Pevonedistat with Combination Chemotherapy for the Treatment of Recurrent or Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Non-Hodgkin Lymphoma
- Patients must have a diagnosis of a relapsed/refractory ALL (including induction failure) or lymphoblastic non-Hodgkin lymphoma
- No known contraindications to intended therapies
- Prior anthracycline exposure: Patients must have had less than 450 mg/m^2 lifetime exposure of anthracycline chemotherapy. For patients whose cumulative dose is between 350-450 mg/m^2, Zinecard is strongly recommended
- At least 3 months since the last treatment with a “VXLD” induction/re-induction type regimen (i.e., anthracycline, steroid, asparaginase and vincristine)
- Eastern Cooperative Oncology Group (ECOG) performance status corresponding to 0, 1, or 2 and/or Karnofsky score above 50%
- Albumin > 2.7 g/dL (repeat if more than 3 days before the first dose)
- Total bilirubin =< upper limit of normal (ULN) except in patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin =< 1.5 x ULN of the direct bilirubin (repeat if more than 3 days before the first dose)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (repeat if more than 3 days before the first dose)
- Creatinine clearance >= 50 mL/min (repeat if more than 3 days before the first dose)
- Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion hemolysis is allowed (repeat if more than 3 days before the first dose)
- White blood cell (WBC) count < 50,000/uL before administration of pevonedistat on cycle 1 day 1. Note: Hydroxyurea or leukapheresis may be used to control the level of circulating leukemic blast cell counts. (if applicable) (repeat if more than 3 days before the first dose)
- Female patients who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential: ** Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 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 patients, even if surgically sterilized (i.e., status post-vasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 4 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
- 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 patient at any time without prejudice to future medical care
- Patients must have recovered from the acute side effects of all prior anticancer therapy * At least 1 week from prior cytotoxic chemotherapy * At least 4 weeks from craniospinal irradiation * At least 4 months since hematopoietic stem cell transplantation (HSCT) with no evidence of acute graft versus host disease (GVHD)
- Treatment with any investigational products within 2 weeks before the first dose of any study drug
- Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures
- Active uncontrolled infection or severe infectious disease, defined as positive blood culture within 48 hours of study registration, need for supplemental oxygen or vasopressors within 48 hours of study entry
- Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period
- Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection
- Patients with other malignancies that do not meet the exception in the criterion above are excluded from participating in the trial
- Life-threatening illness unrelated to cancer
- Patients with uncontrolled coagulopathy or bleeding disorder, deemed not to be related to underlying disease
- Known human immunodeficiency virus (HIV) seropositive
- 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 6 months prior to first dose (patients who had ischemic heart disease such as a (acute coronary syndrome [ACS]), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll); * Cardiomyopathy * 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 4 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 < grade (gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen ** Implantable cardioverter defibrillator ** Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing) ** Pulmonary hypertension
- 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 according to institutional guidelines
- Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography
- Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis
- Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug. Clinically significant metabolic enzyme inducers are not permitted during this study
- Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea
- Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of study drug
- Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
- Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
- No systemic corticosteroids allowed aside from dexamethasone treatment directed at leukemia. Systemic corticosteroids used for physiological replacement (e.g., adrenal insufficiency) are allowed
- Patients who are allergic to PEG-asparaginase or who cannot tolerate any asparaginase because of history of pancreatitis, will go on study without asparaginase. Substitution for Erwinaze is permitted for patients who had an allergic reaction to PEG-asparaginase
- Known intolerance to doxorubicin, pevonedistat or vincristine
- Patients who have started protocol therapy prior to enrollment. Patient may still enroll if intrathecal (IT) therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure
I. To evaluate the safety and tolerability of pevonedistat/vincristine sulfate (vincristine), dexamethasone, pegaspargase (PEG-L-asparaginase), and doxorubicin hydrochloride (doxorubicin) (VXLD) combination therapy in adolescent and young adult (AYA) patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic non-Hodgkin lymphoma, and determine the maximum tolerated dose (MTD), for the purpose of obtaining a recommended phase 2 dose (RP2D) regimen.
I. To evaluate the clinical response rates when pevonedistat is combined with VXLD chemotherapy.
II. To evaluate the biological response of ALL blasts from AYA patients receiving pevonedistat in a window fashion and at later time points.
III. To describe the pharmacokinetics (PK) of pevonedistat given in combination with induction chemotherapy.
OUTLINE: This is a dose-escalation study of pevonedistat.
Patients receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5, vincristine sulfate IV on days 2, 9, 16, and 23, dexamethasone orally (PO) twice daily (BID) on days 2-15, cytarabine intrathecally (IT) on day 1, doxorubicin hydrochloride IV over 15 minutes on day 2, and pegaspargase intramuscularly (IM) on days 9 and 23. Central nervous system (CNS) negative patients also receive methotrexate IT on day 16 and CNS positive patients receive methotrexate IT, cytarabine IT, and hydrocortisone IT on days 9, 16, and 23. Treatment repeats every 29 days for 1 cycle or up to 2 cycles per physician discretion in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 10 days.
Trial Phase Phase I
Trial Type Treatment
University of Miami Miller School of Medicine-Sylvester Cancer Center
Julio Cesar Barredo
- Primary ID 20170602
- Secondary IDs NCI-2019-06936, X15015
- Clinicaltrials.gov ID NCT03349281