Clinical Trials /

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

NCT04521686

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 tumor types, including but not limited to cholangiocarcinoma, chondrosarcoma, and glioma.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 Mutations
  • Official Title: Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 Mutations

Clinical Trial IDs

  • ORG STUDY ID: LOXO-IDH-20002
  • SECONDARY ID: 2020-002863-77
  • NCT ID: NCT04521686

Conditions

  • Cholangiocarcinoma
  • Chondrosarcoma
  • Glioma
  • Any Solid Tumor

Interventions

DrugSynonymsArms
LY3410738LY3410738

Purpose

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 tumor types, including but not limited to cholangiocarcinoma, chondrosarcoma, and glioma.

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 tumor
      types, including but not limited to cholangiocarcinoma, chondrosarcoma, and glioma.

      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. Once the LY3410738 monotherapy RP2D is established, Phase 1 dose
      expansion will begin and will include 4 cohorts to further evaluate safety and clinical
      activity - three cohorts will be administered LY3410738 monotherapy and the fourth cohort
      wiil administer LY3410738 to patients in combination with gemcitabine and cisplatin.

      IDH1 R132 mutations will be identified through standard of care testing as routinely
      performed at each participating site 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.
    

Trial Arms

NameTypeDescriptionInterventions
LY3410738ExperimentalPhase 1 dose escalation - Multiple doses of LY3410738 Phase 1 dose expansion - The maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D)
  • LY3410738

Eligibility Criteria

        Inclusion Criteria:

          1. Evidence of IDH1 R132 mutation in tumor tissue (any solid tumor) or circulating tumor
             DNA (cholangiocarcinoma, chondrosarcoma, and glioma) as determined by molecular
             testing routinely performed at a CLIA, ISO/IEC, CAP, or other similarly certified
             laboratory.

          2. Availability of an archived tumor tissue sample

          3. Eastern Cooperative Oncology Group (ECOG) 0-1

          4. At least 18 years of age

          5. Adequate organ function

          6. Ability to swallow capsules

          7. Ability to comply with outpatient treatment, laboratory monitoring, and required
             clinic visits for the duration of study participation

          8. For cholangiocarcinoma patients, must have adequate biliary drainage (per
             investigator's discretion), with no evidence of ongoing infection.

          9. 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.

             Monotherapy Dose Escalation:

         10. 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.

         11. Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
             appropriate by tumor type.

         12. Prior IDH1 inhibitor treatment is permitted.

             Monotherapy Dose Expansion Cohort 1:

         13. 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.

         14. Measurable disease as determined by RECIST 1.1.

             Monotherapy Dose Expansion Cohort 2:

         15. 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.

         16. Measurable disease as determined by RECIST 1.1 or RANO as appropriate by tumor types.

             Monotherapy Dose Expansion Cohort 3:

         17. 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.

         18. Non-measurable disease only as determined by RECIST 1.1 or RANO as appropriate by
             tumor type.

             Combination Dose Expansion Cohort 4:

         19. Histologically or cytologically confirmed diagnosis of advanced or metastatic
             cholangiocarcinoma, not eligible for curative resection.

         20. 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 the first cycle of cisplatin plus gemcitabine as the
                  first line systemic therapy while waiting for results of locally obtained
                  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.

         21. Measurable disease as determined by RECIST 1.1.

        Exclusion Criteria:

          1. Had an investigational agent or anticancer therapy within 2 weeks; or investigational
             monoclonal antibody within 4 weeks prior to planned start of LY3410738.

          2. Had major surgery within 4 weeks prior to planned start of LY3410738.

          3. 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.

          4. 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

          5. 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.

          6. 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

          7. Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2
             at the time of starting study treatment except for alopecia.

          8. Have clinically significant, uncontrolled cardiac, cardiovascular disease or history
             of myocardial infarction within 6 months prior to planned start of study treatment.

          9. 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.

         10. 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).

         11. 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.

         12. Known human immunodeficiency virus (HIV); excluded due to potential drug-drug
             interactions between anti-retroviral medications and LY3410738.

         13. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
             inducers (Appendix F) and/or strong P-gp inhibitor (Appendix G).

         14. Treatment with proton pump inhibitor (PPIs) within 7 days of starting LY3410738
             (Appendix H). For recommended alternatives, refer to Section 6.4.3.

         15. Clinically significant active malabsorption syndrome or other condition likely to
             affect gastrointestinal absorption of the study drug.

         16. 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.

         17. Pregnancy, lactation or plan to breastfeeding during the study or within 30 days of
             the last dose of study intervention.

         18. Patients with known hypersensitivity to any component of LY3410738 or its formulation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 dose (RP2D)
Time Frame:Up to 24 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Assess the safety and tolerability of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine.
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:To assess the preliminary anti-tumor activity of LY3410738 monotherapy and in combination with cisplatin plus gemcitabine
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Characterize PK properties of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine.
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:To characterize the pharmacodynamic properties of LY3410738 as expressed by change in 2-HG oncometabolite levels in plasma.
Time Frame:Up to 24 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Loxo Oncology, Inc.

Trial Keywords

  • IDH1
  • CNS tumor
  • Cholangiocarcinoma
  • Chondrosarcoma
  • Glioma
  • Glioblastoma
  • Solid tumor
  • Primary CNS tumor
  • Colon cancer
  • Cancer of the Colon
  • Colon Neoplasms
  • Colonic Cancer
  • Neoplasms, Colonic
  • Malignant tumor of Breast
  • Mammary Cancer
  • Mammary Carcinoma, Human
  • Mammary Neoplasm, Human
  • Neoplasms, Breast
  • Tumors, Breast
  • Human Mammary Carcinoma
  • Malignant Neoplasm of Breast
  • Breast Carcinoma
  • Breast Tumors
  • Cancer of the Breast
  • Breast Neoplasms
  • Breast Cancer
  • Thyroid cancer
  • Prostate cancer
  • Melanoma
  • IDH1 R132

Last Updated

August 18, 2020