Clinical Trials /

Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia

NCT02303821

Description:

The purpose of the study is to determine the maximum tolerated dose and assess the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
  • Official Title: Phase 1b Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: CFZ008
  • SECONDARY ID: 2014‐001633‐84
  • NCT ID: NCT02303821

Conditions

  • Acute Lymphoblastic Leukemia (ALL)

Interventions

DrugSynonymsArms
CarfilzomibPR-171, PR171, Kyprolis® (carfilzomib) for InjectionDose Escalation 1
DexamethasoneDose Escalation 1
MitoxantroneDose Escalation 1
PEG-asparaginaseDose Escalation 1
VincristineDose Escalation 1
Intrathecal (IT) MethotrexateDose Escalation 1
Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)Dose Escalation 1
6-MercaptopurineDose Escalation 1
CyclophosphamideDose Escalation 1
CytarabineDose Escalation 1
DaunorubicinDose Escalation 1

Purpose

The purpose of the study is to determine the maximum tolerated dose and assess the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL).

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation 1ExperimentalSubjects will receive carfilzomib in combination with induction chemotherapy, comprising either an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine (Dose Escalation 1) or a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin (Dose Escalation 2). Subjects participating in the Dose Escalation 1 (R3) portion of the study will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects in both dose escalation portions of the study will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle.
  • Carfilzomib
  • Dexamethasone
  • Mitoxantrone
  • PEG-asparaginase
  • Vincristine
  • Intrathecal (IT) Methotrexate
  • Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
  • 6-Mercaptopurine
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin

Eligibility Criteria

        Key Inclusion Criteria:

          1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the
             time of study treatment initiation.

          2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the
             bone marrow (M2 or M3 disease), with or without extramedullary disease.

             a. To be eligible, subjects must have had 1 or more prior therapeutic attempts,
             defined as:

               -  Early first relapse (< 36 months from original diagnosis) after achieving a CR
                  (B-ALL) or first relapse any time following the original diagnosis after
                  achieving a CR (T-ALL)

               -  First refractory bone marrow relapse occurring any time after original diagnosis
                  after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR

               -  Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2
                  relapses) OR

               -  Failing to achieve a CR from original diagnosis after at least 1 induction
                  attempt

          3. Subjects must have fully recovered from the acute toxic effects of all previous
             chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.

          4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit
             of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the
             subject must have a calculated creatinine clearance or radioisotope glomerular
             filtration rate (GFR) ≥ 70 mL/min/1.73 m2, or for children<2 years of age, ≥
             50mL/min/1.73 m2.

          5. Adequate liver function, defined as both of the following:

               1. Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert
                  Syndrome

               2. Alanine aminotransferase (ALT) ≤ 5 × institutional ULN

          6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤
             16 years old, respectively.

        Key Exclusion Criteria:

          1. Known allergy to any of the drugs used in the study. (Subjects who have had a previous
             allergy to PEG-asparaginase are eligible and if able, may receive Erwinia asparaginase
             at the investigator's discretion.)

          2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)

          3. Left ventricular fractional shortening < 30%

          4. History of ≥ Grade 2 pancreatitis

          5. Active graft‑versus‑host disease requiring systemic treatment

          6. Positive culture for or other clinical evidence of infection with bacteria or fungus
             within 14 days of the initiation of study treatment

          7. Down Syndrome

          8. Prior therapy restrictions:

               1. Subjects must have completed therapy with granulocyte‑colony stimulating factor
                  (G‑CSF) or other myeloid growth factors at least 7 days before study treatment
                  initiation, or at least 14 days before study treatment initiation, if pegylated
                  myeloid growth factors were administered.

               2. Subjects must have completed any type of active immunotherapy (e.g., tumor
                  vaccines) at least 42 days before study treatment initiation.

               3. Subjects must have received the last dose of a non-monoclonal antibody biologic
                  agent at least 7 days before study treatment initiation.

               4. At least 3 antibody half‑lives must have elapsed since the last dose of
                  monoclonal antibody (e.g., 66 days for rituximab, 69 days for epratuzumab and 36
                  days for inotuzumab) before subjects may initiate study treatment.

               5. Subjects must not have received other antineoplastic agents with therapeutic
                  intent, excluding hydroxyurea and antimetabolites administered as part of
                  maintenance chemotherapy, within 7 days prior to study treatment initiation

          9. Hepatitis B infection with positive hepatitis B DNA
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame:48 months
Safety Issue:
Description:Safety and tolerability of carfilzomib alone and in combination with induction chemotherapy, as defined by the type, incidence, severity, and outcome of Adverse Events (AEs).

Secondary Outcome Measures

Measure:Maximum plasma concentration (Cmax)
Time Frame:48 months
Safety Issue:
Description:Maximum plasma concentration (Cmax), alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for Cmax will be tabulated and summarized (i.e., mean, standard deviation).
Measure:Total Plasma Exposure - Area Under the Curve (AUC)
Time Frame:48 months
Safety Issue:
Description:Total Plasma Exposure - Area Under the Curve (AUC), alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for AUC will be tabulated and summarized (i.e., mean, standard deviation).
Measure:Time to Peak Concentration (Tmax)
Time Frame:48 months
Safety Issue:
Description:Time to Peak Concentration (Tmax), alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for Tmax will be tabulated and summarized (i.e., mean, standard deviation).
Measure:Total Plasma Clearance
Time Frame:48 months
Safety Issue:
Description:Total Plasma Clearance, alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for Total Plasma Clearance will be tabulated and summarized (i.e., mean, standard deviation).
Measure:Plasma Terminal Half-life
Time Frame:48 months
Safety Issue:
Description:Plasma Terminal Half-life (as appropriate for data collected), alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for Plasma Terminal Half-life will be tabulated and summarized (i.e., mean, standard deviation).
Measure:Minimal Residual Disease (MRD) Status
Time Frame:48 months
Safety Issue:
Description:Proportion of subjects who achieve MRD status < 10-3 and < 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Amgen

Last Updated

October 18, 2019