Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)
Authors: Ziegler David S. , Huynh Van , Burke Michael J. , Gore Lia , Locatelli Franco , O'Brien Maureen M. , Kim Christopher , Obreja Mihaela , Morris Christopher L. , Baruchel André 
Published: November 2021

Abstract
In children with relapsed ALL, salvage options are sub-optimal and relapse remains the leading cause of death. Achieving subsequent complete remission (CR) after relapse is a critical first step to cure, without which, survival is unlikely. A phase 1b trial evaluating carfilzomib combined with VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) in children with relapsed ALL showed preliminary safety and efficacy in highly advanced pediatric ALL (Burke, ASH 2019). The phase 1b portion of this trial was recently completed and a recommended phase 2 dose determined. Patients (pts) were heterogeneous with respect to number of relapses (&gt;1, n = 7), refractory relapse (n = 7), prior stem cell transplant (n = 8) and duration of first remission (&lt;18 mo, n = 15), or none of these risk factors (n = 3). CR with incomplete hematologic recovery or better occurred in 50% overall after 1 cycle of induction (9 of 13 [69%] with B-ALL; 3 of 11 [27%] with T-ALL) and increased to 58% after consolidation (B-ALL, 9 of 13 [69%]; T-ALL, 5 of 11 [45%]). Herein, we describe the design of the phase 2 study (NCT02303821) which is currently enrolling.
This multicenter (~120 sites) phase 2 trial is designed to evaluate the efficacy and safety of carfilzomib in combination with VXLD re-induction when compared with an external control arm in children with relapsed ALL. Eligible pts include those aged ≥1 mo to 21 y originally diagnosed before age 18 with T- or B-cell ALL with bone marrow relapse (≥5% leukemic blasts) or refractory relapse with or without extramedullary disease. Pts with B-cell ALL must have received prior therapy with a targeted B-cell immune agent (blinatumomab, inotuzumab, chimeric antigen receptor T cell [CAR-T] therapy). Major exclusion criteria include prior treatment with carfilzomib or other proteasome inhibitor within &lt;3 mo of enrollment, use of VXLD or similar regimen within 2 mo of enrollment, or allogeneic hematopoietic stem cell transplantation within 3 mo of enrollment.
Pts receive a 28-day cycle of induction therapy. Pts aged &gt;12 mo not progressing may go on to receive an optional cycle of modified Berlin-Frankfurt-Munster consolidation therapy. Carfilzomib will be administered at 20 mg/m 2 on day 1 followed by 56 mg/m 2 on days 2, 8, 9, 15, and 16 of re-induction and 56 mg/m 2 on days 1, 2, 8, 9, 15, and 16 of consolidation. For pts aged ≥12 mo, VXLD re-induction includes vincristine 1.5 mg/m 2 per dose on days 1, 8, 15, and 22, daunorubicin 60 mg/m 2 per dose IV on day 2, PEG-asparaginase 2500 U/m 2 per dose IV on days 4 and 18, and dexamethasone 3 mg/m 2 per dose twice daily on days 1-21. Pts &lt;12 mo receive a modified induction and optional consolidation regimen based on the Interfant-06 chemotherapy backbone. All pts receive intrathecal therapy based on CNS status at time of enrollment. Alternate anthracycline and asparaginase agents may be substituted as part of VXLD per country availability and local practice. Investigators may delete anthracycline therapy based on specified pt risk factors.
The primary objective is to compare the CR rate of carfilzomib-VXLD after 1 cycle of re-induction to an appropriate control arm receiving standard of care re-induction chemotherapy. A minimum of 100 pts with R/R ALL are planned to be treated (T-cell, ~60; B-cell, ~40) in order to provide ≥70% power for showing superiority with a 95% CI for odds ratio that excludes 1 at a 2-sided significance level of 0.05. Analyses will be done separately for pts with T-cell and B-cell ALL. The control arm data will be collected by detailed retrospective chart abstraction at participating centers from the Therapeutic Advances for Childhood Leukemia/Lymphoma consortium for a minimum of 150 B-cell ALL and 70 T-cell ALL pts who fulfil the inclusion/exclusion criteria for the phase 2 trial. These pt data are collected as part of a larger retrospective observational study and do not require pt consent. Secondary objectives include evaluation of safety; CR after consolidation; CR without platelet recovery, CR with partial hematologic recovery, and CR with incomplete hematologic recovery at the end of induction therapy and after consolidation therapy, respectively; minimal residual disease; event free and overall survival; duration of response; proportion of pts able to proceed to stem cell transplant or CAR-T therapy; and pharmacokinetic parameters.
This phase 2 trial is currently enrolling pts globally.

Disclosures
Ziegler: Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gore: Roche/Genentech: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Anchiano: Current equity holder in publicly-traded company; Blueprint Medicines: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Clovis: Current equity holder in publicly-traded company; Mirati: Current equity holder in publicly-traded company; Sanofi Paris: Current equity holder in publicly-traded company. Locatelli: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Miltenyl: Honoraria. O'Brien: Pfizer: Honoraria, Research Funding; Jazz: Honoraria. Kim: Amgen: Current Employment, Current equity holder in publicly-traded company. Obreja: Amgen: Current Employment, Current equity holder in publicly-traded company. Morris: Amgen: Current Employment, Current equity holder in publicly-traded company.

OffLabel Disclosure:
Carfilzomib is approved in the United States for the treatment of adult patients with relapsed or refractory multiple myeloma. It has not been approved for use in pediatric patients with ALL.