Clinical Trials /

Ivosidenib and Venetoclax With or Without Azacitidine in Treating Participants With IDH1 Mutated Hematologic Malignancies

NCT03471260

Description:

This phase Ib/II trial studies the side effects and best dose of venetoclax and how well it works when given together with ivosidenib with or without azacitidine, in treating participants with IDH1-mutated hematologic malignancies. Venetoclax and ivosidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ivosidenib and venetoclax with azacitidine may work better in treating patients with hematologic malignancies compared to ivosidenib and venetoclax alone.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Venetoclax With the mIDH1 Inhibitor Ivosidenib (AG120) in IDH1-Mutated Hematologic Malignancies
  • Official Title: Phase Ib/II Investigator Sponsored Study of the IDH1-Mutant Inhibitor Ivosidenib (AG120) With the BCL2 Inhibitor Venetoclax in IDH1-Mutated Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2017-0490
  • SECONDARY ID: NCI-2018-00921
  • NCT ID: NCT03471260

Conditions

  • Other Diseases of Blood and Blood-forming Organs
  • Advanced Hematologic Malignancies
  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
IvosidenibAG120Ivosidenib + Venetoclax
VenetoclaxABT-199, GDC-0199Ivosidenib + Venetoclax

Purpose

There are 2 parts to this clinical research study: Part 1 (dose escalation) and Part 2 (dose expansion). The goal of Part 1 of this clinical research study is to find the highest tolerable dose of the combination of ivosidenib (AG-120) and venetoclax that can be given to patients with relapsed (has come back) or refractory (has not responded to treatment) acute myeloid leukemia (AML) with an IDH1 mutation (a type of genetic change). The goal of Part 2 is to learn if the highest tolerable dose of ivosidenib and venetoclax found in Part 1 can help to control the disease. The safety of this drug combination will be studied in both parts. This is an investigational study. Ivosidenib is not FDA approved or commercially available. Venetoclax is FDA approved and commercially available for the treatment of a certain type of chronic lymphocytic leukemia (CLL). It is considered investigational to use ivosidenib in combination with venetoclax to treat AML. The study doctor can explain how the study drugs are designed to work. Up to 48 patients will be enrolled on this study. All will take part at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be assigned to a study
      group based on when you join this study. Up to 5 groups of 6 participants will be enrolled in
      Part 1 of the study, and up to 24 participants will be enrolled in Part 2.

      If you are enrolled in Part 1, the dose levels of venetoclax you receive will depend on when
      you join this study. The first group of participants will receive the lowest dose levels of
      venetoclax. Each new group will receive a higher dose of venetoclax than the group before it,
      if no intolerable side effects were seen. This will continue until the highest tolerable dose
      of venetoclax is found.

      All participants will receive the same dose level of ivosidenib.

      If you are enrolled in Part 2, you will receive ivosidenib and venetoclax at the highest dose
      that was tolerated in Part 1.

      Study Drug Administration:

      Each study cycle is 28 days.

      You will take venetoclax by mouth 1 time each day on Days 1-14 of each cycle. You should take
      your dose with about 1 cup (8 ounces) of water and within 30 minutes of eating. Your dose of
      venetoclax will slowly increase over the first 3-5 days until you receive the full dose. Your
      dose level of venetoclax may change while on study, if needed. This will be discussed with
      you.

      You will take ivosidenib by mouth 1 time each day starting with Day 15 of Cycle 1. You may
      take your dose with or without food.

      You will record all of your doses in a study diary, which you should bring with you to each
      study visit. If you miss a dose and it is within 6 hours of the missed dose, you may take it.
      If you vomit after taking a dose, or more than 6 hours has passed since you missed a dose,
      you must not make-up the dose. Continue taking the next dose at your regular time.

      During Cycle 1, you will be admitted into the hospital as an inpatient for at least the first
      5-7 days of your study treatment. During this time, you will also be given standard drugs to
      help prevent . You may ask the study staff for information about how the drugs are given and
      their risks. TLS happens when breakdown products of the cancer cells enter the blood stream
      (causing weakness, low blood pressure, muscle cramps, kidney damage, and/or other organ
      damage).You will stay in the hospital for the first 5-7 days of study treatment. If the
      doctor thinks it is needed, you may need to stay in the hospital longer.

      Length of Treatment:

      You may continue taking the study drugs for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the study drugs if the disease gets worse, if
      intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      TLS Testing:

      During Cycle 1, while you are admitted to the hospital to receive your first doses of
      venetoclax, blood (about 2 tablespoons each time) will be drawn to measure your levels of
      uric acid, potassium, creatinine, phosphorus, and calcium, and to check for symptoms of TLS
      at the following timepoints:

        -  Before each dose.

        -  6-8 hours after each dose.

        -  24 hours after each dose.

      Study Visits:

      On Days 1-4 and 8 of Cycle 1:

        -  Blood (about 3 tablespoons) will be drawn for routine testing. If it was not done at
           screening, on Day 1 only, this blood sample will also be used for biomarker testing.

        -  On Days 1 and 8 only, you will have a physical exam.

      On Day 22 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 3 tablespoons) will be drawn for routine testing.

      On Day 14 of Cycles 1 and 2, blood (about 1 teaspoon each time) will be drawn for PK testing
      before the dose and then 6 more times over the next 24 hours after the dose.

      On Day 15 of Cycles 1 and 2:

        -  You will have a physical exam.

        -  Blood (about 1 tablespoon) will be drawn for routine testing.

        -  You will have an EKG.

      On Day 28 (+/- 4 days ) of Cycle 1 and every odd-numbered cycle (+/- 7 days) after that
      (Cycles 3, 5, 7, and so on) for up to 1 year:

        -  You will have a bone marrow aspirate/biopsy for IDH1, cytogenetic, and biomarker
           testing.

        -  Blood (about 1 tablespoon) will be drawn for biomarker testing.

      On Day 1 of Cycle 2 and every cycle after that:

        -  You will have a physical exam.

        -  Blood (about 3 tablespoons) will be drawn for routine testing.

        -  On Day 1 of Cycle 2 only, you will have an EKG.

      On Day 1 of Cycle 3, you will have an EKG.

      End-of-Treatment (Final) Visit:

      When you have received your last dose of study drug:

        -  You will have a physical exam.

        -  Blood (about 4 tablespoons) will be drawn for routine and biomarker testing.

        -  You will have a bone marrow aspirate/biopsy for IDH1, cytogenetic, and biomarker
           testing.

        -  You will have an EKG.

      End-of- Study Visit:

      About 30 days after your last dose of study drug:

        -  You will have a physical exam.

        -  Blood (about 4 tablespoons) will be drawn for routine and biomarker testing.

      If at any point the study doctor thinks it is needed, you will have a bone marrow
      aspirate/biopsy to check the status of the disease.

      Long-Term Follow-Up:

      One (1) time each month for 3 years after the last participant has enrolled onto the study, a
      member of the study staff will contact you to ask how you are doing. This follow-up will take
      place either by phone or at a regularly scheduled clinic visit. If you are contacted by
      phone, the call should last about 15 minutes.
    

Trial Arms

NameTypeDescriptionInterventions
Ivosidenib + VenetoclaxExperimentalParticipants take Venetoclax by mouth 1 time each day on Days 1-14 of each 28 day cycle. Participants take Ivosidenib by mouth once each day starting with Day 15 of Cycle 1.
  • Ivosidenib
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          1. Age >/= 18 years.

          2. Eastern Cooperative Oncology Group (ECOG) performance status of </= 2.

          3. IDH1-R132 mutated disease status as assessed by local laboratory. 2HG-producing IDH1
             variants outside of R132 (i.e. R100) may be eligible after discussion with the PI.

          4. Relapsed/refractory AML. Treatment-naïve patients who are not eligible for standard
             induction chemotherapy may also be eligible after discussion with the PI if in the
             best interest of the patient. Patients with high-risk MDS or MPN (defined as >/ = 10%
             bone marrow blasts) may also be eligible after discussion with the PI.

          5. Baseline cardiac ejection fraction must be >/= 40 %

          6. Adequate hepatic function (direct bilirubin </= 2 x ULN, ALT and/or AST </= 3x ULN)
             unless deemed to be related to underlying leukemia.

          7. Adequate renal function including creatinine clearance >/= 30 ml/min based on the
             Cockcroft-Gault equation.

          8. Willing and able to provide informed consent

          9. In the absence of rapidly proliferative disease, the interval from prior treatment to
             time of initiation will be at least 7 days for cytotoxic or non-cytotoxic
             (immunotherapy) agents.

         10. Male subjects must agree to refrain from unprotected sex and sperm donation from
             initial study drug administration until 90 days after the last dose of study drug
             administration until 90 days after the last dose of study drug

        Exclusion Criteria:

          1. Patients with known allergy or hypersensitivity to AG120 or venetoclax.

          2. Patients who have previously received either AG120 or venetoclax

          3. Patients with any concurrent uncontrolled clinically significant medical condition,
             including infection, laboratory abnormality, or psychiatric illness which could place
             the patient at unacceptable risk of study treatment.

          4. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted
             during study with the following exceptions (1) intrathecal chemotherapy for
             prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea and/or one
             dose of cytarabine (up to 2 g/m2) or hydroxyurea for patients with rapidly
             proliferative disease is allowed before the start of study therapy and for the first
             four weeks on therapy.

          5. Patients receiving concomitant treatment with strong CYP3A4 inhibitors within 3 days
             of start of study therapy (including posaconazole and voriconazole)

          6. Patients receiving concomitant strong CYP3A inducers (avasimibe, carbamazepine,
             phenytoin, rifampin, rifabutin, St. John's wort) within 3 days of start of study
             therapy.

          7. Patients with active graft-versus-host-disease (GVHD) status post stem cell
             transplant, i.e. patients requiring therapy more than chronic steroid
             immunosuppression and/or phototherapy for chronic skin GVHD will be excluded

          8. Patients with any severe gastrointestinal or metabolic condition which could interfere
             with the absorption of oral study medications.

          9. Patients with a concurrent active malignancy under treatment.

         10. QTc interval using Fridericia's formula (QTcF) >/= 450 msec. Bundle branch block and
             prolonged QTc interval are permitted after discussion with the PI

         11. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.

         12. Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to
             meet this criterion.)

         13. Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy
             test, or women of childbearing potential who are not willing to maintain adequate
             contraception. a) Appropriate highly effective method(s) of contraception include oral
             or injectable hormonal birth control, IUD, and double barrier methods (for example a
             condom in combination with a spermicide).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence and Severity of Adverse Events using Common Toxicity Criteria v 4.0
Time Frame:Start of drug combination up to 30 days after drug combination stopped
Safety Issue:
Description:Dose-limiting toxicity (DLT) defined as any grade 3 or 4, clinically significant non-hematologic adverse event or abnormal laboratory value occurring during the first two cycles on study that cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, underlying illness, concurrent illness, or concomitant medication.

Secondary Outcome Measures

Measure:Evaluate Molecular and Cellular Biomarkers That May be Predictive of Antitumor Activity and/or Resistance to Treatment by Assessment of the Depth of Response and Monitoring of Disease Recurrence by Assessment of MRD in the Bone Marrow
Time Frame:Baseline up to 30 days after study drug combination stopped
Safety Issue:
Description:Blood drawn at various time points. The effects of the combination compared not only to historical outcomes in matched groups of patients, but also at the molecular and cellular level by correlating with karyotype and molecular mutation profile. The NGS gene panel performed on the screening BM aspirate and the progression/relapse BM aspirate.
Measure:Duration of Response (DOR)
Time Frame:3 years
Safety Issue:
Description:Duration of response defined as the number of days from the date of initial response to the date of first documented disease progression/relapse or death, whichever occurs first.
Measure:Event Free Survival (EFS)
Time Frame:Start of study treatment up to 3 years
Safety Issue:
Description:Event-free survival defined as the number of days from the date of treatment initiation to the date of documented treatment failure, relapse, or death from any cause, whichever occurs first.
Measure:Overall Survival (OS)
Time Frame:Start of study treatment up to 3 years
Safety Issue:
Description:OS assessed based on revised IWG response criteria for AML (Cheson et al, JCO 2003)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Other diseases of blood and blood-forming organs
  • Advanced hematologic malignancies
  • Acute myeloid leukemia
  • AML
  • IDH1 mutation
  • Relapsed/refractory
  • Ivosidenib
  • AG120
  • Venetoclax
  • AB-199
  • GDC-0199

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