Clinical Trials /

Safety and Efficacy of Venetoclax With Escalating Doses of Omacetaxine in Patients With Acute Myeloid Leukemia

NCT04926285

Description:

This will be a single arm, open label Phase Ib dose-escalation study of the combination of VEN and OM, conducted using an innovative Bayesian Optimal Interval-design, to find the MTD in participants with relapsed/refractory hematologic malignancies including those failing treatment with venetoclax-containing regimens. Treatment plan will consist of an induction phase, followed by a consolidation phase if applicable.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Venetoclax With Escalating Doses of Omacetaxine in Patients With Acute Myeloid Leukemia
  • Official Title: VEN-OM: Phase Ib Study of Safety and Efficacy of Venetoclax When Combined With Escalating Doses of Omacetaxine in Patients With Relapsed/Refractory Acute Myeloid Leukemia Failing Treatment With Venetoclax-Containing Regimens

Clinical Trial IDs

  • ORG STUDY ID: 2021-0450
  • NCT ID: NCT04926285

Conditions

  • Relapsed or Refractory Hematologic Malignancies

Interventions

DrugSynonymsArms
OmacetaxineCohort 1
VenetoclaxCohort 1

Purpose

This will be a single arm, open label Phase Ib dose-escalation study of the combination of VEN and OM, conducted using an innovative Bayesian Optimal Interval-design, to find the MTD in participants with relapsed/refractory hematologic malignancies including those failing treatment with venetoclax-containing regimens. Treatment plan will consist of an induction phase, followed by a consolidation phase if applicable.

Detailed Description

      This is a Phase Ib study of VEN and OM, the investigator will conduct a Bayesian Optimal
      Interval-designed trial following the approach of Yuan et al 40 to find the MTD with a target
      DLT rate of 2%, 4 pre-specified doses, and between 24 and up to 30 participants. Beginning
      with the first participant treated at the lowest dose of OM 0.625 mg/m2 q12h with VEN 400 mg,
      dose escalation and de-escalation of OM will involve a comparison of the observed DLT rate
      (p) at the current dose with a pair of fixed, pre-specified boundary rates: λe (escalation)
      with p ≤ 0.157; λd (de-escalation) with p ≥ 0.238; or otherwise remain at the same dose per
      the dosing schedule. The trial will start with a cohort size of 1 participant (unless DLT is
      experienced) and escalated for each subsequent participant until the first DLT occurs and the
      current dose cohort is expanded to 3.40 In a simulation of these conditions with a target DLT
      rate of 20% (1), the percentage correct selection of the MTD is between 60% with enrollment
      of 20 participants and 70% with enrollment of 24 participants. Implementation of the trial
      design will be performed using R package 'BOIN'. If the investigator observes an unexpected
      toxicity in Cohort 1 the investigator will use OM 0.5 mg/m2 daily with VEN for Cohort -1
      Following each cycle, participants will be evaluated for complete response (CR) by
      International Working Group (IWG) criteria 41

      The subject visit schedule and procedures are below:

      Screening Visit:

      Physical Exam (vital signs, medical history, prior therapies, height and weight) Urine
      Pregnancy Test, EKG, Blood Work (Complete blood count, (CBC), basic metabolic panel (BMP),
      Uric Acid, Albumin, ALT/AST, bilirubin, alkaline phosphatase, protein, LDH, PT/INR, PTT and
      fibrinogen, HIV, Hepatitis B/C) Bone Marrow Aspirate

      Treatment Visits:

      Day 1 of Each Cycle:

      Physical Exam Urine Pregnancy Test, EKG, (only after 1st, 7th and 11th dose of study
      medication) Blood Work (Complete blood count, (CBC), basic metabolic panel (BMP), Uric Acid,
      Albumin, ALT/AST, bilirubin, alkaline phosphatase, protein, LDH, PT/INR, PTT and fibrinogen,
      HIV, Hepatitis B/C) Study Drug (s) Given

      Day 28 of each Cycle:

      Bone Marrow Biopsy Safety Follow Up Visit: (14 days + 7 days after the last dose of
      treatment) performed 14 days (±7 days) after the last dose of treatment. Physical Exam, Blood
      Work (Complete blood count, (CBC), basic metabolic panel (BMP), Uric Acid, Albumin, ALT/AST,
      bilirubin, alkaline phosphatase, protein, LDH, PT/INR, PTT and fibrinogen, HIV, Hepatitis
      B/C) Long Term Follow Up Visit: (every 2 months ±14 days for 12 months), Physical Exam Blood
      Work (Complete blood count, (CBC), basic metabolic panel (BMP), Uric Acid, Albumin, ALT/AST,
      bilirubin, alkaline phosphatase, protein, LDH, PT/INR, PTT and fibrinogen, HIV, Hepatitis
      B/C)
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalOmacetaxine 0.625 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days
  • Omacetaxine
  • Venetoclax
Cohort 2ExperimentalOmacetaxine 1.25 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days
  • Omacetaxine
  • Venetoclax
Cohort 3ExperimentalOmacetaxine 2.0 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days
  • Omacetaxine
  • Venetoclax
Cohort 4ExperimentalOmacetaxine 2.5 mg/m2 SQ injection q12h days 1-7 with Venetoclax 400 mg orally daily on days 4-28 Cycles are 28 days
  • Omacetaxine
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          1. Age 18-75 years of age at time of consent.

          2. Have relapsed/refractory AML (primary or secondary) and have progressed on ≥ 1 line of
             therapy, at least one of which must have included a VEN-containing regimen.

          3. Eastern Cooperative Oncology Group (ECOG) Performance score 0-2 (see Appendix 1).

          4. Prior cancer treatment must be completed at least 21 days prior to registration and
             the subject must have recovered from all reversible acute toxic effects of the regimen
             (other than alopecia) to ≤ Grade 1 or baseline.

             i. With the exception of Hydroxyurea; if Hydroxyurea is used to reduce the white blood
             blast count to < 25 x 109/L, then it must be discontinued at least 48 hours prior to
             registration and bone marrow/peripheral blood sampling, and the subject must have
             recovered from all reversible acute toxic effects to ≤ Grade 1 or baseline.

          5. Life expectancy of 6 months or greater as determined by the treating physician.

          6. Demonstrate adequate organ function as defined in the table below; all screening labs
             to be obtained within 28 days prior to registration.

             System Laboratory Value Renal Creatinine/Calculated creatinine clearance (CrCl) CrCl ≥
             50 mL/min using the Cockcroft-Gault formula Hepatic Bilirubin ≤ 1.5 × upper limit of
             normal (ULN). Excluding patients diagnosed with Gilbert's syndrome Aspartate
             aminotransferase (AST) ≤ 3 × ULN Alanine aminotransferase (ALT) ≤ 3 × ULN

          7. Provided written informed consent and HIPAA authorization for release of personal
             health information, approved by an Institutional Review Board (IRB).

          8. NOTE: HIPAA authorization may be included in the informed consent or obtained
             separately.

          9. Females of childbearing potential must have a negative serum pregnancy test within 7
             days prior to registration. NOTE: Females are considered of child bearing potential
             unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or they have not experienced menstruation for at
             least 12 consecutive months

         10. Females of childbearing potential and males must be willing to use effective
             contraception during treatment and for at least 30 days after the last dose of
             Venetoclax. Females will be advised to use effective contraception for at least 6
             months after the last dose of omacetaxine and males for at least 3 months after the
             last dose of omacetaxine.

         11. As determined by the enrolling physician or protocol designee, ability of the subject
             to understand and comply with study procedures for the entire length of the study.

        6.2 Exclusion Criteria

        Subjects meeting any of the criteria below may not participate in the study:

          1. Patients with history of prior use of Omacetaxine.

          2. White blood cell count > 25 × 109/L (hydroxyurea permitted to decrease WBC count).

          3. History of other malignancies within 1 year prior to study entry, with the exception
             of: adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
             breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the
             skin; previous malignancy confined and surgically resected (or treated with other
             modalities) with curative intent.

          4. Unresolved > grade 2 DIC.

          5. Investigational drug use within 4 weeks of study entry.

          6. History of CHF requiring treatment, left ventricular ejection fraction ≤ 40%, cardiac
             insufficiency grade III or IV per New York Heart Association classification (NYHA; see
             Appendix 2), or chronic stable angina

          7. Patients who are HIV positive.

          8. Known CNS involvement with AML.

          9. Previous hematopoietic stem cell transplant within 2 months.

         10. Patients who are positive for hepatitis B or C infection with the exception of those
             with an undetectable viral load over the prior 3 months. Subjects with serologic
             evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+) may participate.

         11. Active uncontrolled infection or severe systemic infection. Enrollment is possible
             after control of infection, at discretion of the treating physician.

         12. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study).

         13. Patients who have received strong and/or moderate CYP3A inducers or inhibitors within
             7 days prior to the initiation of study treatment unless therapy is deemed necessary
             by the treating physician. (See Section 8.7.2, Table 3 and Appendix 3).

         14. Patients who have consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or Starfruit within 3 days prior to the
             initiation of study treatment.

         15. Malabsorption syndrome or other condition that precludes enteral route of
             administration.

         16. Psychological, familial, sociological, or geographical condition that would preclude
             study compliance and follow-up.

         17. Unable or unwilling to undergo a screening bone marrow study.

         18. Other severe acute or chronic medical or psychiatric condition, or 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 investigator, would make the patient
             inappropriate for enrollment in this study.

        1. Age 18-75 years of age at time of consent. 2. Have relapsed/refractory AML (primary or
        secondary) and have progressed on ≥ 1 line of therapy, at least one of which must have
        included a VEN-containing regimen.

        3. Eastern Cooperative Oncology Group (ECOG) Performance score 0-2 (see Appendix 1).

        4. Prior cancer treatment must be completed at least 21 days prior to registration and the
        subject must have recovered from all reversible acute toxic effects of the regimen (other
        than alopecia) to ≤ Grade 1 or baseline.

        i. With the exception of Hydroxyurea; if Hydroxyurea is used to reduce the white blood
        blast count to < 25 x 109/L, then it must be discontinued at least 48 hours prior to
        registration and bone marrow/peripheral blood sampling, and the subject must have recovered
        from all reversible acute toxic effects to ≤ Grade 1 or baseline.

        5. Life expectancy of 6 months or greater as determined by the treating physician.

        6. Demonstrate adequate organ function as defined in the table below; all screening labs to
        be obtained within 28 days prior to registration.

        System Laboratory Value Renal Creatinine/Calculated creatinine clearance (CrCl) CrCl ≥ 50
        mL/min using the Cockcroft-Gault formula Hepatic Bilirubin ≤ 1.5 × upper limit of normal
        (ULN). Excluding patients diagnosed with Gilbert's syndrome Aspartate aminotransferase
        (AST) ≤ 3 × ULN Alanine aminotransferase (ALT) ≤ 3 × ULN

        7. Provided written informed consent and HIPAA authorization for release of personal health
        information, approved by an Institutional Review Board (IRB).

        8. NOTE: HIPAA authorization may be included in the informed consent or obtained
        separately.

        9. Females of childbearing potential must have a negative serum pregnancy test within 7
        days prior to registration. NOTE: Females are considered of child bearing potential unless
        they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
        bilateral oophorectomy) or they have not experienced menstruation for at least 12
        consecutive months 10. Females of childbearing potential and males must be willing to use
        effective contraception during treatment and for at least 30 days after the last dose of
        Venetoclax. Females will be advised to use effective contraception for at least 6 months
        after the last dose of omacetaxine and males for at least 3 months after the last dose of
        omacetaxine.

        11. As determined by the enrolling physician or protocol designee, ability of the subject
        to understand and comply with study procedures for the entire length of the study.

        Exclusion Criteria:

          1. Patients with history of prior use of Omacetaxine.

          2. White blood cell count > 25 × 109/L (hydroxyurea permitted to decrease WBC count).

          3. History of other malignancies within 1 year prior to study entry, with the exception
             of: adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
             breast; basal cell carcinoma of the skin or localized squamous cell carcinoma of the
             skin; previous malignancy confined and surgically resected (or treated with other
             modalities) with curative intent.

          4. Unresolved > grade 2 DIC.

          5. Investigational drug use within 4 weeks of study entry.

          6. History of CHF requiring treatment, left ventricular ejection fraction ≤ 40%, cardiac
             insufficiency grade III or IV per New York Heart Association classification (NYHA; see
             Appendix 2), or chronic stable angina

          7. Patients who are HIV positive.

          8. Known CNS involvement with AML.

          9. Previous hematopoietic stem cell transplant within 2 months.

         10. Patients who are positive for hepatitis B or C infection with the exception of those
             with an undetectable viral load over the prior 3 months. Subjects with serologic
             evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+) may participate.

         11. Active uncontrolled infection or severe systemic infection. Enrollment is possible
             after control of infection, at discretion of the treating physician.

         12. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study).

         13. Patients who have received strong and/or moderate CYP3A inducers or inhibitors within
             7 days prior to the initiation of study treatment unless therapy is deemed necessary
             by the treating physician. (See Section 8.7.2, Table 3 and Appendix 3).

         14. Patients who have consumed grapefruit, grapefruit products, Seville oranges (including
             marmalade containing Seville oranges) or Starfruit within 3 days prior to the
             initiation of study treatment.

         15. Malabsorption syndrome or other condition that precludes enteral route of
             administration.

         16. Psychological, familial, sociological, or geographical condition that would preclude
             study compliance and follow-up.

         17. Unable or unwilling to undergo a screening bone marrow study.

         18. Other severe acute or chronic medical or psychiatric condition, or 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 investigator, would make the patient
             inappropriate for enrollment in this study.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of Omacetaxine in combination with Venetoclax
Time Frame:12 months
Safety Issue:
Description:What is the MTD of Omacetaxine in combination with Venetoclax?

Secondary Outcome Measures

Measure:Efficacy of Omacetaxine in combination with Venetoclax
Time Frame:16 weeks
Safety Issue:
Description:Number of participants achieving Overall Response Rate (ORR) after 3 cycles which includes Complete Response (CR) and Complete Remission with Incomplete hematologic recovery (CRi )
Measure:Evaluate AEs
Time Frame:12 months
Safety Issue:
Description:Number of participants having treatment related AES using CTCAE v5.0 criteria
Measure:Overall Survival (OS)
Time Frame:6 months
Safety Issue:
Description:Number of participants having OS measured from the date of entry to the date of death from any cause
Measure:Overall Survival (OS)
Time Frame:12 months
Safety Issue:
Description:Number of participants having OS measured from the date of entry to the date of death from any cause
Measure:Event Free Survival (EFS)
Time Frame:6 months
Safety Issue:
Description:Number of participants having EFS measured from the date of entry to the date of treatment failure, disease relapse, or death from any cause
Measure:Event Free Survival (EFS)
Time Frame:12 months
Safety Issue:
Description:Number of participants having EFS measured from the date of entry to the date of treatment failure, disease relapse, or death from any cause

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Illinois at Chicago

Last Updated

June 22, 2021