2024-511722-31-00
Active, not recruiting
Phase 1/2
A Phase 1b/2 Open-Label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy
Overview
- Phase
- Phase 1/2
- Status
- Active, not recruiting
- Sponsor
- Celgene Corp.
- Enrollment
- 70
- Locations
- 7
- Primary Endpoint
- 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.
Overview
Brief Summary
Ph Ib Dose Finding Stage: - To assess the safety and tolerability of the combination treatments of oral AG-120 when administered with subcutaneous (SC) azacitidine and oral AG-221 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
- To establish the recommended combination dose (RCD) of oral AG-120 and oral AG-221 when administered with SC azacitidine. Ph Ib AG-120 Expansion Stage:- To assess the safety and tolerability of the combination treatments of oral AG-120 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 mutation who are not candidates to receive intensive IC. Ph II AG-221 Randomized Stage: - To assess the efficacy of oral AG-221 when administered with SC azacitidine versus SC azacitidine alone in subjects with newly diagnosed AML with an IDH2 mutation, who are not candidates to receive intensive IC.
Eligibility Criteria
- Ages
- 18 years to 65+ years (65+ Years, 18-64 Years)
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
- •Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
- •Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
- •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.
- •Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D).
- •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)
- •Agree to serial bone marrow aspirate/biopsies.
- •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).
- •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
- •Subject is suspected or proven to have acute promyelocytic leukemia based onmorphology, immunophenotype, molecular assay, or karyotype (Appendix B).
- •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)
- •Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
- •Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
- •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).
- •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).
- •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).
- •Subject has known or suspected hypersensitivity to any of the components of study therapy.
- •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.)
- •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.
Outcomes
Primary Outcomes
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.
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.
2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
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).
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).
Secondary Outcomes
- 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).
- 2. Sponsor Derived CR and CRh - Rate of CR/ CRh and CR + CRh based on laboratory data
- 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.
- 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.
- 5. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
- 6. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).
- 7. Sponsor Derived CR - Rate of CR based on laboratory data
- 8. Sponsor Derived CR and CRh - Rate of CR +CRh based on laboratory data
- 9. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).
- 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
- 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)
- 12. Time to sponsored assessed CR and CRh - Time from first dose of study drug to first documented CR / CRh
- 13. Duration of sponsor assessed CR and CRh - Time from the first documented CR/CRh to documented morphologic relapse, progression
- 14. Overall Survival - Time from randomization to death due to any cause.
- 15. One-year survival - The probability of survival at 1 year from randomization
- 16. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.
- 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)
- 18. Healthcare resource utilization (Exploratory) - Information about all resource use (eg, hospitalization)
- 19. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization
- 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.
- 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.
Investigators
GSM-CT
Scientific
Celgene Corp.
Study Sites (7)
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