AzTrials
AzTrials

Refractory Acute Lymphoblastic LeukemiaPhase 1NCT03349281

Pevonedistat With VXLD Chemotherapy for Adolescent/Young Adults With Relapsed/Refractory ALL or Lymphoblastic NHL

A Phase 1 study testing Pevonedistat, Vincristine and Dexamethasone in people with Refractory Acute Lymphoblastic Leukemia and Relapsed Acute Lymphoblastic Leukemia, run by Julio Barredo, MD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 16 to 39 years
What is being tested?
Pevonedistat, Vincristine and Dexamethasone
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
1 siteUnited States
Study dates
25 Mar 2019to 12 Oct 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 to 39 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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%.
Show all 26Show fewer
  • 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
  • If they are of childbearing potential:
  • Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception (see Appendix), 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 [eg, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
  • Male patients, even if surgically sterilized (ie, status postvasectomy), 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 [eg, calendar, ovulation, symptothermal, postovulation 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 transplant (HSCT) with no evidence of acute graft vs host disease (GVHD).

Who cannot join

  • 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.
Show all 37Show fewer
  • 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);
  • 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 < 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);
  • Clinically significant pulmonary hypertension requiring pharmacologic therapy.
  • Uncontrolled high blood pressure (ie, 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.
  • 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 or vincristine.
  • Patients who have started protocol therapy prior to enrollment. Patient may still enroll if IT therapy was given within 72 hours of study enrollment as part of the diagnostic lumbar procedure.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University of Miami

    Miami, Florida, 33136

Other trials in United States

About this study

Official title: 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

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.

Read the detailed description

This is a phase I study of the addition of pevonedistat to induction chemotherapy for AYA patients (16-39 years of age) with relapsed/refractory ALL utilizing a traditional 3+3 design with dose expansion cohort of 6 patients. Starting dose level for pevonedistat is 15 mg/m2. If the number of dose-limiting toxicities (DLTs) is greater than 1 out of 3 patients in the starting dose level, next dose level is 10 mg/m2 (dose level -1). Chemotherapy will consist of pevonedistat in combination with a standard VXLD regimen. The duration of each cycle will be 29 days.

Being tested
Pevonedistat, Vincristine, Dexamethasone, PEG-asparaginase, Doxorubicin
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PevonedistatDrug

    Also called TAK-924, MLN4924

    Administered each cycle on days 1, 3 and 5.

  • VincristineDrug

    Also called Oncovin, VCR, LCR

    Administered each cycle on days 2, 9, 16 and 23.

  • DexamethasoneDrug

    Also called Decadron, Hexadrol, Dexone, Dexameth

    Taken orally each cycle on days 2 through 15.

  • PEG-asparaginaseDrug

    Also called Oncaspar, Pegaspargase, Polyethylene Glycol Conjugated L-asparaginase-H

    Administered via intramuscular injection (IM) each cycle on days 9 and 23.

  • DoxorubicinDrug

    Also called Adriamycin

    Administered via IV each cycle on day 2.

  • CytarabineDrug

    Also called ARA-C

    Administered to all subjects via IT injection on day 1; and on days 9, 16, and 23 to CNS positive subjects.

  • MethotrexateDrug

    Also called MTX, Amethopterin

    Administered via IT injection to CNS negative subjects on day 16; and to CNS positive subjects on days 9, 16 and 23.

  • HydrocortisoneDrug

    Also called Cortisol

    Administered via IT injection to CNS positive subjects on days 9, 16, and 23.

Study groups in NCT03349281
Study groupRoleWhat they receive
Dose Level 1: Pevonedistat 15 + VXLDExperimental* 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.
Receives: Drug: Pevonedistat; Drug: Vincristine; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone
Dose Level -1: Pevonedistat 10 + VXLDActive 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.
Receives: Drug: Pevonedistat; Drug: Vincristine; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone
Dose Level 2: Pevonedistat 20 + VXLDActive 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.
Receives: Drug: Pevonedistat; Drug: Vincristine; Drug: Dexamethasone; Drug: PEG-asparaginase; Drug: Doxorubicin; Drug: Cytarabine; Drug: Methotrexate; Drug: Hydrocortisone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: From Cycle 1 Day 1 to up to 30 days post last dose of protocol therapy, about 90 days

  2. 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

    Measured: From Cycle 1 Day 1 to up to 30 days post last dose of protocol therapy, about 90 days

Secondary outcomes (6)

  1. Rate of Clinical Response in Study Participants Receiving Protocol Therapy

    Rate of overall response (complete response (CR) + partial response (PR)) in study participants receiving Pevonedistat/VXLD therapy. Responses will be documented according to International Working Group (IWG) Response Criteria. Morphologic complete remission (CR), cytogenetic CR, and molecular CR will be assessed by blood counts and simultaneous examination of the bone marrow for percentage of bone marrow blasts, as well as cytogenetics and molecular studies of bone marrow mononuclear cells.

    Measured: Up to two cycles, about 60 days

  2. Pharmacodynamics (PD): Expression Levels of Endoplasmic Reticulum (ER) Stress Response and Unfolded Protein Response (UPR) in Primary ALL Cells to Pevonedistat Therapy

    Primary acute lymphoblastic leukemia (ALL) cells will be obtained from peripheral blood and/or bone marrow of study participants. Primary cells will be assayed for cell death and cell cycle using standard methodology. Expression levels of endoplasmic reticulum (ER) stress/unfolded protein response (UPR) will be analyzed. A total of 6 samples will be analyzed to establish the PD of pevonedistat, the first three at the time it is given as a single agent (day 1 window) and the following 3 when given in combination with chemotherapy. A sample will be collected from peripheral blood in Cycle 1 on Day 1 pre-dose (immediately before the administration of pevonedistat), 6 and 24 hours post-dose; and on Day 3 pre-dose, 4, 6 and 24 hours post-dose.

    Measured: Cycle 1 Days 1 to 4

  3. Pharmacokinetics (PK): Maximum (Peak) Plasma Concentration (Cmax) of Pevonedistat

    Cmax is the maximum (or peak) plasma concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose. Serial blood samples for the determination of plasma concentrations of pevonedistat will be collected at pre-specified time points during Cycle 1 to characterize the PK of pevonedistat in combination with VXLD therapy. Plasma for measuring pevonedistat concentrations will be collected pre-dose on day 3, at the end of infusion (EOI), 30 minutes, 1, 2, 4, 6, 24, 48 and 72 hours post pevonedistat dose (10 PK blood draws in total).

    Measured: Cycle 1 Days 3 to 6

  4. Pharmacokinetics (PK): Single-dose time to reach maximum (peak) concentration (Tmax) of Pevonedistat

    Tmax is the time it takes a drug or other substance to reach the maximum concentration (Cmax). Serial blood samples for the determination of plasma concentrations of pevonedistat will be collected at pre-specified time points during Cycle 1 to characterize the PK of pevonedistat in combination with VXLD therapy. Plasma for measuring pevonedistat concentrations will be collected pre-dose on day 3, at the end of infusion (EOI), 30 minutes, 1, 2, 4, 6, 24, 48 and 72 hours post pevonedistat dose (10 PK blood draws in total).

    Measured: Cycle 1 Days 3 to 6

  5. Pharmacokinetics (PK): Area Under the Curve (AUC) of Plasma Concentration of Pevonedistat

    The area under the plasma concentration-time curve from time 0 to 24 hours post-dose (AUC24hr), and AUC extrapolated to infinity (AUCinf) will be assessed. Serial blood samples for the determination of plasma concentrations of pevonedistat will be collected at pre-specified time points during Cycle 1 to characterize the PK of pevonedistat in combination with VXLD therapy. Plasma for measuring pevonedistat concentrations will be collected pre-dose on day 3, at the end of infusion (EOI), 30 minutes, 1, 2, 4, 6, 24, 48 and 72 hours post pevonedistat dose (10 PK blood draws in total).

    Measured: Cycle 1 Days 3 to 6

  6. Pharmacokinetics (PK): Terminal disposition phase half-life (t1/2) of Plasma Concentration of Pevonedistat

    Terminal disposition phase half-life (t1/2) will be assessed. Half-life (t1/2) is the amount of time it takes for the drug concentration in the plasma to decline by half. Serial blood samples for the determination of plasma concentrations of pevonedistat will be collected at pre-specified time points during Cycle 1 to characterize the PK of pevonedistat in combination with VXLD therapy. Plasma for measuring pevonedistat concentrations will be collected pre-dose on day 3, at the end of infusion (EOI), 30 minutes, 1, 2, 4, 6, 24, 48 and 72 hours post pevonedistat dose (10 PK blood draws in total).

    Measured: Cycle 1 Days 3 to 6

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Nov 2017
  2. Study start25 Mar 2019
  3. Primary completion11 Aug 2021
  4. Study completion12 Oct 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03349281
Sponsor's protocol ID
20170602
Other IDs
X15015
Status last verified
Oct 2022
First submitted
7 Nov 2017
Last updated
20 Oct 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Pevonedistat, Vincristine and Dexamethasone in people with Refractory Acute Lymphoblastic Leukemia and Relapsed Acute Lymphoblastic Leukemia, run by Julio Barredo, MD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of Toxicity in Study Participants Receiving Protocol Therapy (time frame: From Cycle 1 Day 1 to up to 30 days post last dose of protocol therapy, about 90 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03349281.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2022.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in