Safety and Efficacy of Venetoclax With Escalating Doses of Omacetaxine in Patients With Acute Myeloid Leukemia (VEN-OM)

  • STATUS
    Recruiting
  • End date
    Jul 25, 2025
  • participants needed
    30
  • sponsor
    University of Illinois at Chicago
Updated on 25 May 2022

Summary

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.

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)

Details
Condition Relapsed or Refractory Hematologic Malignancies
Treatment Omacetaxine, venetoclax
Clinical Study IdentifierNCT04926285
SponsorUniversity of Illinois at Chicago
Last Modified on25 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Age 18-75 years of age at time of consent
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
Eastern Cooperative Oncology Group (ECOG) Performance score 0-2 (see Appendix 1)
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
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
Life expectancy of 6 months or greater as determined by the treating physician
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 ≤
5 × upper limit of normal (ULN). Excluding patients diagnosed with Gilbert's
syndrome Aspartate aminotransferase (AST) ≤ 3 × ULN Alanine aminotransferase
(ALT) ≤ 3 × ULN
Provided written informed consent and HIPAA authorization for release of personal health information, approved by an Institutional Review Board (IRB)
NOTE: HIPAA authorization may be included in the informed consent or obtained separately
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
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
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

White blood cell count > 25 × 109/L (hydroxyurea permitted to decrease WBC count)
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
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
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
Active uncontrolled infection or severe systemic infection. Enrollment is possible after control of infection, at discretion of the treating physician
Subjects meeting any of the criteria below may not participate in the study
Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
Patients with history of prior use of Omacetaxine
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)
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
Malabsorption syndrome or other condition that precludes enteral route of administration
Unresolved > grade 2 DIC
Psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up
Investigational drug use within 4 weeks of study entry
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
Patients who are HIV positive
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
Known CNS involvement with AML
Previous hematopoietic stem cell transplant within 2 months
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
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
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
Unable or unwilling to undergo a screening bone marrow study
Provided written informed consent and HIPAA authorization for release of personal health
information, approved by an Institutional Review Board (IRB)
NOTE: HIPAA authorization may be included in the informed consent or obtained
Eastern Cooperative Oncology Group (ECOG) Performance score 0-2 (see Appendix 1)
separately
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
Life expectancy of 6 months or greater as determined by the treating physician
they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or
Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 28 days prior to registration
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
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
White blood cell count > 25 × 109/L (hydroxyurea permitted to decrease WBC count)
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
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
Exclusion Criteria
Patients with history of prior use of Omacetaxine
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
Unresolved > grade 2 DIC
Active uncontrolled infection or severe systemic infection. Enrollment is possible
Investigational drug use within 4 weeks of study entry
after control of infection, at discretion of the treating physician
Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
Patients who are HIV positive
mother is being treated on study)
Known CNS involvement with AML
Patients who have received strong and/or moderate CYP3A inducers or inhibitors within
Previous hematopoietic stem cell transplant within 2 months
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)
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
Malabsorption syndrome or other condition that precludes enteral route of
administration
Psychological, familial, sociological, or geographical condition that would preclude
Unable or unwilling to undergo a screening bone marrow study
study compliance and follow-up
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
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