Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To determine overall survival rate at 1 year of the regimen in patients with newly diagnosed acute myeloid leukemia (AML). (Cohort A) II. To determine the complete remission (CR)/complete remission without recovery of counts (CRi) rate of the regimen in patients with relapsed/refractory AML or high-risk myelodysplastic syndrome (MDS). (Cohort B)

SECONDARY OBJECTIVES:

I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, event-free survival, and overall survival).

II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).

III. To determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.

II. To evaluate clonal evolution from diagnosis to relapse.

OUTLINE:

INDUCTION (CYCLE 1): Patients receive azacitidine intravenously (IV) over 30-60 minutes or subcutaneously (SC) on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 6 months thereafter.

• Azacitidine (Drug), also known as 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza: Given IV or SC
• Trametinib (Drug), also known as GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist: Given PO
• Venetoclax (Drug), also known as ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto: Given PO

Primary outcomes

• Participants With a Response [Up to 2.5 years]: Overall response is defined as the number of participants achieving Complete Remission (CR) or Complete Remission without recovery of counts (CRi) CR is Normalization of the peripheral blood and bone marrow with </= to 5 % blasts with a granulocyte count of 1 x 10\^9/L or greater and a platelet count of 100 x 10\^9/L and complete resolution of all extramedullary disease. CRi is Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets < 100 x 10\^9/L or neutrophils < 1 x 10\^9/L).

Secondary outcomes

• Minimal Residual Disease Negativity [Up to time of relapse, assessed up to 2.5 years]: Will be assessed by flow cytometry and estimated along with 95% credible intervals.
• Relapse-free Survival [From documented CR/CRi until relapse or death, assessed until study completion]: Relapse-free survival is the time from documented CR/CRi until relapse or death.
• Event-free Survival [From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed until study completion]: Event-free survival is the time from the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death).
• Overall Survival [From the first day of treatment to time of death from any cause, assessed until study completion]: Overall survival is defined as the time from the first day of treatment to time of death from any cause.
• Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation [Up to 2.5 years]: Will be totaled based on the number of participants who continue with hematopoietic stem cell transplantation post treatment.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Diagnosis:

  * Cohort A (frontline): Newly diagnosed AML
  * Cohort B (relapsed/refractory): Relapsed/refractory AML or relapsed/refractory MDS or chronic myelomonocytic leukemia (CMML) that is intermediate-2 or high-risk by the International Prognostic Scoring System with >= 10% blasts harboring a Ras pathway-activating mutation. Eligible mutations include: activating mutations of KIT, HRAS/NRAS/KRAS, BRAF, CBL or PTPN11 or loss of function mutation of NF1. Other mutations not listed here that are anticipated to activate Ras signaling may be considered for enrollment after discussion with the principal investigator (PI)
* Performance status =< 2 (Eastern Cooperative Oncology Group \[ECOG\] scale)
* Total serum bilirubin =< 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3 x ULN, unless due to the underlying leukemia approved by the PI
* Creatinine clearance >= 30 mL/min
* Ability to swallow
* Signed informed consent

Exclusion Criteria:

* Patients suitable for and willing to receive intensive induction chemotherapy (cohort A only)
* Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment)
* Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI
* Consumed strong inducer of CYP3A or p-glycoprotein within 3 days of study enrollment. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wart
* Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for cytoreduction) permitted
* Pregnant women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception throughout the study period and for at least 6 months after the last dose of study drugs. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control throughout the study period and for at least 4 months after the last dose of study drugs. Lactating women (or those planning to breastfeed) should not breastfeed during treatment of trametinib and for at least 2 months after the last dose of trametinib

Participant flow

Outcome results

• Participants With a Response (Primary), Count of participants, Participants: Cohort A (Newly Diagnosed AML Patients) 2; Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) 2
• Minimal Residual Disease Negativity (Secondary), Count of participants, Participants: Cohort A (Newly Diagnosed AML Patients) 1; Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) 1
• Relapse-free Survival (Secondary), Median, Months: Cohort A (Newly Diagnosed AML Patients) 19 (5.6 to 32.3); Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) NA (31.0 to 34.6)
• Event-free Survival (Secondary), Median, Months: Cohort A (Newly Diagnosed AML Patients) 1.8 (0.5 to 36.4); Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) 2.1 (0.2 to 35.9)
• Overall Survival (Secondary), Median, Months: Cohort A (Newly Diagnosed AML Patients) 2.5 (0.5 to 36.4); Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) 2.4 (0.5 to 38.6)
• Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation (Secondary), Count of participants, Participants: Cohort A (Newly Diagnosed AML Patients) 0; Cohort B (Relapsed/Refractory AML or Higher-risk MDS or CMML Patients) 1

Adverse events

Time frame: All-Cause Mortality monitored/assessed up to 3.5 years, Adverse Events monitored/assessed up to 2.5 years

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2021-02-08)
• Informed Consent Form (PDF, 2020-06-04)

• Nicholas Short, Principal investigator, M.D. Anderson Cancer Center