Phase 1b/2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia
- Conditions
- Relapsed or Refractory Acute Lymphoblastic LeukemiaMedDRA version: 21.0Level: LLTClassification code 10025230Term: Lymphatic leukemiaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-001633-84-GR
- Lead Sponsor
- Onyx Therapeutics, Inc., an Amgen Inc. subsidiary
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- A
- Sex
- All
- Target Recruitment
- 144
Phase 1b:
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.
• To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:
o 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) OR
o 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
o Relapse after achieving a CR following the first or subsequent relapse (i.e., = 2 relapses) OR
o 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:
o Total bilirubin = 1.5 × institutional ULN except in the presence of Gilbert Syndrome
o Alanine aminotransferase (ALT) = 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores = 50 for subjects > 16 years old or = 16 years old, respectively.
see protocol for additional phase 1b inclusion criteria
Phase 2:
1. Subject’s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
2. Age = 1 month to = 21 years. Subjects = 18 years must have had their original diagnosis at < 18 years of age
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL
4. Subjects must have a documented first remission, = 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
5. T-cell ALL with bone marrow relapse (defined as = 5% leukemia blasts in bone marrow) or refractory relapse with or without extramedullary disease.
OR
B-cell ALL with bone marrow relapse or refractory relapse (defined as =5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy as treatment for a prior relapse (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease. Subjects that received blinatumomab for treatment of MRD positive disease during first remission do not qualify.
see protocol for additional Phase 2 inclusion criteria
Are the trial subjects under 18? yes
Number of subjects for this age range: 144
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0
phase 1b:
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 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:
o 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.
o Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
o 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.
o Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
o 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
see protocol for addition phase 1b exclusion criteria
Phase 2:
1. Prior treatment with carfilzomib.
2. Prior treatment with a proteasome inhibitor (other than carfilzomib) within < 3 months of enrollment or to which a subject did not respond (response is defined as bone marrow with < 5% blasts).
3. Treatment with a chemotherapy regimen including a vinca alkaloid, steroid, L asparaginase, and anthracycline combination with or without other chemotherapy agents within 2 months of enrollment (eg VXLD, VPLD, R3).
4. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen. An exception is allowed for allergy to asparaginase products if Erwinia Asparaginase is unable to be administered, or if PEG-Asparaginase or Erwinia Asparaginase are not available in the country, these subjects may still be included.
5. Autologous HSCT within 6 weeks prior to start of study treatment.
6. Allogeneic HSCT within 3 months prior to start of study treatment.
Please see protocol for additional phase 2 exclusion criteria
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method