Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations

Sponsor

Eli Lilly and Company (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04521686

Collaborator

Loxo Oncology, Inc. (Industry)

200

Enrollment

Locations

Arms

34.5

Anticipated Duration (Months)

5.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, multicenter Phase 1 study to evaluate safety, tolerability and preliminary efficacy of oral LY3410738 in patients with isocitrate dehydrogenase 1 (IDH1) arginine 132 (R132)-mutant advanced solid tumors, including but not limited to cholangiocarcinoma, chondrosarcoma, and glioma or isocitrate dehydrogenase 2 (IDH2) arginine 140 (R140) or arginine 172 (R172) mutant cholangiocarcinoma.

Condition or Disease	Intervention/Treatment	Phase
Cholangiocarcinoma Chondrosarcoma Glioma Any Solid Tumor	Drug: LY3410738 Drug: Gemcitabine Drug: Cisplatin Drug: Durvalumab	Phase 1

Detailed Description

This is an open-label, multicenter Phase 1 study to evaluate safety, tolerability and preliminary efficacy of oral LY3410738 in patients with IDH1 R132-mutant advanced solid tumors, including but not limited to cholangiocarcinoma, chondrosarcoma, and glioma or IDH2 R140 or R172 mutant cholangiocarcinoma.

This study includes 2 parts: Phase 1 dose escalation and Phase 1 dose expansion. The Phase 1 dose escalation monotherapy cohort will enroll any eligible patient with IDH1 R132-mutant advanced solid tumor or IDH1 or IDH2 mutant cholangiocarcinoma. The Phase 1 dose expansion will include 5 cohorts to further evaluate safety and clinical activity. Three cohorts will be administered LY3410738 monotherapy. The fourth cohort will administer LY3410738 at or below the monotherapy RP2D in combination with gemcitabine and cisplatin. The fifth cohort (US only) will administer LY3410738 at or below the monotherapy RP2D in combination with durvalumab.

IDH1 R132, IDH2 R140, or IDH2 R172 mutations will be identified through genomic testing utilizing material collected prior to patient consent. Molecular assays utilized for enrollment are required to be performed in CLIA, ISO/IEC, CAP, or other similarly certified laboratory. Enrollment of patients with cholangiocarcinoma, chondrosarcoma or glioma may be made based on molecular tests performed in either tumor or blood. Enrollment of patients with other tumor types is limited to testing performed in tumor tissue.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations

Actual Study Start Date :

Oct 16, 2020

Anticipated Primary Completion Date :

Feb 1, 2023

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY3410738 Phase 1 dose escalation - Multiple doses of LY3410738	Drug: LY3410738 Oral LY3410738
Experimental: LY3410738 alone or in combination with gemcitabine and cisplatin or in combination with durvalumab Phase 1 dose expansion - The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of LY3410738 alone or in combination with gemcitabine plus cisplatin or in combination with durvalumab	Drug: LY3410738 Oral LY3410738 Drug: Gemcitabine Intravenous gemcitabine Other Names: LY188011 Drug: Cisplatin Intravenous cisplatin Drug: Durvalumab Intravenous durvalumab

Arm

Intervention/Treatment

Experimental: LY3410738

Phase 1 dose escalation - Multiple doses of LY3410738

Drug: LY3410738

Oral LY3410738

Experimental: LY3410738 alone or in combination with gemcitabine and cisplatin or in combination with durvalumab

Phase 1 dose expansion - The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of LY3410738 alone or in combination with gemcitabine plus cisplatin or in combination with durvalumab

Drug: LY3410738

Oral LY3410738

Drug: Gemcitabine

Intravenous gemcitabine

Other Names:

LY188011

Drug: Cisplatin

Intravenous cisplatin

Drug: Durvalumab

Intravenous durvalumab

Outcome Measures

Primary Outcome Measures

Recommended Phase 2 Dose (RP2D) [Up to 24 months]

Secondary Outcome Measures

Objective Response Rate [Up to 24 months]
Assess the safety and tolerability of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine or in combination with durvalumab [Up to 24 months]
To assess the preliminary anti-tumor activity of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine or in combination with durvalumab [Up to 24 months]
Characterize PK properties of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine or in combination with durvalumab [Up to 24 months]
To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma [Up to 24 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Evidence of IDH1 R132 mutation (any solid tumor) or circulating tumor DNA IDH2 R140 or IDH2 R172 mutation (cholangiocarcinoma only) as determined by molecular testing performed at a CLIA, ISO/IEC, CAP, or other similarly certified laboratory. For cholangiocarcinoma, chondrosarcoma, and glioma, molecular testing can be performed on tumor tissue or circulating tumor DNA. For all other solid tumor types, molecular testing must be performed on tumor tissue.
Availability of an archived tumor tissue sample. Patients without an available archival tumor tissue sample must be discussed with the sponsor's Medical Monitor prior to enrollment.
Eastern Cooperative Oncology Group (ECOG) 0-1.
At least 18 years of age.
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.
For cholangiocarcinoma patients, must have adequate biliary drainage (per investigator's discretion), with no evidence of ongoing infection.
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. Patients enrolled to Dose Expansion Cohort 4 shall also follow cisplatin/gemcitabine contraception duration requirements as determined by labels and/or local guidelines.

Monotherapy Dose Escalation:

A locally advanced or metastatic solid tumor, where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the investigator.
Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate by tumor type.
Prior IDH1 inhibitor treatment is permitted.

Monotherapy Dose Expansion Cohort 1:

Histologically or cytologically confirmed diagnosis of advanced or metastatic cholangiocarcinoma, following 1 to 2 lines of prior systemic treatment for advanced disease. Prior IDH1 inhibitor treatment is not permitted.
Measurable disease as determined by RECIST 1.1.

Monotherapy Dose Expansion Cohort 2:

A locally advanced or metastatic solid tumor (except for cholangiocarcinoma), where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the investigator.
Measurable disease as determined by RECIST 1.1 or RANO as appropriate by tumor types.

Monotherapy Dose Expansion Cohort 3:

A locally advanced or metastatic solid tumor, where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the investigator.
Non-measurable disease only as determined by RECIST 1.1 or RANO as appropriate by tumor type.

Combination Dose Expansion Cohort 4:

Histologically or cytologically confirmed diagnosis of advanced or metastatic cholangiocarcinoma, not eligible for curative resection.
No prior systemic therapy for advanced or metastatic disease with the following exceptions:

Patients who received adjuvant chemotherapy are eligible, if the adjuvant therapy was completed at least 6 months prior to the development of advanced or metastatic disease.
Patients who are receiving up to two cycles of cisplatin plus gemcitabine as the first line systemic therapy while waiting for results of molecule profiling including IDH1 mutational status, are eligible, provided that a radiographic assessment during screening demonstrates the absence of interval disease progression since initiation of chemotherapy treatment, and all other eligibility criteria are met.

Measurable disease as determined by RECIST 1.1.

Exclusion Criteria:

Had an investigational agent or anticancer therapy within 2 weeks; or investigational monoclonal antibody within 4 weeks prior to planned start of LY3410738.
Had major surgery within 4 weeks prior to planned start of LY3410738.
Had radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment.
Patients with cholangiocarcinoma: underwent hepatic radiation, chemoembolization and radiofrequency ablation, radioembolization or other locoregional therapy <4 weeks, have history of hepatic encephalopathy of any grade, have ascites requiring intervention such as diuretics or paracentesis, have ongoing cholangitis, have mixed hepatocellular biliary tract cancer histology or history of liver transplant.
Have active CNS metastases are not eligible. Patients with asymptomatic and treated brain metastases may participate provided that they are stable and are not requiring steroid treatment. Patients with suspected or confirmed leptomeningeal disease are not eligible even if treated.
Have primary CNS tumors are eligible provided that they do not have leptomeningeal disease and are on a stable or decreasing steroid dose for 7 days prior to screening. Patients with evidence of intracranial hemorrhage either by MRI or CT are not eligible
Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 at the time of starting study treatment except for alopecia.
Have clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of study treatment.
Have active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which in the opinion of the investigator and the sponsor makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
Known active hepatitis B virus (HBV). Note: Controlled (treated) hepatitis will be allowed if they meet the following criteria, antiviral therapy for HBV must be given for at least 1 month prior to first dose of study drug, and HBV viral load must be less than 2000 IU/ml (104 copies/ml) prior to the first dose of study drug. Those on active HBV therapy with viral loads under 2000 IU/ml (104 copies/ml) should stay on the same therapy throughout the study treatment (Appendix E).
Known active hepatitis C virus (HCV). Note: Untreated patients with chronic infection by HCV are allowed on study. In addition, successfully treated patients (defined as sustained virologic response SVR12 or SVR24) are allowed, as long as there is 4 weeks between achieving sustained viral response (SVR12 or SVR24) and starting study drug.
Known human immunodeficiency virus (HIV); excluded due to potential drug-drug interactions between anti-retroviral medications and LY3410738.
Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (Appendix F) and/or P-gp inhibitors (Appendix G).
Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
Active second malignancy unless in remission and with life expectancy > 2 years. Refer to protocol exclusion criteria (Section 4.2) for examples of allowed second malignancies.
Pregnancy, lactation or plans to breastfeed during the study or within 3 months of the last dose of study intervention.
Patients with known hypersensitivity to any component of LY3410738 or its formulation.

Combination Dose Expansion Cohort 5:

Prior treatment with anti-PD 1 or anti-PD L1 therapies.
History of Grade 3 or higher immune-related adverse events (irAEs).
Active autoimmune disease that has required systemic antiautoimmune treatment in the past 2 years.

Endocrine replacement therapy is not considered a form of systemic therapy and is allowed.

Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids which should not exceed 10 mg/day of prednisone or equivalent corticosteroid.
Active interstitial lung disease or history of noninfectious pneumonitis Grade 2 or higher that required treatment with systemic corticosteroids or immunosuppressive drugs.
History of hypersensitivity to durvalumab or any excipient.
Has received a live vaccine within 30 days prior to the first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic of Scottsdale	Phoenix	Arizona	United States	85054
2	The University of Arizona Cancer Center	Tucson	Arizona	United States	85724
3	USC Norris Cancer Hospital	Los Angeles	California	United States	90033
4	UCSF Medical Center at Mission Bay	San Francisco	California	United States	94143
5	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224
6	University of Chicago Pritzker School of Medicine	Chicago	Illinois	United States	60637
7	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
8	The John Hopkins Hospital	Baltimore	Maryland	United States	21287
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
11	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
12	Mayo Clinic	Rochester	Minnesota	United States	55902
13	Memorial Sloan Kettering Cancer Center	Middletown	New Jersey	United States	07748
14	Memorial Sloan Kettering Cancer Center	Commack	New York	United States	11725
15	Memorial Sloan Kettering Cancer Center	Harrison	New York	United States	10604
16	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
17	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
18	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
19	South Texas Accelerated Research Therapeutics, LLC	San Antonio	Texas	United States	78229
20	St Vincent's Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
21	Institut Bergonié - Centre Régional de Lutte Contre Le Cancer de Bordeaux et Sud Ouest	Bordeaux		France	33076
22	Gustave Roussy	Villejuif Cedex		France	94805
23	Prince of Wales Hospital	Hong Kong	Shatin, New Territories	Hong Kong
24	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577
25	Kanagawa Cancer Center	Yokohama	Kanagawa	Japan	241-8515
26	Osaka University Hospital	Suita-shi	Osaka	Japan	565-0871
27	Shizuoka Cancer Center	Nagaizumi	Shizuoka	Japan	411-8777
28	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
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 Hospital	Singapore		Singapore	669606
32	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
33	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
34	China Medical University Hospital	Taichung City		Taiwan	40447
35	National Cheng-Kung Uni. Hosp.	Tainan		Taiwan	704