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BESPONSA™ Clinical Studies (inotuzumab ozogamicin)

14. CLINICAL STUDIES

Patients With Relapsed or Refractory ALL – INO-VATE ALL

The safety and efficacy of BESPONSA were evaluated in INO-VATE ALL (NCT01564784) a randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL. Patients were stratified at randomization based on duration of first remission (< 12 months or ≥ 12 months, salvage treatment (Salvage 1 or 2) and patient age at randomization (< 55 or ≥ 55 years). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. All patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least 1 tyrosine kinase inhibitor and standard chemotherapy. Table 1 shows the dosing regimen used to treat patients.

Among all 326 patients who were randomized to receive BESPONSA (N=164) or Investigator's choice of chemotherapy (N=162), 215 patients (66%) had received 1 prior treatment regimen for ALL and 108 patients (33%) had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 18–79 years), 276 patients (85%) had Philadelphia chromosome-negative ALL, 206 patients (63%) had a duration of first remission < 12 months, and 55 patients (17%) had undergone a HSCT prior to receiving BESPONSA or Investigator's choice of chemotherapy. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics.

All evaluable patients had B-cell precursor ALL that expressed CD22, with ≥ 90% of evaluable patients exhibiting ≥ 70% leukemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at a central laboratory.

The efficacy of BESPONSA was established on the basis of CR, the duration of CR, and proportion of MRD-negative CR (< 1 × 10-4 of bone marrow nucleated cells by flow cytometry) in the first 218 patients randomized. CR, duration of remission (DoR), and MRD results in the initial 218 randomized patients were consistent with those seen in all 326 randomized patients.

Among the initial 218 randomized patients, 64/88 (73%) and 21/88 (24%) of responding patients per EAC achieved CR/CRi in Cycles 1 and 2, respectively, in the BESPONSA arm, and 29/32 (91%) and 1/32 (3%) of responding patients per EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the Investigator's choice of chemotherapy arm.

Table 8 shows the efficacy results from this study.

Table 8. Efficacy Results in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)
CR*CRiCR/CRi*,
BESPONSA
(N=109)
HIDAC, FLAG, or MXN/Ara-C
(N=109)
BESPONSA
(N=109)
HIDAC, FLAG or MXN/Ara-C
(N=109)
BESPONSA
(N=109)
HIDAC, FLAG, or MXN/Ara-C
(N=109)
Abbreviations: CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high-dose cytarabine; HR=hazard ratio; MRD=minimal residual disease; MXN/AraC=mitoxantrone + cytarabine; N/n=number of patients; OS=overall survival; PFS=progression-free survival.
*
CR, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 109/L and absolute neutrophil counts [ANC] ≥ 1 × 109/L) and resolution of any extramedullary disease.
CRi, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets < 100 × 109/L and/or ANC < 1 × 109/L) and resolution of any extramedullary disease.
1-sided p-value using Chi-squared test.
§
DoR, based on a later cutoff date than the CR/CRi, was defined for patients who achieved CR/CRi per Investigator's assessment as time since first response of CR* or CRi per Investigator's assessment to the date of a PFS event or censoring date if no PFS event was documented.
MRD-negativity was defined by flow cytometry as leukemic cells comprising < 1 × 10-4 (< 0.01%) of bone marrow nucleated cells.
#
Rate was defined as the number of patients who achieved MRD negativity divided by the total number of patients who achieved CR/CRi per EAC.
Responding (CR/CRi) patients
n (%)
[95% CI]
39 (35.8)
[26.8–45.5]
19 (17.4)
[10.8–25.9]
49 (45.0)
[35.4–54.8]
13 (11.9)
[6.5–19.5]
88 (80.7)
[72.1–87.7]
32 (29.4)
[21.0–38.8]
p-value<0.0001
DoR§
n391845148432
Median, months
[95% CI]
8.0
[4.9–10.4]
4.9
[2.9–7.2]
4.6
[3.7–5.7]
2.9
[0.6–5.7]
5.4
[4.2–8.0]
3.5
[2.9–6.6]
MRD-negativity
n356343699
Rate# (%)
[95% CI]
35/39 (89.7)
[75.8–97.1]
6/19 (31.6)
[12.6–56.6]
34/49 (69.4)
[54.6–81.7]
3/13 (23.1)
[5.0–53.8]
69/88 (78.4)
[68.4–86.5]
9/32 (28.1)
[13.7–46.7]

Among the initial 218 patients, as per EAC assessment, 32/109 patients (29%) in the BESPONSA arm achieved complete remission with partial hematologic recovery (CRh; defined as <5% blasts in the bone marrow, ANC > 0.5 × 109/L, and platelet counts > 50 × 109/L but not meeting full recovery of peripheral blood counts) versus 6/109 patients (6%) in the Investigator's choice of chemotherapy arm, and 71/109 patients (65%) in the BESPONSA arm achieved CR/CRh versus 25/109 patients (23%) in the Investigator's choice of chemotherapy arm.

Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a follow-up HSCT.

Figure 1 shows the analysis of overall survival (OS). The analysis of OS did not meet the pre-specified boundary for statistical significance.

Figure 1. Kaplan-Meier Curve for Overall Survival (Intent-to-Treat Population)

Figure 1

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