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

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ClinicalTrials.gov Identifier: NCT02303821
Recruitment Status : Recruiting
First Posted : December 1, 2014
Last Update Posted : October 21, 2019
Sponsor:
Collaborators:
Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) - Study Design & Execution Collaborator
Innovative Therapies For Children with Cancer Consortium
Information provided by (Responsible Party):
Amgen

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia (ALL) Drug: Carfilzomib Drug: Dexamethasone Drug: Mitoxantrone Drug: PEG-asparaginase Drug: Vincristine Drug: Intrathecal (IT) Methotrexate Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) Drug: 6-Mercaptopurine Drug: Cyclophosphamide Drug: Cytarabine Drug: Daunorubicin Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
Study Start Date : December 2014
Estimated Primary Completion Date : March 18, 2020
Estimated Study Completion Date : March 18, 2020


Arm Intervention/treatment
Experimental: Dose Escalation 1

Subjects 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.

Drug: Carfilzomib
Other Names:
  • PR-171
  • PR171
  • Kyprolis® (carfilzomib) for Injection

Drug: Dexamethasone
Drug: Mitoxantrone
Drug: PEG-asparaginase
Drug: Vincristine
Drug: Intrathecal (IT) Methotrexate
Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
Drug: 6-Mercaptopurine
Drug: Cyclophosphamide
Drug: Cytarabine
Drug: Daunorubicin



Primary Outcome Measures :
  1. Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 48 months ]
    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).

  2. Key Laboratory Analytes [ Time Frame: 48 months ]
    Changes from baseline in key laboratory analytes.

  3. Vital Signs [ Time Frame: 48 months ]
    Changes from baseline in vital signs

  4. Physical Findings [ Time Frame: 48 months ]
    Changes from baseline in physical findings

  5. Time to Toxicity [ Time Frame: 48 months ]
    Time to toxicity will be evaluated to differentiate single-agent carfilzomib from carfilzomib in combination with induction chemotherapy

  6. Maximum Tolerated Dose (MTD) [ Time Frame: 48 months ]
    Maximum tolerated dose (MTD) of carfilzomib in combination with induction chemotherapy. Determination of the MTD as the dose that has the highest posterior probability of having a dose-limiting toxicity (DLT) rate within the target toxicity interval (20%-33%), while the posterior probability of excessive/unacceptable toxicity (>33%-100%) is less than 40%.


Secondary Outcome Measures :
  1. Maximum plasma concentration (Cmax) [ Time Frame: 48 months ]
    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).

  2. Total Plasma Exposure - Area Under the Curve (AUC) [ Time Frame: 48 months ]
    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).

  3. Time to Peak Concentration (Tmax) [ Time Frame: 48 months ]
    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).

  4. Total Plasma Clearance [ Time Frame: 48 months ]
    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).

  5. Plasma Terminal Half-life [ Time Frame: 48 months ]
    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).

  6. Minimal Residual Disease (MRD) Status [ Time Frame: 48 months ]
    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)



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02303821


Contacts
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Contact: Amgen Call Center 866-572-6436 medinfo@amgen.com

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Sponsors and Collaborators
Amgen
Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) - Study Design & Execution Collaborator
Innovative Therapies For Children with Cancer Consortium
Investigators
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Study Director: Christopher Morris, MD Amgen

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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT02303821     History of Changes
Other Study ID Numbers: CFZ008
2014‐001633‐84 ( EudraCT Number )
First Posted: December 1, 2014    Key Record Dates
Last Update Posted: October 21, 2019
Last Verified: October 2019
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cytarabine
Dexamethasone
Dexamethasone acetate
Hydrocortisone
Cyclophosphamide
Methotrexate
Vincristine
Daunorubicin
Mitoxantrone
Asparaginase
Mercaptopurine
Pegaspargase
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones