cRIB Protocol for Pediatric Leukemia
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
Disqualifiers: Secondary tumor, CNS pathology, cardiovascular disease, infections, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?To learn if cyclophosphamide, vincristine, and dexamethasone (called mini hyper-CVD) in combination with intrathecal (delivered into the spine) chemotherapy (methotrexate, hydrocortisone, cytarabine) and compressed rituximab, blinatumomab, and inotuzumab ozogamicin (called cRIB) can help to control the disease.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like single-dose intravenous cytarabine, steroids, or hydroxyurea are allowed before starting the study without a washout period (time without taking certain medications). It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drugs used in the cRIB Protocol for Pediatric Leukemia?
Research shows that blinatumomab, a key drug in the cRIB Protocol, has been effective in treating relapsed or refractory acute lymphoblastic leukemia (ALL) in children, with response rates between 34% to 66%. Additionally, a case study reported successful remission in a child with high-risk B-ALL using a combination of chemotherapy and immunotherapy, including blinatumomab, inotuzumab ozogamicin, and rituximab.
12345What safety data exists for Blinatumomab in treating pediatric leukemia?
Blinatumomab has been associated with serious side effects like cytokine release syndrome (a severe immune reaction) and neurologic events (such as seizures and confusion) in children with leukemia. However, it is considered a well-tolerated treatment option, with lower rates of serious adverse events compared to standard chemotherapy.
678910What makes the cRIB Protocol for Pediatric Leukemia treatment unique?
The cRIB Protocol is unique because it combines chemotherapy with a condensed sequence of immunotherapy drugs, including rituximab, inotuzumab ozogamicin, and blinatumomab, which have shown promise in treating relapsed or refractory pediatric leukemia. This approach aims to reduce toxicities and improve remission rates compared to traditional chemotherapy alone.
15111213Eligibility Criteria
This trial is for pediatric to young adult patients (1-25 years old) with relapsed or refractory B-cell lineage acute lymphocytic leukemia. They must have a certain level of physical ability, proper liver and kidney function, and not be pregnant or breastfeeding. Participants need to use effective contraception and cannot have uncontrolled infections, HIV, hepatitis B/C, severe heart conditions, active GvHD requiring treatment, or other serious medical issues.Inclusion Criteria
I have leukemia in my brain but don't feel any symptoms.
Baseline laboratory data within specified limits
I am between 1 and 24 years old.
+5 more
Exclusion Criteria
I am still recovering from my last cancer treatment.
I have Down syndrome or a bone marrow failure condition.
I am currently experiencing symptoms of Graft-versus-Host Disease.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive mini-hyper-CVD with inotuzumab ozogamicin, blinatumomab, and rituximab in 28-day cycles with a 7-day rest period between cycles
28 days per cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests mini hyper-CVD chemotherapy combined with intrathecal chemo and condensed doses of rituximab, blinatumomab, inotuzumab ozogamicin (cRIB). It aims to see if this regimen can control the disease better in those who can't receive standard treatments due to intolerance or risk factors.
2Treatment groups
Experimental Treatment
Group I: Leukemia CNS1 or 2Experimental Treatment11 Interventions
Each study block, or cycle, is 28 days. Between every cycle below, Participants will have a 7-day rest period in which no study drug is given.
Group II: Leukemia CNS 3Experimental Treatment11 Interventions
Each study block, or cycle, is 28 days. Between every cycle below, Participants will have a 7-day rest period in which no study drug is given.
Blinatumomab is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Blincyto for:
- Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
- High-risk first relapse BCP-ALL
🇺🇸 Approved in United States as Blincyto for:
- Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL)
- First or second complete remission with minimal residual disease (MRD)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
References
Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia. [2022]Relapsed or refractory pediatric patients with B-acute lymphoblastic leukemia (B-ALL) have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male child with high-risk B-ALL that was refractory to several re-induction regimens. He was put into minimal residual disease-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin, and blinatumomab, termed mini-hyper-CVD (cyclophosphamide, vincristine, and dexamethasone) plus CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab). This regimen was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.
Moving immunotherapy into the front line in ALL. [2020]Although almost 90% of children with acute lymphoblastic leukemia (ALL) and ∼60% of children with acute myeloid leukemia are cured with frontline therapy, relapse and chemotherapy resistance are significant challenges that contribute to morbidity and mortality. Even with long-term survival, the acute and chronic burdens of therapy are major issues for patients and families. Long-term side effects occur, including cardiac, endocrinologic, neurcognitive, orthopedic, and psychosocial problems, and healthy survivorship is frequently compromised. With goals of minimizing relapse and/or decreasing traditional chemotherapy-associated toxicities, exploration of immunotherapeutic strategies has moved to the forefront in pediatric cancer. New immunotherapy approaches provide a major paradigm shift in oncology overall, often curing previously incurable patients. The past several years have yielded successful uses across a variety of malignancies, and enthusiasm continues to rise for applying these therapies more broadly. Herein we discuss current approaches incorporating the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin (InO), and CD19-directed chimeric antigen receptor T cells in children with relapsed/refractory B-cell ALL and discuss the potential for using these immunotherapies in the treatment of newly diagnosed children.
SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia. [2023]Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population.
Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL. [2023]We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant.
Blinatumomab in Pediatric Acute Lymphoblastic Leukemia-From Salvage to First Line Therapy (A Systematic Review). [2021]Acute lymphoblastic leukemia is by far the most common malignancy in children, and new immunotherapeutic approaches will clearly change the way we treat our patients in future years. Blinatumomab is a bispecific T-cell-engaging antibody indicated for the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R-ALL). The use of blinatumomab in R/R ALL has shown promising effects, especially as a bridging tool to hematopoietic stem cell transplantation. For heavily pretreated patients, the response to one or two cycles of blinatumomab ranges from 34% to 66%. Two randomized controlled trials have very recently demonstrated an improved reduction in minimal residual disease as well as an increased survival for patients treated with blinatumomab compared to standard consolidation treatment in first relapse. Current trials using blinatumomab frontline for high-risk patients or as a consolidation treatment post-transplant will show whether efficacy is even higher in less heavily pretreated patients. Due to the distinct pattern of adverse events compared to high-dose conventional chemotherapy, blinatumomab could play an important role for patients with a risk for severe chemotherapy-associated toxicities. This systematic review discusses all published results for blinatumomab in children as well as all ongoing clinical trials.
Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. [2020]In the phase 3 TOWER study, blinatumomab demonstrated an overall survival benefit over standard-of-care chemotherapy (SOC) in adults with relapsed or refractory (r/r) Philadelphia chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL). Nearly all patients in both treatment arms experienced an adverse event (AE), and the incidence rate of serious AEs was higher for blinatumomab. However, as treatment exposure differed between the 2 arms, we conducted an exploratory safety analysis comparing exposure-adjusted event rates (EAERs) of blinatumomab vs SOC. Analyses were conducted for all patients who received therapy (safety population). Patients received a median (range) of 2 cycles (1-9) of blinatumomab (N = 267) vs 1 cycle (1-4) of SOC (N = 109). Grade ≥3 AE rates were generally higher in cycle 1 of blinatumomab than in cycle 2 (76% vs 37%). After adjusting for time on treatment, EAERs of grade ≥3 were significantly lower for blinatumomab vs SOC overall (10.73 vs 45.27 events per patient-year; P < .001) and for events of clinical interest, including infections (1.63 vs 6.49 events per patient-year; P < .001), cytopenias (3.64 vs 20.07 events per patient-year; P < .001), and neurologic events (0.38 vs 0.95 events per patient-year; P = .008). The EAER of grade ≥3 cytokine-release syndrome was higher for blinatumomab than for SOC (0.16 vs 0 events per patient-year; P = .038). These data further support the role of blinatumomab as an efficacious and well-tolerated treatment option for patients with r/r Ph- ALL. This trial was registered at www.clinicaltrials.gov as #NCT02013167.
FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia. [2019]On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-of-care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single-arm trial of blinatumomab in patients with Ph-positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph-negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph-positive and Ph-negative precursor B-cell R/R ALL. IMPLICATIONS FOR PRACTICE: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7-month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single-arm trial of blinatumomab for treatment of relapsed or refractory Ph-positive precursor B-cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B-cell ALL that is Ph positive or Ph negative.
The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia: A systematic review and meta-analysis. [2022]Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that has proven efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Despite its efficacy, it has also been associated with the development of potentially serious adverse events such as the cytokine release syndrome (CRS) and neurologic events. The present meta-analysis aimed to assess the safety profile of blinatumomab in terms of serious adverse events, CRS, and neurologic events (such as seizure and encephalopathy) in pediatric patients with B-cell ALL.
Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia. [2020]Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life-threatening toxicity. The bispecific T-cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B-cell depletion, the safety of its use during severe chemotherapy-induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy-associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.
FDA Approval: Blinatumomab. [2021]On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit.
Results of a pilot study for the treatment of childhood acute nonlymphoblastic leukemia. [2019]Eighteen children with acute nonlymphoblastic leukemia were entered on a pilot protocol. The drugs used were vincristine, daunorubicin, cytosine arabinoside, and prednisolone for remission induction, high-dose cyclophosphamide together with vincristine and mercaptopurine for consolidation, and cycles of vincristine, prednisolone, mercaptopurine, methotrexate, and daunorubicin for maintenance therapy. Prophylactic central nervous system therapy (cranial radiotherapy 2400 rad and intrathecal methotrexate 10 mg/m2 for five doses) was given once remission had been achieved. Fourteen of the 18 children (78%) achieved complete remission (CR) and 50% of those achieving CR remain in CR for 35+ to 87+ months. Survival for all children ranges from 2 to 88+ months with 50% remaining alive for 36+ to 88+ months. The protocol was well tolerated with minimal side effects. These results together with those of other recently reported studies indicate an improving prognosis for acute nonlymphoblastic leukemia in childhood.
Efficacy and safety of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukemia: A systematic review and meta-analysis. [2023]Objectives: Several clinical trials have been conducted to evaluate the effects of blinatumomab in childhood B cell acute lymphoblastic leukemia (B-ALL). We conducted this meta-analysis to validate the efficacy and safety of blinatumomab in pediatric patients with relapsed/refractory B-ALL (R/R B-ALL). Methods: We searched and investigated all relevant studies in the PubMed, Web of Science, Embase, and Cochrane Library databases. The primary outcomes were complete response (CR), overall survival (OS), event free survival (EFS), minimal residual disease (MRD) response, allogeneic hematopoietic stem cell transplantation (allo-HSCT) and were calculated separately for randomized controlled trials (RCTs) and single-arm studies. The secondary end points were adverse effects (AEs) and the relapse rate. The Cochrane, bias assessment tool, was used to assess the risk of bias in RCTs. The methodological quality of single-arm studies was assessed using the methodological index for non-randomized studies (MINORS) tool. Results: The meta-analysis included two RCTs and 10 single-arm studies, including 652 patients in total. Our study showed that in the single-arm studies, the combined CR rate was 0.56 (95% confidence interval (CI): 0.45 -0.68), the odds ratios (ORs) of OS was 0.43 (95% CI 0.32 -0.54), the EFS rate was 0.30 (95% CI: 0.20 -0.40), the MRD response was 0.51 (95% CI: 0.34 -0.68), allo-HSCT rate was 0.62 (95% CI: 0.50 -.74), the AE rate was 0.65 (95% CI: 0.54 -0.76) and the relapse rate was 0.32 (95% CI: 0.27 -0.38). In the RCTs, the blinatumomab-treated group compared with the chemotherapy group had a combined OS rate of 0.12 (95% CI: 0.05 -0.19) and an EFS rate of 2.16 (95% CI: 1.54 -3.03). The pooled MRD response rate was 4.71 (95% CI:2.84 -7.81), allo-HSCT was 3.24 (95% CI: 1.96 -5.35), the AE rate was 0.31 (95% CI: 0.16 -0.60), and the relapse rate was 0 .69 (95% CI: 0.43 -1.09). Conclusion: According to this meta-analysis, blinatumomab shows potent therapeutic efficacy and limited AEs in children with R/R B- ALL. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022361914.
Treatment of acute lymphoblastic leukemia in children. Long-term results of two trials. [2007]Eighty-eight children younger than 15 years with acute lymphoblastic leukemia were treated with two similar protocols. Both regimens consist of multidrug combinations, with CNS prophylaxis. Sixty-four patients were enrolled on first protocol 0171 with vincristine and prednisone induction therapy. After remission induction patients were randomized on two arms: regimen A which consists of intensive courses of methotrexate with vincristine and prednisone reinductions and administration of cyclophosphamide. Regimen B is similar to regimen A, only courses of methotrexate are alternated with courses of 6-mercaptopurine during consolidation and intensification therapy. In maintenance phase both regimens have daily administration of 6-mercaptopurine and twice weekly administration of methotrexate, with vincristine and prednisone reinductions. The second protocol 0276/A is similar to regimen B of protocol 0171, but L-asparaginase is administered in the end of induction phase and total duration of therapy since induction of complete remission is prolonged from 2.5 to 4 years. Complete remission rate ranged from 92 to 96% in the patients achieving complete remission. In protocol 0171 actuarial proportion of children alive in complete remission for more than 10 years is 60% at present. The actual median survival of all children treated with protocol 0171 is 46+ months and actual median duration of complete remission is 43+ months. There was no significant difference between patients treated with methotrexate alone and those treated with combination of methotrexate and 6-mercaptopurine during consolidation and intensification phase. In protocol 0171 the relapse rate was 28% and the death rate in complete remission was 15%. More than 70% of complete responders in protocol 0276 is in continuous complete remission from 2+ to 57+ months, relapse rate is only 4% at present and the death rate in complete remission is 9% in this protocol.