}

France

Earliest CTIS Part Ii Submission Date

19-06-2024

Latest Decision Or Authorization Date

19-07-2024

Processing Time Days

30

Number Of Sites

2

Number Of Participants

21

Italy

Earliest CTIS Part Ii Submission Date

19-06-2024

Latest Decision Or Authorization Date

22-07-2024

Processing Time Days

33

Number Of Sites

2

Number Of Participants

29

Netherlands

Earliest CTIS Part Ii Submission Date

19-06-2024

Latest Decision Or Authorization Date

14-08-2024

Processing Time Days

56

Number Of Sites

1

Number Of Participants

5

Germany

Earliest CTIS Part Ii Submission Date

19-06-2024

Latest Decision Or Authorization Date

18-07-2024

Processing Time Days

29

Number Of Sites

2

Number Of Participants

15

Primary sponsor

Full Name

Celgene Corp.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development (Smolensk) LLC

Responsibilities

Codes: 11, 12, 15 (Monitoring), 6

Name

Endpoint Clinical Inc.

Responsibilities

IVRS30 – treatment randomisation

Third parties

• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"sponsorDuties codes: 7","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"University Of Rochester","duties_or_roles":"Routine clinical pathology testing","organisation_type":"Educational Institution"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"IVRS30 – treatment randomisation","organisation_type":"Pharmaceutical company"}
• {"country":"Russian Federation","full_name":"PPD Development (Smolensk) LLC","duties_or_roles":"Codes: 11, 12, 15 (Monitoring), 6","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Quest Diagnostics Nichols Institute Inc.","duties_or_roles":"Routine clinical pathology testing, Clinical chemistry, Clinical microbiology","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Medical Research Council (MRC)","duties_or_roles":"Routine clinical pathology testing","organisation_type":"Health care"}