B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive blood cancer; about 30% of B-ALL cases in adults have a mutation called BCR-ABL that drives the disease. Blinatumomab is an antibody drug that targets B-ALL cells and helps the immune system to kill them. It is usually given intravenously, but a newer formulation can be given under the skin. Ponatinib is a drug, taken by mouth, that targets and kills leukemia cells that have the BCR-ABL mutation. The goal of this clinical trial is to test the effectiveness of treating patients with BCR-ABL positive B-ALL with blinatumomab given subcutaneously (under the skin) combined with ponatinib tablets. The study will also evaluate what side effects occur using this combination. Participants will first receive ponatinib tablets for 70 days, along with prednisone for the first month. This will be followed by blinatumomab injections 3 times per week for 4 weeks, repeated for 5 treatment cycles, along with ponatinib. Participants will then continue ponatinib tablets alone for 5 years from the start of treatment. During treatment, participants will undergo regular blood and bone marrow tests to see how well the treatment is working, and to check for side effects. The effect of this treatments on their quality of life will also be evaluated.
This Phase II clinical trial will evaluate with efficacy and tolerance of subcutaneous (sc) blinatumomab (blina) combined with ponatinib for previously untreated patients with BCR-ABL (Ph) positive B-cell acute lymphoblastic leukemia (ALL). Participants will, after a brief steroid pre-phase, receive induction therapy with ponatinib 30 mg/day x 70 days, with prednisone for the first month. They will then receive 5 cycles of consolidation therapy with sc blina. The first cycle will consist of blina 250 mcg sc daily x 7 days, then 500 mcg sc 3x/week x 3 weeks. Cycles 2-5 will consist of blina 500 mcg sc 3x/week x 4 weeks. There will be a 2 week break in between each consolidation cycle. Ponatinib will continue at 30 mg daily through the end of consolidation. Participants will then receive maintenance therapy with ponatinib 15 mg/day until 5 years from the start of induction. Intrathecal chemotherapy will be administered for a total of 15 doses; this will include 7 doses during induction, 1 dose in between each consolidation cycle, and 4 during maintenance. Efficacy will be determined by bone marrow assessments for MRD at various timepoints. The primary endpoint is the measurable residual disease (MRD) response after the end of consolidation cycle 2, by both BCR-ABL PCR (MRD4 or greater) and by IgR (MRD negativity by Clonoseq\[R\]). The CR rate, MRD response duration, RFS and OS will also be assessed. Toxicity will be evaluated throughout the study and graded using CTCAE V5. Quality of life will be assessed at various timepoints using QLQ-C30.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Previous studies have used intravenous blinatumomab combined with a TKI (ponatinib or dasatinib) for patients with BCR-ABL positive B-ALL. This study is using subcutaneous blinatumomab combined with ponatinib for previously untreated patients with this disease.
University of Alberta
Edmonton, Alberta, Canada
• MR4 rate for BCR-ABL1 by PCR after 2 cycles of blinatumomab
After 2 cycles of blinatumomab, the bone marrow will be tested for MRD by PCR for BCR-ABL. The rate of MRD4 (MRD\<10\[-4\]) at this timepoint will constitute a primary outcome.
Time frame: At end of cycle 2 of blinatumomab (each cycle is 28 days).
Complete molecular response (CMR) by IgR (Clonoseq[R]) after 2 cycles of blinatumomab.
After 2 cycles of Blinatumomab the marrow will be tested for MRD by Clonoseq. The rate of MRD negativity by IgR will constitute a primary outcome.
Time frame: At end of cycle 2 of Blinatumomab (each cycle being 28 days).
Complete response rate
Complete response rate (CR and CRh) of ponatinib + prednisone
Time frame: Determined at the end of the 70 day induction phase
Patient and caregiver experience
EORTC QLQ-C30 scores
Time frame: At screening, end of induction (Day 70), end of cycles 2 and 5 of blinatumomab, and one year after start of maintenance therapy with ponatinib.
Molecular response duration
The duration of MR4 by PCR and CMR by Clonoseq will be determined in follow-up bone marrow assessments.
Time frame: From the time of documented remission at Day 70 of induction, until the date of first documented molecular progression, assessed up to 5 years from the start of treatment.
Relapse-free survival (RFS)
Time from primary outcome to molecular disease progression.
Time frame: From the date of documented remission at day 70 until the date of first documented relapse or date of death from any cause, whichever came first, assessed up to 5 years from the start of treatment.
Overall survival (OS)
Time from start of treatment until death form any cause or last follow-up.
Time frame: From the date of enrollment until the date of death from any cause or last follow-up, assessed up to 5 years from the start of treatment.
Safety and tolerability
Safety and tolerability of the ponatinib plus blinatumomab combination, based on TEAE's, graded by CTCAE V5, as well as by CRS and ICANS grading.
Time frame: From the start of study treatment through the completion of study treatment at 5 years.
Prognostic factors for remission
Correlation of primary efficacy endpoints (MR4, CMR) with diagnostic NGS, IKZFplus genotype, age and baseline WBC
Time frame: At the primary endpoint at the end of cycle 2 of blinatumomab (each cycle being 28 days).
Prognostic factors for relapse-free survival
Correlation of RFS with diagnostic NGS, IKZFplus genotype, age and baseline WBC
Time frame: From date of documented remission at day 70 of induction, until the date of relapse or date of death from any cause, whichever came first, assessed up to 5 years.
Prognostic factors for overall survival
Correlation of OS with diagnostic NGS, IKZFplus genotype, age and baseline WBC
Time frame: From date of enrollment until the date of death from any cause or last follow-up, assessed up to 5 years.
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