Pevonedistat With VXLD Chemotherapy for Adolescent/Young Adults With Relapsed/Refractory ALL or Lymphoblastic NHL
A Phase I Trial of Pevonedistat in Combination With Induction Chemotherapy for Adolescent and Young Adults With Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Non-Hodgkin Lymphoma
2 other identifiers
interventional
6
1 country
1
Brief Summary
The investigators postulate that Pevonedistat will be effective in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) when combined with a standard backbone ALL chemotherapy regimen.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Mar 2019
Typical duration for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 7, 2017
CompletedFirst Posted
Study publicly available on registry
November 21, 2017
CompletedStudy Start
First participant enrolled
March 25, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 11, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
October 12, 2022
CompletedOctober 20, 2022
October 1, 2022
2.4 years
November 7, 2017
October 19, 2022
Conditions
Outcome Measures
Primary Outcomes (2)
Rate of Toxicity in Study Participants Receiving Protocol Therapy
Rate of study participants receiving Pevonedistat/VXLD therapy who experience dose limiting toxicities (DLTs), serious adverse events (SAEs) and and grade 3 or higher adverse events (AEs). Toxicities will be assessed in terms of nature, grade and attribution to protocol therapy using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03.
From Cycle 1 Day 1 to up to 30 days post last dose of protocol therapy, about 90 days
Determination of the Maximum Tolerated Dose (MTD) in Study Participants Receiving Protocol Therapy
Determination of the maximum tolerated dose (MTD) of Pevonedistat/VXLD therapy for the purpose of obtaining a recommended phase 2 dose (RP2D) regimen
From Cycle 1 Day 1 to up to 30 days post last dose of protocol therapy, about 90 days
Secondary Outcomes (6)
Rate of Clinical Response in Study Participants Receiving Protocol Therapy
Up to two cycles, about 60 days
Pharmacodynamics (PD): Expression Levels of Endoplasmic Reticulum (ER) Stress Response and Unfolded Protein Response (UPR) in Primary ALL Cells to Pevonedistat Therapy
Cycle 1 Days 1 to 4
Pharmacokinetics (PK): Maximum (Peak) Plasma Concentration (Cmax) of Pevonedistat
Cycle 1 Days 3 to 6
Pharmacokinetics (PK): Single-dose time to reach maximum (peak) concentration (Tmax) of Pevonedistat
Cycle 1 Days 3 to 6
Pharmacokinetics (PK): Area Under the Curve (AUC) of Plasma Concentration of Pevonedistat
Cycle 1 Days 3 to 6
- +1 more secondary outcomes
Study Arms (3)
Dose Level 1: Pevonedistat 15 + VXLD
EXPERIMENTAL* Pevonedistat: 15 mg/m2 intravenously (IV) * Vincristine: 1.5 mg/m2/dose IV push * Dexamethasone: 10 mg/m2/day divided twice daily * PEG-asparaginase: 2000 IU's/m2/day, capped at maximal dose of 3750 IU's. * Doxorubicin: 60 mg/m2/day IV * Intrathecal (IT) chemotherapy via injection per protocol: * All subjects: Cytarabine 70 mg ; * For central nervous system (CNS) negative subjects: Methotrexate 15 mg; * For CNS positive subjects (Triple IT Therapy): Cytarabine 30 mg, Methotrexate 15 mg, and Hydrocortisone 15 mg.
Dose Level -1: Pevonedistat 10 + VXLD
ACTIVE COMPARATOR* Pevonedistat: 10 mg/m2 IV * Vincristine: 1.5 mg/m2/dose IV push * Dexamethasone: 10 mg/m2/day divided twice daily * PEG-asparaginase: 2000 IU's/m2/day, capped at maximal dose of 3750 IU's. * Doxorubicin: 60 mg/m2/day IV * Intrathecal (IT) chemotherapy via injection per protocol: * All subjects: Cytarabine 70 mg ; * For CNS negative subjects: Methotrexate 15 mg; * For CNS positive subjects (Triple IT Therapy): Cytarabine 30 mg, Methotrexate 15 mg, and Hydrocortisone 15 mg.
Dose Level 2: Pevonedistat 20 + VXLD
ACTIVE COMPARATOR* Pevonedistat: 20 mg/m2 IV * Vincristine: 1.5 mg/m2/dose IV push * Dexamethasone: 10 mg/m2/day divided twice daily * PEG-asparaginase: 2000 IU's/m2/day, capped at maximal dose of 3750 IU's. * Doxorubicin: 60 mg/m2/day IV * Intrathecal (IT) chemotherapy via injection per protocol: * All subjects: Cytarabine 70 mg ; * For CNS negative subjects: Methotrexate 15 mg; * For CNS positive subjects (Triple IT Therapy): Cytarabine 30 mg, Methotrexate 15 mg, and Hydrocortisone 15 mg.
Interventions
Administered each cycle on days 1, 3 and 5.
Administered each cycle on days 2, 9, 16 and 23.
Taken orally each cycle on days 2 through 15.
Administered via intramuscular injection (IM) each cycle on days 9 and 23.
Administered via IV each cycle on day 2.
Administered to all subjects via IT injection on day 1; and on days 9, 16, and 23 to CNS positive subjects.
Administered via IT injection to CNS negative subjects on day 16; and to CNS positive subjects on days 9, 16 and 23.
Administered via IT injection to CNS positive subjects on days 9, 16, and 23.
Eligibility Criteria
You may qualify if:
- Male or female patients 16-39 years of age (AYA).
- 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/m2 lifetime exposure of anthracycline chemotherapy. For patients whose cumulative dose is between 350-450 mg/m2, 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%.
- Clinical laboratory values within the following parameters (repeat if more than 3 days before the first dose):
- Albumin \> 2.7 g/dL
- Total bilirubin ≤ 2.5 x upper limit of normal (ULN).
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN,
- Creatinine clearance ≥ 50 mL/min;
- White blood cell (WBC) count \< 50,000/µL 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)
- Female patients who:
- Are postmenopausal (see Appendix for definition) for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- +11 more criteria
You may not qualify if:
- 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 nonmelanoma 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 # 5 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 (ie, 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; see appendix);
- Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as a (ACS), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll);
- +22 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Julio Barredo, MDlead
- Takedacollaborator
Study Sites (1)
University of Miami
Miami, Florida, 33136, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY CHAIR
Julio Barredo, MD
University of Miami
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Professor
Study Record Dates
First Submitted
November 7, 2017
First Posted
November 21, 2017
Study Start
March 25, 2019
Primary Completion
August 11, 2021
Study Completion
October 12, 2022
Last Updated
October 20, 2022
Record last verified: 2022-10
Data Sharing
- IPD Sharing
- Will not share