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* 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.

* 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.

* 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.

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.

PEG-asparaginase

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.

Julio Barredo, MD

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.

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.

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

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.

Determination of the maximum tolerated dose (MTD) of Pevonedistat/VXLD therapy for the purpose of obtaining a recommended phase 2 dose (RP2D) regimen

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.

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.

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).

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).

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).

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).

Spots Global Cancer Trial Database for Pevonedistat With VXLD Chemotherapy for Adolescent/Young Adults With Relapsed/Refractory ALL or Lymphoblastic NHL

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