A Phase II Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of the ITCC-059 Study
Authors: Brivio Erica , Locatelli Franco , Thano Adriana , Petit Arnaud , Vormoor Britta Julia , Rives Susana , Bielorai Bella , Rossig Claudia , Rizzari Carmelo , Van Der Velden Vincent H.J. , Ammerlaan Anneke C.J. , Den Boer Monique L. , Sleight Barbara , Engstler Gernot , Stary Jan , Bautista Sirvent Francisco José , Chen-Santel Christiane , Bruno Bénédicte , Bertrand Yves , Rialland Fanny , Plat Geneviève , Reinhardt Dirk , Vinti Luciana , von Stackelberg Arend , Zwaan Christian Michel 
Published: November 2020

Background:
Inotuzumab ozogamicin (InO) was well tolerated and demonstrated anti-leukemia activity in heavily pre-treated pediatric patients (pts) with CD22-positive relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the Phase (Ph) I ITCC-059 study. With the established recommended phase 2 dose (RP2D) (1.8 mg/m2/course, as in adults) a consecutive Ph II study has been performed, sponsored by Erasmus MC and supported by Pfizer (NTR57360).
Study design:
Pts aged 1-18 years with R/R CD22+ BCP-ALL were included after informed consent was obtained. Key inclusion criteria included, M2/M3 marrow and adequate liver and kidney function. Overall response rate (ORR) was the primary endpoint, and included CR, CRp (ANC &gt;500/µL but PLT ≤50.000/µL) and CRi (ANC ≤500/µL and/or PLT ≤50,000/µL). Secondary endpoints included safety, minimal residual disease (MRD) levels and durability of response. The study consisted of a single-stage design to test the null hypothesis (H0) ORR ≤30% and the alternative hypothesis of ORR &gt;55%. With 25 pts, the study had 80% power to reject H0 at a significance level of 0.05. Central MRD analysis by flow cytometry was considered negative if &lt;0.01%. Survival analysis used the Kaplan-Meier method. Results are based on a database snapshot on June 30, 2020.
Results:
32 pts were enrolled (Jun 2019-Apr 2020), including 2 screen failures and 2 pts who did not start treatment due to rapidly progressive disease. The median age of the 28 treated pts was 7.5 years (range 1-17); 19 pts were male (68%); 6 (21.5%) were primary refractory, 16 (57%) had ≥2nd relapse and 6 (21.5%) had 1st relapse post-HSCT (median 2 prior regimens, range 2-7). 50% of the pts had received a previous HSCT, 3 (11%) CAR T-cell therapy and 7 (25%) blinatumomab. Median baseline WBC was 3.1 x109/L (range 0.7-132). At time of data snapshot, 48 courses of InO were administered (range 1-4 per pt); one pt was still receiving InO. Disease response was not assessed in 1 pt (discontinued early due to sinusoidal obstruction syndrome (SOS)), 27 pts were evaluable for efficacy analyses.
Twenty-two pts achieved a response (ORR 81.5%; 95% CI 61.9%, 93.7%), all after the first cycle (CR n=14, CRp n=1, CRi n=7). Hence, the primary objective was achieved (P-value&lt;0.0001). Overall 21/22 (95%) achieved MRD-negativity as best response (of whom 82% after course 1).
When combining these results with pts treated at the RP2D in the Ph I study (n=13), 33/40 (82.5%) achieved a response (94% of whom achieved MRD-negativity). Of 9 primary refractory patients included in Ph I and II, 3 (33%) did not respond to InO.
The median follow-up time was 7.3 months (mo). The EFS at 6 and 12 mo was 57.9% (95% CI: 40.3−83.3) and 24.8% (95% CI: 9.8−62.9); and OS at 6 and 12 mo was 61.6% (95% CI: 43.3−87.8) and 54.8% (95% CI: 35.9−83.6), respectively. The median EFS was reached at 6.34 mo (95% CI 2.53, NA). The cumulative incidence of non-response or relapse was 32% and 57% at 6 and 12 mo; 3 pts died in CR (2 due to HSCT complications, 1 due to neurological deterioration considered related to previous CNS leukemia and prolonged intrathecal treatment).
Nine of 22 responding pts underwent HSCT (median 35 days after the last InO dose, range 20-72); 4 are still in CR. Three responders received consolidation with CAR T (52, 55 and 215 days after last Ino dose), all are still in CR.
Four cases of VOD/SOS were reported. One case occurred during InO treatment (gr 3, resolved). Three of 9 transplanted pts (33%) developed post-HSCT SOS. None of these pts received prophylactic defibrotide. One pt, previously transplanted and treated with CAR T, received 1 course of InO prior to a second HSCT and developed SOS (gr 3), ongoing at the time of death due to multiorgan failure. The other 2 pts developed gr 2 SOS after 2 and 3 courses of InO before their first HSCT, both events resolved.
All pts had at least 1 adverse event (AE) during the study and 19 pts reported at least 1 of gr 3-4 AE. The most common AE was fever. Detailed data will be presented at the meeting.
Conclusion:
InO was well tolerated in this Ph II study which confirmed remarkable activity in these heavily pretreated pts. The ORR was 81.5% with 95% MRD-negativity; 55% of pts remained alive after 1 year. Twelve pts proceeded to consolidation treatment (either HSCT or CAR T). In contrast with the Ph I cohort (where no pts developed SOS post 7 HSCTs), 3 cases of SOS were recorded here after 9 HSCTs.
A Ph I cohort of this study combining InO with chemotherapy in R/R pediatric ALL is ongoing.

Disclosures
Brivio: Pfizer Inc.: Other: Erasmus MC received institutional funding for the study from Pfizer. Rossig:BMS: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sleight:Pfizer Inc.: Current Employment. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees. von Stackelberg:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau. Zwaan:Servier, Sanofi, Daiichi Sankyo, Novartis, Janssen, Roche, Incyte, Pfizer, Celgene: Consultancy; Pfizer, Celgene, BMS: Research Funding; Jazz Pharmaceuticals: Other: Travel funding.