A clinical trial to evaluate the safety and effectiveness of a combination of either AG-12or AG-221 tablets with azacitidine injections in patients withnewly diagnosed Acute Myeloid Leukemia (AML) and who have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH 1 or IDH2) and are not candidates to receive intensive induction chemotherapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celgene Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

29 Nov 2016 → ongoing

Decision date (initial)

2024-07-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Celgene Corporation

External identifiers

EU CT number

2024-511722-31-00

EudraCT number

2015-003951-23

ClinicalTrials.gov

NCT02677922

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenomic, Efficacy, Pharmacokinetic, Safety, Dose response, Pharmacogenetic, Pharmacodynamic

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.

Secondary objectives 1

1. Ph Ib Dose Finding Stage: - To assess the preliminary efficacy of the combination treatments of oral AG-120 when administered with 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. Ph Ib AG-120 Expansion Stage: - To assess the preliminary efficacy 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 evaluate the safety of oral AG-221 when administered with SC azacitidine. - To characterize the PK of oral AG-221 when administered with SC azacitidine. - To evaluate the effect of oral AG-221 when administered with SC azacitidine versus SC azacitidine alone on health-related quality-of-life (HRQoL) outcomes.

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

BMS will provide access to individual anonymised participant data upon request from qualified researchers, and subject to certain criteria. Additional information regarding Bristol Myer Squibb’s dad shring policy and process can be found at: Research and clinical trial disclosure commitment - Bristol Myers Squibb (bms.com)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. 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.
5. 5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D).
6. 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)
7. 7. Agree to serial bone marrow aspirate/biopsies.
8. 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).
9. 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 22

1. 1. Subject is suspected or proven to have acute promyelocytic leukemia based onmorphology, immunophenotype, molecular assay, or karyotype (Appendix B).
2. 2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C).
3. 3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.
4. 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.
5. 5. Subject has received more than 1 cycle of prior treatment with azacitidine, or subject has received any prior treatment with decitabine for MDS.
6. 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.
7. 7. Subject has immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
8. 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.
9. 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)
10. 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)
11. 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
12. 12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
13. 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).
14. 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).
15. 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).
16. 16. Subject has known or suspected hypersensitivity to any of the components of study therapy.
17. 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.)
18. 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.
19. 19. Female subject who is pregnant or lactating.
20. 20. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
21. 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.
22. 22. Subject has any condition that confounds the ability to interpret data from the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 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. 2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
3. 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 endpoints 22

1. 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. 2. Sponsor Derived CR and CRh - Rate of CR/ CRh and CR + CRh based on laboratory data
3. 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. 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. 5. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
6. 6. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).
7. 7. Sponsor Derived CR - Rate of CR based on laboratory data
8. 8. Sponsor Derived CR and CRh - Rate of CR +CRh based on laboratory data
9. 9. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).
10. 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. 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. 12. Time to sponsored assessed CR and CRh - Time from first dose of study drug to first documented CR / CRh
13. 13. Duration of sponsor assessed CR and CRh - Time from the first documented CR/CRh to documented morphologic relapse, progression
14. 14. Overall Survival - Time from randomization to death due to any cause.
15. 15. One-year survival - The probability of survival at 1 year from randomization
16. 16. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.
17. 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. 18. Healthcare resource utilization (Exploratory) - Information about all resource use (eg, hospitalization)
19. 19. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization
20. 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. 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.
22. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celgene Corp.

Sponsor organisation

Celgene Corp.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543-4000

Country

United States

Scientific contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Public contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Third parties 6

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications