A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

Abstract

This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.

Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

“…Additionally, it is recommended to use prophylactic pharmacologic agents (e.g., ursodiol), to limit the inotuzumab use to two cycles if HCT is planned, and to avoid HCT conditioning regimens that contain dual alkylating agents (e.g., thiotepa and melphalan) and concomitant hepatotoxic drugs (e.g., azoles) [ 152 ]. In a pediatric phase I study that used fractionated weekly dosing for relapsed/refractory B-ALL, complete remission was seen in 80% of the patients and 84% of those with available flow cytometry data had negative MRD [ 153 ].…”

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series

“…Our cohort showed a lower MRD‐negativity rate compared both to the adult and the available paediatric data in older children treated with InO 4–7 . No descriptive results of the three patients aged 2–4 years were included in the retrospective cohort published by Bohjwani; one KMT2A ‐r patient in the ITCC‐059 cohort achieved CR and at relapse 7% of the blasts were CD22‐negative 6,9 …”

“…Phase I–II trials with InO in paediatric R/R ALL did not include infants 4,5 . Paediatric results with InO reflect the positive experience reported in adults, with response rates ranging from 58% to 80%, and the majority of responders becoming MRD‐negative (65–84%) 4–7 …”

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies

“…In another cohort including children with r/r ALL treated with InO only one IFD was recorded (2%), while severe neutropenia was estimated at 44.9% [ 76 ]. A recent phase I study of InO in pediatric r/r ALL reported neutropenia in 56% of treated children, but low severe infection rates (8%; one with lung infection and one with sepsis after AHSCT) [ 77 ]. A retrospective study of r/r precursor B-cell ALL in pediatric patients under compassionate use with InO and blinatumomab recorded two severe infections (6.5%) that led to death [ 78 ].…”