Clinical Trials /

Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation

NCT02073994

Description:

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced solid tumors, including glioma, that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four arms of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression, unacceptable toxicity occurs or at Investigator discretion.

Related Conditions:
  • Cholangiocarcinoma
  • Chondrosarcoma
  • Glioma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation
  • Official Title: A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation

Clinical Trial IDs

  • ORG STUDY ID: AG120-C-002
  • NCT ID: NCT02073994

Conditions

  • Cholangiocarcinoma
  • Chondrosarcoma
  • Glioma
  • Other Advanced Solid Tumors

Interventions

DrugSynonymsArms
AG-120AG-120

Purpose

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced solid tumors, including glioma, that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four arms of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Anticipated time on study treatment is until disease progression, unacceptable toxicity occurs or at Investigator discretion.

Trial Arms

NameTypeDescriptionInterventions
AG-120ExperimentalAG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression, development of other unacceptable toxicity or Investigator discretion.
  • AG-120

Eligibility Criteria

        Key Inclusion Criteria:

          1. Dose Escalation

               1. Subjects must have histologically or cytologically confirmed, IDH1 gene-mutated
                  advanced solid tumors, including glioma, that have recurred or progressed
                  following standard therapy, or that have not responded to standard therapy.

               2. Subjects must have evaluable disease by RECIST v1.1 for subjects without glioma
                  or by RANO criteria for subjects with glioma.

          2. Dose Expansion: Cholangiocarcinoma

               1. Subjects must have histologically-confirmed diagnosis of IDH1 gene-mutated
                  cholangiocarcinoma Stage II, III, or IV (intra-hepatic, extra-hepatic and
                  perihilar) that is not eligible for curative resection, transplantation, or
                  ablative therapies. Tumors of mixed histology are not allowed.

               2. Cholangiocarcinoma subjects must have progressed following gemcitabine-based
                  regimen.

               3. Cholangiocarcinoma subjects must have radiographically measurable disease in at
                  least one site not previously treated with radiation, chemoembolization,
                  radioembolization, or other local ablative procedures; a new area of tumor
                  progression within or adjacent to a previously-treated lesion, if clearly
                  measurable by a radiologist, is acceptable.

          3. Dose Expansion: Chondrosarcoma

             a. Subjects must have IDH1 gene-mutated chondrosarcoma that is either locally advanced
             or metastatic and not amenable to complete surgical excision.

          4. Dose Expansion: Non-enhancing Glioma

               1. Subjects must have progressive glioma that is solely non-enhancing on MRI.

               2. Progression of glioma must have occurred over 12 months or less.

               3. Subject must have available at least 3 prior full sets of scans (not including
                  screening), each separated by at least 2 months with less than or equal to 5 mm
                  slice thickness and up to 1 mm interslice gap on either 2D T2 weighted image, 3D
                  T2 weighted image, or FLAIR.

               4. Subjects must not have had prior surgery (biopsy allowed) or radiation therapy
                  within 6 months of enrollment.

          5. Dose Expansion: Solid Tumors Not Otherwise Eligible for the Cholangiocarcinoma,
             Chondrosarcoma, or Non-enhancing Glioma Cohorts

               1. IDH1 gene-mutated solid tumors refractory to conventional therapy or the subject
                  does not tolerate the conventional therapy

               2. Subjects must have radiographically measurable disease in at least one site not
                  previously treated with radiation, chemoembolization, radioembolization, or other
                  local ablative procedures; a new area of tumor progression within or adjacent to
                  a previously-treated lesion, if clearly measurable by a radiologist, is
                  acceptable.

          6. Subject must be ≥18 years of age.

          7. Subjects must have documented IDH1 gene-mutated disease based on local test
             evaluation. (Centralized testing will be performed retrospectively.)

          8. Subjects must be amenable to serial peripheral blood sampling, urine sampling, and
             biopsies during the study.

          9. Subject must be able to understand and willing to sign an informed consent. A legally
             authorized representative may consent on behalf of a subject who is otherwise unable
             to provide informed consent, if acceptable to and approved by the site and/or site's
             Institutional Review Board (IRB)/Independent Ethics Committee (IEC).

         10. Subjects must have ECOG PS of 0 to 1.

         11. Subjects must have expected survival of ≥3 months.

         12. Subjects must have adequate bone marrow function as evidenced by:

               1. Absolute neutrophil count ≥1.5 ×109/L;

               2. Hemoglobin >9 g/dL (Subjects are allowed to be transfused to this level)

               3. Platelets ≥ 75 × 109/L.

         13. Subjects must have adequate hepatic function as evidenced by:

               1. Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due
                  to Gilbert's disease or disease involvement following approval by the Medical
                  Monitor;

               2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
                  phosphatase (ALP) ≤2.5 × ULN. For subjects with bone metastases and/or suspected
                  disease-related liver or biliary involvement, ALP must be ≤5 × ULN.

         14. Subjects must have adequate renal function as evidenced by:

             a. Serum creatinine ≤2.0 × ULN OR b. Creatinine clearance >40 mL/min based on the
             Cockcroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in
             kg) x (0.85 if female)/72 x serum creatinine

         15. Subjects must be recovered from any clinically relevant toxic effects of any prior
             surgery, radiotherapy, or other therapy intended for the treatment of cancer. (For
             example, subjects with residual Grade 1 toxicity or stable Grade 2 peripheral
             neuropathy due to prior chemotherapy are allowed with approval of the Medical
             Monitor.)

         16. Female subjects with reproductive potential must agree to undergo medically supervised
             pregnancy test prior to starting study drug. The first pregnancy test will be
             performed at screening (within 7 days prior to first study drug administration), and
             on the day of the first study drug administration and confirmed negative prior to
             dosing. Subjects with reproductive potential are defined as sexually mature women who
             have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion or who
             have not been naturally postmenopausal (i.e., who have not menstruated at all) for at
             least 24 consecutive months (i.e., has had menses at any time in the preceding 24
             consecutive months). Females of reproductive potential, as well as fertile men with
             partners who are female of reproductive potential, must agree to abstain from sexual
             intercourse or to use two highly effective forms of contraception from the time of
             giving informed consent, during the study and for 90 days (females and males)
             following the last dose of AG-120. A highly effective form of contraception is defined
             as hormonal oral contraceptives, injectables, patches, intrauterine devices,
             double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with
             spermicidal foam, cream, or gel), or male partner sterilization.

        Exclusion Criteria:

          1. Subjects who received systemic anticancer therapy or radiotherapy <21 days prior to
             their first day of study drug administration.

          2. Subjects who received an investigational agent <14 days prior to their first day of
             study drug administration. In addition, the first dose of AG-120 should not occur
             before a period ≥5 half-lives of the investigational agent has elapsed.

          3. Subjects taking the following sensitive cytochrome P450 (CYP) 3A4 substrate
             medications are excluded from the study unless they can be transferred to other
             medications prior to enrolling: alfentanil, aprepitant, budesonide, buspirone,
             conivaptan, darifenacin, darunavir, dronedarone, eletriptan, eplerenone, felodipine,
             indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam,
             nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, tolvaptan, tipranavir,
             triazolam, ticagrelor, vardenafil and/or the CYP2B6 substrates: bupropion, efavirenz.

          4. Subjects taking the following P-glycoprotein (P-gp) transporter-sensitive substrate
             medications are excluded from the study unless they can be transferred to other
             medications prior to enrolling: aliskiren, ambrisentan, colchicine, dabigatran
             etexilate, digoxin, fexofenadine, maraviroc, posaconazole, ranolazine, saxagliptin,
             sitagliptin, talinolol, and tolvaptan.

          5. Subjects for whom potentially curative anticancer therapy is available.

          6. Subjects who are pregnant or breast feeding.

          7. Subjects with an active severe infection that required anti-infective therapy or with
             an unexplained fever >38.5°C during screening visits or on their first day of study
             drug administration (at the discretion of the Investigator, subjects with tumor fever
             may be enrolled).

          8. Subjects with known hypersensitivity to any of the components of AG-120.

          9. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart
             failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan
             within approximately 28 days of C1D1.

         10. Subjects with a history of myocardial infarction within the last 6 months.

         11. Subjects with known unstable or uncontrolled angina pectoris.

         12. Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.

         13. Subjects with heart-rate corrected QT (QTc) interval ≥ 450 msec or with other factors
             that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure,
             hypokalemia, family history of long QT interval syndrome). Subjects with right bundle
             branch block and a prolonged QTc interval should be reviewed by the Medical Monitor
             for potential inclusion.

         14. Subjects taking medications that are known to prolong the QT interval (see Section
             9.11.3).

         15. Subjects with known infection with human immunodeficiency virus (HIV) or active
             hepatitis B or C.

         16. Subjects with any other medical or psychological condition, deemed by the Investigator
             to be likely to interfere with a subject's ability to sign informed consent,
             cooperate, or participate in the study.

         17. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
             that limit the ingestion or gastrointestinal absorption of drugs administered orally.

         18. Subjects with brain metastases that are untreated, symptomatic, or require therapy to
             control symptoms; or any radiation, surgery, or other therapy, including those used to
             control symptoms, within 2 months of first dose. Subjects with glioma who are on a
             stable, steroid dosing regimen 5 days prior to the screening MRI may be permitted to
             enroll with Medical Monitor approval.

         19. Subjects with a history of Grade 4 astrocytoma (applicable only to subjects enrolled
             in the dose expansion non-enhancing glioma cohort).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety/tolerability: incidence of adverse events
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Dose Limiting Toxicities of AG-120 in subjects with advanced solid tumors, including glioma
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:
Measure:Pharmacokinetics of AG-120 in subjects with advanced solid tumors, including glioma
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Such parameters will include max concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life.
Measure:Pharmacodynamic relationship of AG-120 and 2-HG
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:PD parameters will be summarized using the following descriptive statistics: n, Mean, SD, CV%, Median, Min, and Max, GeoMean, and GeoCV%. PK/PD correlations between exposure to AG-120 and the extent of suppression of 2-HG will be explored using graphical display of data.
Measure:Clinical Activity associated with AG-120 in subjects with advanced solid tumors, including glioma
Time Frame:Up to 26 weeks, on average
Safety Issue:
Description:The clinical activity of AG-120 will be evaluated by assessing response to treatment according to RECIST v1.1 for subjects without glioma or by modified RANO criteria for subjects with glioma

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Institut de Recherches Internationales Servier

Trial Keywords

  • chondrosarcoma
  • cholangiocarcinoma
  • glioma
  • advanced solid tumors
  • IDH1
  • AG-120

Last Updated

August 18, 2021