Abstract

Abstract 2612

Background:

Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic antitumor agent. CD22 is expressed on a majority of B-cell acute lymphoblastic leukemia (ALL). An initial study suggested INO efficacy and tolerability in ALL (Lancet Oncol 2012;13:403-11).

Objectives:

The current phase 1, multicenter, dose-escalation study was performed to optimize the INO dose and schedule (weekly dosing) based on safety, efficacy, and pharmacokinetic data in CD22+ relapsed or refractory ALL. The safety and efficacy of INO at the recommended dose and schedule will subsequently be further evaluated in a 12-patient (pt) expanded cohort.

Methods:

Eligible pts were aged ≥18 y with CD22+ ALL (defined as ≥20% blasts CD22+ by flow cytometry) refractory to initial induction or in relapse (≥first relapse), with no evidence of central nervous system disease. INO was administered in 28-d cycles (see Table), with a maximum of 6 cycles. The final dose was to be determined based on both toxicity (ie, rate of dose-limiting toxicities [DLT] at each dose level) and evidence of efficacy using the EffTox V2.10 software (Biometrics 2004;60:684–693). Adverse event (AE) severity was assessed per CTCAE V3 with DLTs defined as any of the following INO-related events during Cycle 1: grade ≥4 non-hematologic toxicity; prolonged myelosuppression (absolute neutrophil count [ANC] <500/μL or platelets <25,000/μL in bone marrow) with no evidence of leukemia persisting >45 d from last dose; grade 3 non-hematologic toxicity persisting >7 d from the last dose; grade ≥3 elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin persisting >7 d; or any toxicity resulting in permanent INO discontinuation. Weekly teleconferences with investigators were used to assess toxicity. Complete response (CR) was defined as <5% bone marrow blasts with absence of peripheral blasts, ANC ≥1,000/μL, platelets >100,000/μL, and no extramedullary disease; incomplete CR (CRi) was similar but permitted ANC <1,000/μL and/or platelets ≤100,000/μL.

Results:

We report preliminary data for 13 pts (see Table ), with a median duration of follow-up of 147 d (range, 30–188 d). Median age was 56 y (range, 23–65 y), and 69% of pts were male. Five (39%) pts were in salvage 1, 2 (15%) were in salvage 2, and 4 (31%) were in salvage ≥3. Two pts had prior allogeneic stem cell transplant. Three (23%) pts were Ph+ and 7 (54%) pts had circulating blasts at baseline; median baseline WBC was 2.01×103/mm3 (range, 0.5–29.11×103/mm3).

The single DLT observed to date was transient grade 4 elevated lipase occurring at INO dose level 3. The most frequent (≥10% of pts) treatment-related AEs were thrombocytopenia (31%, all grade 3/4), neutropenia (15%), and elevated ALT (15%). Treatment-related elevated AST and alkaline phosphatase were each reported for 8% of pts. Reported dose delays were due to thrombocytopenia (n = 3), neutropenia (n = 2), elevated LFT (n = 2), bacteremia, increased blood creatinine, periorbital cellulitis, and QTc prolongation (n = 1 each). Fourteen serious AEs were reported for 9 pts, including 2 cases each of febrile neutropenia and septic shock.

Responses were observed across all INO doses explored to date (see Table ). The preliminary response rate was 82% (9/11 evaluable pts), including 36% of pts with a CR and 45% with a CRi. Median time to response was 43 d (range, 28–56 d). Six of 9 (67%) pts who achieved CR/CRi also achieved minimal residual disease (<1 blast out of 104 mononuclear cells by flow cytometry).

Seven pts discontinued treatment, including 1 each due to disease progression and an AE (acute renal failure, not treatment related), and 5 pts who proceeded to transplant. Four deaths were reported, including 1 due to disease progression and 3 due to sepsis occurring within 30 d after stem cell transplantation.

Conclusions:

INO had a safety profile consistent with prior reports, characterized by hematologic, gastrointestinal, and hepatic events and infection. The remarkable response rate of 82% for single-agent INO in this relapsed/refractory population warrants further exploration in CD22+ ALL. Updated results will be presented at the meeting.

INO dose levelnDay 1 (mg/m2)Day 8 (mg/m2)Day 15 (mg/m2)Day 28Total dose (mg/m2)/cycleDLTsCR/CRi rate, n (%)
0.8 0.4 Bone marrow and disease assessments 1.2 2/3 (67) 
0.8 0.4 0.4  1.6 5/6 (83) 
0.8 0.5 0.5  1.8 2/2 (100) 
1.0 0.5 0.5  2.0 – – 
INO dose levelnDay 1 (mg/m2)Day 8 (mg/m2)Day 15 (mg/m2)Day 28Total dose (mg/m2)/cycleDLTsCR/CRi rate, n (%)
0.8 0.4 Bone marrow and disease assessments 1.2 2/3 (67) 
0.8 0.4 0.4  1.6 5/6 (83) 
0.8 0.5 0.5  1.8 2/2 (100) 
1.0 0.5 0.5  2.0 – – 
Disclosures:

Stock:Tau for work done through the CALGB/ALLIANCE: Research Funding. Wang:Pfizer Inc: Employment, Equity Ownership. Volkert:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer Inc: Employment, Equity Ownership. Advani:Pfizer Inc: Consultancy, Honoraria, Research Funding.

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Author notes

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Asterisk with author names denotes non-ASH members.