This is a phase Ib study with a 3 + 3 dose escalation design followed by a dose-expansion
phase.
The study hypothesis is that the combination of pevonedistat, azacitidine, and venetoclax
will be effective, safe, and well tolerated in patients with AML.
The primary objective of this portion of the study is to determine a recommended phase 2 dose
(RP2D) of pevonedistat, azacitidine, and venetoclax. The investigators will use a variation
of the 3+3 design where both escalation and de-escalation are possible. A minimum of nine and
a maximum of 24 subjects will be needed for the phase 1 part of the study (dose-escalation
phase). The dose limiting toxicity (DLT) observation period for dose escalation will be
during cycle 1.
Prior to enrolling patients at the next applicable dose level, all patients must complete the
DLT period of the current dose level. The Data Safety Monitoring Committee will review the
results of each dose level before the next applicable dose level opens for enrollment.
Dose Expansion Phase
The primary objective of this portion of the study is to confirm the feasibility and
tolerance of the combination of pevonedistat, azacitidine, and venetoclax in patients with
AML. Given that the dose-escalation phase described above will be able to establish the RP2D,
the dose-expansion phase will employ this dose. In addition to relapsed/refractory AML
patients, newly diagnosed AML patients can also be included in this phase to assess the
feasibility and tolerance of this combination regimen.
A minimum of six patients will be enrolled in the dose-expansion phase, which could be
expanded based on the safety and tolerability.
Inclusion Criteria:
- Voluntary written consent must be given before performance of any study-related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the subject at any time without prejudice to future medical care.
- Male or female subjects 18 years or older.
- Patients must have a diagnosis of morphologically documented AML or secondary AML
[from prior conditions, such as myelodysplastic syndrome (MDS), or therapy-related AML
(t-AML), as defined by World Health Organization (WHO) criteria.
- During the dose-escalation phase, only subjects with relapsed/refractory AML will be
eligible.
- During the expansion phase, subjects with relapsed/refractory AML will be eligible OR
subjects with newly diagnosed AML unable or unwilling to receive intensive induction
chemotherapy will be eligible.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
- Clinical laboratory values within the following parameters:
- Albumin >2.7 g/dL.
- Total bilirubin ≤ institutional upper limit of normal (ULN). Patient with total
bilirubin > ULN may enroll if direct bilirubin ≤1.5 x institutional ULN of the direct
bilirubin.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ×
institutional ULN.
- Creatinine clearance ≥ 30 mL/min (calculated by Cockcroft-Gault formula).
- White blood cell (WBC) count < 25,000/μL before administration of pevonedistat on
cycle 1 day 1. (Note: Hydroxyurea may be used to meet this criterion.)
- Prothrombin time (PT) and partial thromboplastin time (PTT) < 1.5 institutional ULN.
- Female subjects who:
- Are postmenopausal for at least one year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential:
- Agree to practice one highly effective method and one additional effective (barrier)
method of contraception, at the same time, from the time of signing the informed
consent through four months after the last dose of study drug (female and male condoms
should not be used together), OR
- Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] withdrawal, spermicides only, and lactational
amenorrhea are not acceptable methods of contraception).
- Male subjects, even if surgically sterilized (i.e., status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment
period from the time of signing the informed consent through and through four months
after the last dose of study drug (female and male condoms should not be used
together), OR
- Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides
only, and lactational amenorrhea are not acceptable methods of contraception.)
Exclusion Criteria:
- Acute promyelocytic leukemia.
- Extramedullary only relapse AML.
- Treatment with systemic antineoplastic therapy or radiation within 14 days before the
study enrollment. The use of hydroxyurea for leukoreduction is permitted. Subjects
must have recovered from the side effects of prior therapy per treating physician
discretion.
- Hematopoietic Stem Cell Transplantation (HCT) within 100 days of enrollment, or
evidence of veno-occlusive disease (VOD) at any time post-transplant, or active acute
graft-versus-host disease requiring systemic immunosuppressive therapy.
- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of study procedures.
- Current systemic treatment with strong or moderate cytochrome P3A (CYP3A) inducers
within seven days prior to enrollment.
- Any evidence of spontaneous tumor lysis syndrome (TLS).
- Active, significant, uncontrolled infection or severe infectious disease requiring
therapy (bacterial, viral or fungal) as per the discretion of the treating physician.
- Presence of another active malignancy (requiring treatment) diagnosed within 12 months
with the exception of
- adequately treated non-melanoma skin cancer.
- adequately treated melanoma grade 2 or less.
- cervical intraepithelial neoplasia.
- 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.
- adequately treated prostate cancer.
- Life-threatening illness with life expectancy < 6 months unrelated to cancer.
- Known HIV positive patients who do not meet the following criteria:
- Cluster of differentiation (CD4) count > 350 cells/mm^3.
- Undetectable viral load.
- Maintained on modern therapeutic regimens utilizing non-cytochrome (CYP)-interactive
agents.
- No history of AIDS-defining opportunistic infections.
- Known hepatitis B surface antigen seropositive or known or suspected active hepatitis
C infection.
Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting
of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must
have an undetectable hepatitis B viral load. Patients who have positive hepatitis C
antibody may be included if they have an undetectable hepatitis C viral load.
- Known hepatic cirrhosis or severe pre-existing hepatic impairment
- Known cardiopulmonary disease defined as:
- Unstable angina.
- Congestive heart failure [New York Heart Association (NYHA) Class III or IV].
- Myocardial infarction (MI) within six months prior to enrollment (subjects who had
ischemic heart disease such as a (ACS), MI, and/or revascularization greater than six
months before screening and who are without cardiac symptoms may enroll).
- Symptomatic cardiomyopathy.
- Clinically significant pulmonary hypertension requiring pharmacologic therapy.
- Clinically significant arrhythmia.
- History of polymorphic ventricular fibrillation or torsade de pointes.
- Permanent atrial fibrillation [a fib], defined as continuous a fib for ≥ 6 months.
- Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring
cardioversion in the four weeks before screening.
- Grade 3 a fib defined as symptomatic and incompletely controlled medically, or
controlled with device (e.g., pacemaker), or ablation and
- Patients with paroxysmal a fib or < Gr 3 a fib for period of at least six months are
permitted to enroll provided that their rate is controlled on a stable regimen.
- Subject has chronic respiratory disease that requires continuous oxygen, or
significant history of renal, neurologic, psychiatric, endocrinologic, metabolic,
immunologic, hepatic, cardiovascular disease, or any other medical condition that in
the opinion of the investigator would adversely affect his/her participating in this
study.
- Treatment with any investigational products, other than the study drugs, within 14
days before the study enrollment or during the study period.
- Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic
blood pressure > 95 mm Hg).
- Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated as per institutional
guidelines.
- Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
radionuclide angiography.
- Patients with uncontrolled coagulopathy or bleeding disorder.
- Known moderate-to-severe chronic obstructive pulmonary disease, interstitial lung
disease, and pulmonary fibrosis.
- Major surgery within 14 days before the enrollment or a scheduled major surgery during
study period.
- Known central nervous system (CNS) involvement with AML.
- Gastrointestinal (GI) tract disease that causes an inability to take oral medications,
malabsorption syndrome, prior surgical procedures affecting absorption, uncontrolled
inflammatory GI disease (e.g. Crohn's disease, ulcerative colitis).
- Female subjects who are both lactating and breastfeeding or of childbearing potential
who have a positive serum test during screening.
- Female subjects who intend to donate eggs (ova) during the course of this study or
four months after receiving their last dose of study drug(s).
- Male subjects who intend to donate sperm during the course of this study or four
months after receiving their last dose of study drug(s).
- Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade
containing Seville oranges) or star fruit from the day of consent to throughout the
study period.
