Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations

Sponsor

Eli Lilly and Company (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04603001

Collaborator

Loxo Oncology, Inc. (Industry)

260

Enrollment

Locations

Arms

26.9

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, multi-center Phase 1 study of LY3410738, an oral, covalent IDH inhibitor, in patients with IDH1 and/or IDH2-mutant advanced hematologic malignancies who may have received standard therapy

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS) Chronic Myelomonocytic Leukemia (CMML) Myeloproliferative Neoplasms (MPNs)	Drug: LY3410738 Drug: Venetoclax Drug: Azacitidine	Phase 1

Detailed Description

This study includes 2 parts: dose escalation and dose expansion. The dose escalation will enroll eligible patients with select IDH-mutant advanced hematologic malignancies. Once the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of LY3410738 is established, the dose expansion will begin and enroll into 5 cohorts to further evaluate safety and clinical activity

Study Design

Study Type:

Interventional

Anticipated Enrollment :

260 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations

Actual Study Start Date :

Dec 1, 2020

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation Arm A (Monotherapy) Patients not requiring a strong CYP3A4 inhibitor.	Drug: LY3410738 Oral LY3410738
Experimental: Dose Escalation Arm B (Monotherapy) Patients requiring a strong CYP3A4 inhibitor for active management or prevention of a lifethreatening condition, such as an azole administered to prevent invasive fungal infection.	Drug: LY3410738 Oral LY3410738
Experimental: Dose Escalation Arm C - US Only (LY3410738, Venetoclax, and Azacitidine) Patients with no prior venetoclax therapy and not requiring a strong CYP3A4 inhibitor for anti-fungal prophylaxis or active treatment within 7 days of starting LY3410738.	Drug: LY3410738 Oral LY3410738 Drug: Venetoclax Oral venetoclax Drug: Azacitidine Subcutaneous or intravenous azacitidine
Experimental: Cohort 1 Patients with R/R AML harboring an IDH1 R132 mutation who have received a prior IDH inhibitor.	Drug: LY3410738 Oral LY3410738
Experimental: Cohort 2 Patients with R/R AML harboring an IDH1 R132 mutation who have not received a prior IDH inhibitor.	Drug: LY3410738 Oral LY3410738
Experimental: Cohort 3 Patients with R/R MDS, chronic myelomonocytic leukemia (CMML) or other advanced hematologic malignancy harboring an IDH1 R132 mutation.	Drug: LY3410738 Oral LY3410738
Experimental: Cohort 4 Patients with R/R AML, MDS, CMML or other advanced hematologic malignancy harboring IDH2 mutations.	Drug: LY3410738 Oral LY3410738
Experimental: Cohort 5 - US Only Patients with newly diagnosed AML, R/R AML, or other advanced hematologic malignancy harboring IDH1 and/or IDH2 mutations with no prior venetoclax therapy. Strong CYP3A4 inhibitor for anti-fungal prophylaxis allowed but not required.	Drug: LY3410738 Oral LY3410738 Drug: Venetoclax Oral venetoclax Drug: Azacitidine Subcutaneous or intravenous azacitidine

Outcome Measures

Primary Outcome Measures

To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) [Up to 30 months]
For Dose Escalation
To assess the activity of LY3410738 as measured by the overall response rate (ORR) per the investigator assessment [Up to 30 months]
For Dose Expansion

Secondary Outcome Measures

To determine the safety profile and tolerability of LY3410738 including acute and chronic toxicities by collecting and evaluating adverse events and treatment emergent adverse events [Up to 30 months]
For Dose Escalation
To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points [Up to 30 months]
For Dose Escalation
To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma [Up to 30 months]
For Dose Escalation
To assess the activity of LY3410738 as measured by the overall response rate (ORR) per investigator assessment [Up to 30 months]
For Dose Escalation
To assess the activity of LY3410738 as measured by Best Overall Response per investigator assessment [Up to 30 months]
For Dose Expansion
To assess the activity of LY3410738 by Complete Response Rate plus partial hematologic recovery (AML patients) [Up to 30 months]
For Dose Expansion
To assess the activity of LY3410738 by Duration of Response [Up to 30 months]
For Dose Expansion
To assess the activity of LY3410738 by Hematologic improvement in patients with MDS [Up to 30 months]
For Dose Expansion
To determine the safety profile and tolerability of LY3410738 including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events [Up to 30 months]
For Dose Expansion
To characterize the pharmacokinetics (PK) properties of LY3410738 by collecting and evaluating serum at protocol specified time points [Up to 30 months]
For Dose Expansion
To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma. [Up to 30 months]
For Dose Expansion

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Advanced IDH mutant hematologic malignancy including:

-- For Dose Escalation Arm C and Dose Expansion Cohort 5: Patients with newly diagnosed AML who are 75 years or older or have comorbidities that preclude the use of intensive chemotherapy, as well as patients with R/R AML, and/or other advanced hematologic malignancies, harboring IDH1/IDH2 mutations

Patients must have received prior therapy
Blasts at least 5% in bone marrow.
Patients must have a qualifying IDH1 R132, IDH2 R140 or IDH2 R172 mutation
Eastern Cooperative Oncology Group (ECOG) 0-2
Adequate organ function
Ability to swallow capsules or tablets
Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.

Exclusion Criteria:

Investigational agent or anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter; or investigational monoclonal antibody within 4 weeks prior to planned start of LY3410738
For Dose Escalation Arm C and Dose Expansion Cohort 5:
Prior venetoclax treatment is not allowed.
Patients are allowed to receive up to 1 cycle of single agent azacitidine or azacitidine plus venetoclax while waiting for results of locally obtained molecular profiling, including IDH1/IDH2 mutational status, prior to starting on study.
Major surgery within 4 weeks prior to planned start of LY3410738.
Active, uncontrolled clinically significant systemic bacterial, viral, fungal or parasitic infection or an unexplained fever > 38.5ºC during screening or on the first day of study drug administration.
Another concurrent malignancy requiring active therapy.
Active central nervous system involvement
Any unresolved toxicities from prior therapy greater than CTCAE v5.0 Grade 2 at the time of starting study treatment except for alopecia.
History of hematopoietic stem cell transplant (HSCT) or CAR-T therapy within 60 days of the first dose of LY3410738
Clinically significant cardiovascular disease
Active hepatitis B virus (HBV)
Active hepatitis C virus (HCV)
Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the study drug
Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or P-gp inhibitor, with the exception of patients being treated with allowed antifungal inhibitors of CYP3A4
Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738
Any serious underlying medical or psychiatric condition (e.g. alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to understand informed consent or that in the opinion of the investigator would contraindicate the patient's participation in the study or confound the results of the study
Known human immunodeficiency virus (HIV), excluded due to potential drug-drug interactions between anti-retroviral medications and LY3410738
Pregnancy, lactation or plan to breastfeeding during the study or within 90 days of the last dose of study intervention
Known hypersensitivity to any of the components of LY3410738 or its formulation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	UCLA Medical Center	Los Angeles	California	United States	90095
3	University of California, Davis - Health Systems	Sacramento	California	United States	95817
4	H Lee Moffitt Cancer Center	Tampa	Florida	United States	33612-9497
5	Northwestern University	Chicago	Illinois	United States	60611
6	University of Chicago Hospital	Chicago	Illinois	United States	60637
7	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
8	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0002
9	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
10	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27514
11	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
12	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
13	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
14	The Alfred Hospital	Melbourne	Victoria	Australia	3004
15	Linear Clinical Research Limited	Nedlands	Western Australia	Australia	6009
16	Cliniques universitaires Saint-Luc	Brussels		Belgium	1200
17	BC Cancer Vancouver	Vancouver	British Columbia	Canada	V5Z 4E6
18	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G2M9
19	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
20	Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus)	Helsinki		Finland	00290
21	Institut Paoli-Calmettes	Marseille		France	13273
22	Hopital Saint Louis	Paris		France	75010
23	Centre hospitalier universitaire de Haut Leveque	Pessac Cedex		France	33604
24	Centre Hospitalier Lyon Sud	Pierre Benite Cedex		France	69495
25	Institut Claudius Regaud	Toulouse cedex 9		France	31059
26	Medizinische Hochschule Hanover	Hannover	Niedersachsen	Germany	30625
27	Rambam Medical Center	Haifa		Israel	3109601
28	Asan Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	05505
29	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	06351
30	Seoul National University Hospital	Seoul		Korea, Republic of	03080
31	National University Cancer Institute	Singapore		Singapore	119228
32	Singapore General Hospital	Singapore		Singapore	169608
33	Clinico Y Provincial Barcelona	Barcelona		Spain	8036
34	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain	28040
35	Hospital Universitario La Fe de Valencia	Valencia		Spain	46026
36	China Medical University Hospital	Taichung City		Taiwan	40447
37	National Taiwan University Hospital	Taipei		Taiwan	10002