Tomivosertib With Azacitide and Venetoclax for the Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia Who Are Not Suitable for Intensive Chemotherapy
Study Details
Study Description
Brief Summary
This phase I/Ib trial tests the safety, side effects, and best dose of tomivosertib in combination with the standard treatment of azacitidine and venetoclax for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable for intensive chemotherapy. Tomivosertib may stop the growth of cancer cells and may kill them by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing them, stopping them from dividing, or by stopping them from spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving tomivosertib with azacitide and venetoclax may kill more cancer cells in patients with newly diagnosed AML who are not suitable for intensive chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
PRIMARY OBJECTIVE:
- To determine the maximum tolerated dose (MTD) of tomivosertib in combination with azacitidine and venetoclax (dose limiting toxicities [DLTs] to be evaluated by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 criteria).
SECONDARY OBJECTIVES:
-
To assess the adverse event profile of tomivosertib, azacitidine, and venetoclax.
-
To estimate the rate of complete remission (CR). III. To estimate the rate of overall response. IV. To estimate the duration of response (DOR). V. To estimate progression free survival (PFS). VI. To estimate overall survival (OS). VII. To assess the outcomes for patients who undergo allogeneic hematopoietic stem cell transplant (HSCT).
EXPLORATORY OBJECTIVES:
-
To measure eIF4E phosphorylation before treatment and correlate with treatment response.
-
To measure MCL1 expression before and after treatment and correlate with treatment response.
-
To assess the steady-state pharmacokinetics of tomivosertib when it is combined with azacitidine, and venetoclax.
OUTLINE: This is a dose finding study of tomivosertib followed by a dose expansion study.
Patients receive tomivosertib orally (PO), azacitidine subcutaneously (SC) or intravenously (IV), and venetoclax PO while on study. Patients undergo bone marrow biopsy and/or aspirate throughout the study and blood sample collection at baseline and on study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (tomivosertib, azacitidine, venetoclax) Patients receive tomivosertib PO, azacitidine SC or IV, and venetoclax PO while on study. Patients undergo bone marrow biopsy and/or aspirate throughout the study and blood sample collection at baseline and on study. |
Drug: Azacitidine
Given SC or IV
Other Names:
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
Procedure: Bone Marrow Aspirate
Undergo bone marrow aspirate
Other Names:
Procedure: Bone Marrow Biopsy
Undergo bone marrow biopsy
Other Names:
Drug: Tomivosertib
Given PO
Other Names:
Drug: Venetoclax
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of dose-limiting toxicity (DLTs) [From the initiation of trial therapy (cycle 1 day 1), and throughout the first cycle of treatment for a total of 28 days]
A DLT is defined as treatment-emergent and possibly, probably or definitely related toxicity attributable to the addition of tomivosertib to the standard of care treatment of venetoclax and azacitidine. Toxicity is assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Secondary Outcome Measures
- Frequency of adverse events [Up to 18 months]
Safety and tolerability will be summarized by providing a frequency of adverse events (CTCAE version 5.0) by severity, type, timing, and attribution for toxicities of any grade, with rates of >= grade 3 toxicities also analyzed separately. Adverse event rates will be summarized and accompanied by 95% exact binomial confidence intervals.
- Overall response rate [Up to 18 months]
The proportion of treated patients who experience an objective response (complete remission [CR], complete remission with incomplete platelet recovery [CRp], complete remission with incomplete hematological recovery [CRi] and partial remission [PR]) per International Working Group AML Response Criteria. Will be summarized as a proportion with a corresponding exact 95% confidence interval (CI).
- Complete remission rate (CRR) [Up to 18 months]
The proportion of treated patients who experience CR, CRp, and CRi will be reported. The first date of response for CR, CRp, or CRi will be used for the calculation of CRR. Will be summarized as a proportion with a corresponding exact 95% CI.
- Duration of response (DOR) [Time between the day of first documented response to trial therapy (CR, CRp, and CRi or PR), whichever is first recorded, and subsequent disease progression, assessed up to 18 months]
Will be analyzed using the Kaplan-Meier method. The median of DOR, if estimable, will be reported along with the confidence intervals.
- Progression free survival (PFS) [Time between the initiation of trial therapy and the day of first documented disease progression or death from any cause, assessed up to 18 months]
Will be analyzed using the Kaplan-Meier method. The median of PFS, if estimable, will be reported along with the confidence intervals.
- Overall survival (OS) [Time between the initiation of trial therapy and the date of death from any cause, assessed up to 18 months]
Will be analyzed using the Kaplan-Meier method. The median of OS, if estimable, will be reported along with the confidence intervals.
- Transplantation rate [Up to 18 months]
Defined as the proportion of patients who proceed to allogeneic stem cell transplant after treatment. Will be summarized as a proportion with a corresponding exact 95% CI.
- OS for patients who proceed to transplant [From initiation of therapy until the patient completes follow-up, or experiences death from any cause, assessed up to 18 months]
Will estimate the OS for patients who proceed to transplant, compared to those who do not undergo transplant.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients age >= 18 years
-
Patients with newly diagnosed previously untreated AML (based on the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias) who are not suitable for intensive chemotherapy based on one or more of the following three criteria:
-
Age >= 75 years
-
Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3
-
One or more of the following comorbidities:
-
Severe cardiac comorbidity (including congestive heart failure requiring treatment, ejection =< 50%, chronic stable angina, prior anthracycline exposure with increased risk for cardiomyopathy)
-
Pulmonary comorbidity (including diffusion capacity of the lung for carbon monoxide [DLCO] =< 65% or forced expiratory volume in 1 second [FEV1] =< 65%)
-
Moderate hepatic impairment with total bilirubin > 1.5 to 3 times the upper limit of normal
-
Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m2 to < 45 mL/min/1.73 m2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
-
Any other comorbidity or molecular/cytogenetic subtype of AML (to be documented in the electronic medical record [EMR]) that the physician judges would not benefit from intensive chemotherapy; the comorbidity and molecular/cytogenetic subtype of AML must be reviewed and approved by the lead principal investigator before study enrollment NOTE regarding prior treatment for AML: For disease control during screening and before the start of cycle 1 day 1 (C1D1), per institutional practice, patients may receive steroids, hydroxyurea or leukapheresis to control white blood cell (WBC). Patients may have received prior hypomethylating agent and/or venetoclax and/or investigational treatment for antecedent myeloid neoplasm. Hydroxyurea may be given during screening and cycle 1 to control WBC
-
For patients with a known history of human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have a viral load undetectable for 6 months prior to registration
-
For patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
-
Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
-
Patients must agree to serial bone marrow aspirate/biopsies
-
The effects of venetoclax and tomivosertib on the developing human fetus are unknown. Azacitidine is classified by the Food and Drug Administration (FDA) as a pregnancy category D medication, indicating it may cause fetal harm when administered to a pregnant woman. For these reasons, patients of child-bearing potential (POCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) and refrain from donating eggs from the time of informed consent, for the duration of study treatment, and for 30 days following completion of study therapy. Should a patient become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately. People with sperm-producing reproductive capacity treated or enrolled on this protocol must also agree to use adequate contraception (or abstinence or vasectomy) and refrain from donating sperm from the time of informed consent, for the duration of study therapy, and 30 days after completion of study therapy.
NOTE: A POCBP is any person with an egg-producing reproductive tract (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
-
Has not undergone a hysterectomy or bilateral oophorectomy
-
Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
-
POCBP must have a negative serum beta-subunit of human chorionic gonadotropin (beta-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) within 14 days prior to registration on study and have a negative serum beta-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment. NOTE: The screening serum pregnancy test can be used as the test prior to the start of study treatment if it is performed within the 72-hour timeframe
-
Patients must provide written, signed, and dated informed consent prior to study registration. Patient must have the ability to understand and the willingness to sign a written informed consent document. The patient must be willing and able to comply with the protocol for the duration of the study. NOTE: No study-specific screening procedures may be performed until written consent has been obtained
Exclusion Criteria:
-
Patients who are receiving any other investigational agents
-
Patients who have a prior or concurrent malignancy that may interfere with study treatment or safety. NOTE: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (i.e., cancers under observation that do not require treatment, resectable skin cancer, low risk prostate cancer, ductal carcinoma in situ [DCIS], lobular carcinoma in situ [LCIS], etc.) are eligible per lead primary investigator (PI) discretion. Patients with prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) are eligible
-
Patients who have conditions that would interfere with drug absorption
-
Patients who have conditions that would interfere with their ability to swallow oral medications
-
Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to tomivosertib, azacitidine, and/or venetoclax
-
Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:
-
Uncontrolled systemic infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, antifungal therapy and/or other treatment)
-
Unstable angina pectoris
-
Cardiac ventricular arrhythmia, except for patients that can be successfully treated with rate control or anti-arrhythmic agents
-
Psychiatric illness/social situations that would limit compliance with study requirements
-
Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
-
Patients who are pregnant or nursing. Pregnant people are excluded from this study because azacitidine is pregnancy category D per the FDA, with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the pregnant person with azacitidine, breastfeeding should be discontinued if the person is treated with azacitidine
-
Patient must avoid consuming grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), star fruit or St. John's Wort before the anticipated first dose of venetoclax and continue to not consume these agents while on treatment with ventoclax
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Northwestern University | Chicago | Illinois | United States | 60611 |
Sponsors and Collaborators
- Northwestern University
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Shira N Dinner, Northwestern University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NU 22H08
- NCI-2023-00767
- NU 22H08
- STU00218776
- P30CA060553