Phase II Study of Pedi-Crib: Mini-Hyper-CVD with Condensed Rituximab, Inotuzumab Ozogamicin and Blinatumomab (cRIB) for Relapsed Therapy for Pediatric Patients with B-Cell Lineage Acute Lymphocytic Leukemia

Background and Significance: Despite notable advances in bringing immunotherapy to pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), the most commonly used relapsed protocol’s induction cycle, ALLR3, yielded a death rate of 2% and severe infection rate of 90% with responders having a high rate (38%) of detectable disease (minimal residual disease (MRD)) at the end of the first cycle. A less intensive re-induction regimen has also been used, AALL01P2, but still has significant toxicity, with a 40% rate of fever and neutropenia, a 2.4% death rate and a 60% rate of detectable disease at the end of the first cycle. Given the need for stem cell transplant (SCT) to consolidate the remission, the intensive chemotherapy, and its associated toxicities (cardiopulmonary dysfunction from anthracyclines, peg-asparaginase toxicities, neuropathies, and/or serious viral, bacterial, and fungal infections) can delay or alter the much-needed SCT.

A novel approach with a new re-induction cycle is needed with reduced chemotherapy with less myelosuppression and yet utilizing targeted immunotherapy for increased efficacy. The integration of chemotherapy with targeted therapies such as rituximab, inotuzumab and blinatumomab has been proven effective in elderly patients with de novo B-ALL and in relapsed/refractory adults with B-ALL. Case series have been published using this regimen in pediatrics. Given this reassuring data of efficacy and safety profile, we have created a Phase 2 trial (NCT05645718) to evaluate the clinical efficacy of the sequential combination of mini-hyper-CVD with inotuzumab ozogamicin, blinatumomab and rituximab in relapsed B-ALL pediatrics patients.

The proposed study looks to use reduced chemotherapy given concurrently with immunotherapy, within the same month and most notably, while the blood counts are recovering in the second half of the month. If the aims of the project are achieved, this could be the new standard of care for relapsed pediatric B-ALL. Scientific knowledge will also be expanded using bio-banked and analyzed patient samples.

Study Design and Methods: Pedi-cRIB (NCT05645718) is a Phase 2 open-label, single site, single-arm trial to determine the clinical efficacy of the sequential combination of mini-hyper-CVD (cycle 1 cyclophosphamide, dexamethasone, vincristine alternating with cycle 2 with intermediate dosed methotrexate and cytarabine) given concurrently with inotuzumab ozogamicin, blinatumomab and rituximab. If patient does not have CD20, they can still be enrolled but will not receive rituximab. Treatment cycles will be 28 days for 6 cycles with maintenance therapy should the patient not choose to undergo SCT. Patients with B-ALL aged 1 to 25 who are unable to receive anthracyclines or is PEG-asparaginase intolerant will be eligible. Patients will need adequate cardiac, hepatic, and renal function and Lansky score ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are > 16 years old. Patient will need to have recovered from previous chemotherapy prior to enrollment. The primary objective is to evaluate the clinical efficacy of the combination based upon the complete response rate after the first cycle. The secondary objective is to summarize efficacy and to evaluate the safety of this combination. The exploratory objectives are to summarize associations between genomic alterations in ALL (current biomarker expression of the disease) with relation to the incidence of transition to SCT in patients with partial response or stable disease after the induction cycle(s).

Simon's optimal two-stage design will be used for conducting the trial. In stage I, a total number of 9 patients is accrued. If there are 3 or fewer responses among these 9 patients, the study will be stopped early for futility. Otherwise, an additional 18 patients will be accrued in stage II, resulting in a total sample size of 27. We will use Bayesian toxicity monitoring rules to monitor the toxic event rate and stop the trial if there is strong evidence at any time that this rate exceeds 20%.

In this Phase 2 study we will investigate the combination of chemotherapy given concurrently with immunotherapy in attempt to improve response rates and prolong survival for relapsed or refractory pediatric patients with B-ALL.