Clinical Trials /

Ivosidenib (AG-120) With Nivolumab in IDH1 Mutant Tumors

NCT04056910

Description:

In this study, response to treatment and (progression free and overall) survival will be described and safety events of ivosidenib in combination with nivolumab will be summarized in patients with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ivosidenib (AG-120) With Nivolumab in IDH1 Mutant Tumors
  • Official Title: Phase II Study of IDH1 Inhibitor Ivosidenib and Nivolumab in IDH1 Mutant Gliomas and Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: HCC 19-096
  • NCT ID: NCT04056910

Conditions

  • Advanced Solid Tumor
  • IDH1 Mutation
  • Glioma

Interventions

DrugSynonymsArms
ivosidenib and nivolumabConcurrent dosing of ivosidenib and nivolumab

Purpose

In this study, response to treatment and (progression free and overall) survival will be described and safety events of ivosidenib in combination with nivolumab will be summarized in patients with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas.

Detailed Description

      This study will describe the safety, response rate, progression free and overall survival,
      and summarize safety events of ivosidenib in combination with nivolumab in participants with
      advanced solid tumors (nonresectable or metastatic) or enhancing gliomas. Participants are
      required to have a histologically consistent diagnosis of IDH1 gene mutated tumor that is not
      eligible for curative therapy. Enrolled subjects will receive orally administered ivosidenib
      dosed daily on 28-day cycles and nivolumab will be infused every 28 days. Participants will
      be assessed at every visit for adverse events starting from the first dose of study
      treatment. Assessment (CT or MRI) for evaluation of disease response will be conducted every
      8 weeks (±7 days) from the first day of treatment cycle 1 and/or at any time when progression
      of disease is suspected. A Post-Treatment Follow-Up Visit for safety will occur 28 (+/- 5)
      days after the last dose of study drug.
    

Trial Arms

NameTypeDescriptionInterventions
Concurrent dosing of ivosidenib and nivolumabExperimentalIvosidenib will be administered concurrently with nivolumab on a Q28 day schedule.
  • ivosidenib and nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be ≥18 years of age.

          -  Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably
             collected within the last 3 years) of an advanced solid tumor for which curative
             treatment is not available and have undergone appropriate standard of care treatment
             options (in the opinion of the treating investigator).

          -  Have a documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most
             recent banked tumor tissue available) based on CLIA certified sequencing
             (R132C/L/G/H/S mutation variants tested).

               -  For glioma, must have both 1) contrast enhancing disease and 2) WHO 2016 grade II

          -  Have an ECOG PS score of 0 or 1 (Appendix 11.1)

          -  Have at least one evaluable and measurable lesion as defined by RECIST v1.1 (solid
             tumors) or RANO Criteria (glioma).

          -  Have recovered from toxicities associated with prior anticancer therapy to baseline or
             ≤ grade 1 unless stabilized under medical management per investigator.

          -  Have adequate bone marrow function as evidenced by:

               -  Absolute neutrophil count ≥ 1,500/mm3 or 1.5 × 109/L

               -  Hemoglobin ≥ 8 g/dL

               -  Platelets ≥ 100,000/mm3 or 100 × 109/L

          -  Have adequate hepatic function as evidenced by:

               -  Serum total bilirubin ≤ 2 × upper limit of normal (ULN), unless considered due to
                  Gilbert's disease

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × ULN in
                  the presence of liver metastases (or primary hepatic tumor) OR ≤ 2× ULN within
                  glioma patients

          -  Have adequate renal function as evidenced by:

             • Serum creatinine < 1.5 × ULN OR Creatinine clearance ≥ 50 mL/min based on the
             Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in
             kg) x (0.85 if female)/72 x serum creatinine

          -  Be able to understand and willing to sign the informed consent form (or have legal
             representation) and to comply with scheduled visits, treatment plans, procedures, and
             laboratory tests, including serial peripheral blood sampling, biopsies, and urine
             sampling, during the study. A legally authorized representative may consent on behalf
             of a participant who is otherwise unable to provide informed consent if acceptable to
             and approved by the IRB/Independent Ethics Committee (IEC).

          -  Female participants with reproductive potential must have negative serum pregnancy
             testing within 24 h prior to the initial administration of study drug, then every 4
             weeks±1 week, or a negative confirmation from an obstetrician in case of equivocal
             serum pregnancy results. Females of 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 (ie, who have not menstruated)
             for at least 24 consecutive months (ie, have not had menses at any time in the
             preceding 24 consecutive months).

          -  Women of child-bearing potential (WOCBP) receiving nivolumab will be instructed to
             adhere to contraception for a period of 5 months after the last dose of nivolumab. Men
             receiving nivolumab and who are sexually active with WOCBP will be instructed to
             adhere to contraception for a period of 7 months after the last dose of nivolumab.

          -  Effective forms of contraception are defined as hormonal oral contraceptives,
             injectables, patches, intrauterine devices, intrauterine hormone-releasing systems,
             bilateral tubal ligation, condoms with spermicide, or male partner sterilization.

        Exclusion Criteria:

          -  Received a prior IDH inhibitor.

          -  Received prior checkpoint therapy (anti-PD1/L1 or anti-CTLA4 antibody)

          -  Received systemic anticancer therapy or an investigational agent < 2 weeks prior to
             Day 1). In addition, the first dose of study treatment should not occur before a
             period ≥ 5 half-lives (t1/2)of the investigational agent has elapsed.

          -  For solid tumor patients: received radiotherapy to metastatic sites of disease < 2
             weeks prior to Day 1 and for glioma patients have received radiation within 3 months
             prior.

          -  For solid tumor patients, have underwent hepatic radiation, chemoembolization, and
             radiofrequency ablation < 4 weeks prior to Day 1.

          -  Participants must not have a diagnosis of immunodeficiency or is receiving systemic
             steroid therapy at a dose of > 10 mg prednisone daily or equivalent at time of first
             dose of study treatment.

          -  Participants must not have active autoimmune disease that has required systemic
             treatment in the past 2 years (ie, with use of disease modifying agents,
             corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine,
             insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitary
             insufficiency, etc.) is not considered a form of systemic treatment.

          -  Participants must not have a known history of non-infectious pneumonitis that required
             steroids for treatment.

          -  Participants must not have evidence of interstitial lung disease.

          -  For solid tumor patients, have known symptomatic brain metastases requiring steroids.
             Participants with previously diagnosed brain metastases are eligible if they have
             completed their treatment and have recovered from the acute effects of radiation
             therapy or surgery prior to study entry, have discontinued corticosteroid treatment
             for these metastases for at least 1 week and have radiographically stable disease for
             at least 1 month prior to study entry.

          -  Have a history of another primary cancer that is active requiring treatment,
             progressing or for which the treating investigator believes will make disease
             assessment unreliable.

          -  Have evidence of intracranial or intra-tumoral hemorrhage either by MRI or computed
             tomographic (CT) scan. Participants with resolving post-surgical changes, punctate
             hemorrhage, or hemosiderin are eligible.

          -  Underwent major surgery within 4 weeks of Day 1 or have not recovered from
             post-surgery toxicities.

          -  Are pregnant or breastfeeding.

          -  Are taking known strong CYP3A4 inducers or sensitive CYP3A4 substrate medications with
             a narrow therapeutic window (Appendix 0), unless they can be transferred to other
             medications within ≥5 t1/2 prior to dosing.

          -  Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with a
             narrow therapeutic window (Appendix 0), unless they can be transferred to other
             medications within ≥ 5 t1/2 prior to administration of study treatment.

          -  Have an active infection requiring systemic anti-infective therapy or with an
             unexplained fever > 38.5°C within 7 days of Day 1 (at the discretion of the treating
             investigator) participants with tumor fever may be enrolled).

          -  Have any known hypersensitivity to any of the components of ivosidenib or nivolumab.

          -  Have 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 0); myocardial infarction; unstable angina; and/or stroke.

          -  Have a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) (Appendix
             0) ≥ 480 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).
             Bundle branch block and prolonged QTcF interval are permitted with approval of the
             Medical Monitor.

          -  Are taking medications that are known to prolong the QT interval (Appendix 0), unless
             they can be transferred to other medications within ≥ 5 t1/2 prior to dosing or unless
             the medications can be properly monitored during the study. (If equivalent medication
             is not available, QTcF should be closely monitored.)

          -  Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive
             human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency
             syndrome (AIDS) related illness. Participants with a sustained viral response to HCV
             treatment or immunity to prior HBV infection will be permitted. Participants with
             chronic HBV that is adequately suppressed per institutional practice will be
             permitted.

          -  Have any other acute or chronic medical or psychiatric condition, including recent
             (within 12 months of Day 1) or active suicidal ideation or behavior, or a laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the treating investigator, would make the
             participant inappropriate for entry into this study.

          -  Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous
             gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other
             conditions that limit the ingestion or gastrointestinal absorption of drugs
             administered orally. Gastroesophageal reflux disease under medical treatment is
             allowed (assuming no drug interaction potential).

          -  Have been committed to an institution by an order issued either by the judicial or
             administrative authorities.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Occurrence of dose limiting toxicity (DLT)
Time Frame:Up to 24 months
Safety Issue:
Description:The occurrence (number) of dose limiting toxicity (DLT) in patients receiving ivosidenib plus nivolumab. DLT describes side effects of the treatment that are serious enough to prevent an increase in dose or level of that treatment.

Secondary Outcome Measures

Measure:Adverse Events Related to Treatment
Time Frame:Up to 24 months
Safety Issue:
Description:Adverse events per NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0), experienced by patients related to their receiving the treatment combination of ivosidenib and nivolumab.
Measure:Overall Survival (OS)
Time Frame:Up to 36 months
Safety Issue:
Description:The length of time from the start of treatment that patients diagnosed with the disease are still alive.
Measure:Objective Tumor Progression
Time Frame:Up to 24 months
Safety Issue:
Description:Solid Tumor-Progression per RECIST v1.1 Criteria:Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. Glioma-Tumor progression per RANO Criteria: Progressive Disease: No CR, PR, SD prior to PD. Progression: 25% or more increase in enhancing lesions despite stable or increasing steroid dose, increase (significant) in non-enhancing FLAIR/T2W lesions, not attributable to other non-tumor causes, any new lesions; clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jason J. Luke, MD

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