Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents and immunomodulating agents, other Antineoplastic agent, monoclonal antibodies and antibody drug conjugates, CD22 (Clusters of Differentiation 22) inhibitors,, ATC code: L01XC26 L01FB01.

Mechanism of action

Inotuzumab ozogamicin is an ADC composed of a CD22-directed monoclonal antibody that is covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inotuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody that specifically recognises human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic product.

N-acetyl-gamma-calicheamicin is covalently attached to the antibody via an acid-cleavable linker.
Nonclinical data suggest that the anticancer activity of BESPONSA is due to the binding of the ADC to CD22-expressing tumour cells, followed by internalisation of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Clinical efficacy and safety

Patients with relapsed or refractory ALL who have received 1 or 2 prior treatment regimens for ALL - Study 1

The safety and efficacy of BESPONSA in patients with relapsed or refractory CD22-positive ALL were evaluated in an open-label, international, multicentre, Phase 3 study (Study 1) in which patients were randomised to receive BESPONSA (N=164 [164 received treatment]) or Investigator’s choice of chemotherapy (N=162 [143 received treatment]), specifically fludarabine plus cytarabine plus granulocyte colony-stimulating factor (FLAG) (N=102 [93 received treatment]), mitoxantrone/cytarabine (MXN/Ara-C) (N=38 [33 received treatment]), or high dose cytarabine (HIDAC) (N=22 [17 received treatment]).

Eligible patients were ≥ 18 years of age with Philadelphia chromosome negative (Ph-) or Ph+ relapsed or refractory B-cell CD22-positive precursor ALL.

CD22 expression was assessed using flow cytometry based on bone marrow aspirate. In patients with an inadequate bone marrow aspirate sample, a peripheral blood sample was tested. Alternatively, CD22 expression was assessed using immunohistochemistry in patients with an inadequate bone marrow aspirate and insufficient circulating blasts.

In the clinical study, the sensitivity of some local tests was lower than the central laboratory test.
Therefore, only validated tests with demonstrated high sensitivity should be used.

All patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 prior induction chemotherapy regimens for ALL. Patients with Ph+ B-cell precursor ALL were required to have failed treatment with at least 1 second or third generation TKI and standard chemotherapy.
Table 1 (see section 4.2) shows the dosing regimen used to treat patients.

The co-primary endpoints were CR/CRi, assessed by a blinded independent endpoint adjudication committee (EAC), and overall survival (OS). The secondary endpoints included MRD negativity, duration of remission (DoR), HSCT rate, and progression-free survival (PFS).
The primary analysis of CR/CRi and MRD negativity was conducted in the initial 218 randomised patients and the analysis of OS, PFS, DoR, and HSCT rate was conducted in all 326 randomised patients.

Among all 326 randomised patients (ITT population), 215 (66%) patients had received 1 prior treatment regimen and 108 (33%) patients had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 18-79 years), 206 (63%) patients had a duration of first remission < 12 months, and 55 (17%) patients had undergone an HSCT prior to receiving BESPONSA or Investigator’s choice of chemotherapy. The 2 treatment groups were generally balanced with respect to the baseline demographics and disease characteristics. A total of 276 (85%) patients had Ph- ALL.
Of the 49 (15%) patients with Ph+ ALL, 4 patients did not receive a prior TKI, 28 patients received 1 prior TKI, and 17 patients received 2 prior TKIs. Dasatinib was the most commonly received TKI (42 patients), followed by imatinib (24 patients).

Baseline characteristics were similar in the initial 218 patients randomised.

Of the 326 patients (ITT population), 253 patients had samples that were evaluable for CD22 testing by both local and central laboratory. By central and local laboratory tests, 231/253 (91.3%) patients and 130/253 (51.4%) patients, respectively, had ≥ 70% CD22-positive leukaemic blasts at baseline.

Table 6 shows the efficacy results from this study.

Table 6.     Study 1: Efficacy results in patients ≥ 18 years of age with relapsed or refractory B-cell precursor ALL who received 1 or 2 prior treatment regimens for ALL 
BESPONSA                    HIDAC, FLAG, or
(N=109)                 MXN/Ara-C (N=109)
CRa/CRib; n (%) [95% CI]                               88 (80.7%)                      32 (29.4%) [72.1%-87.7%]                   [21.0%-38.8%]
2-sided p-value < 0.0001
CRa; n (%) [95% CI]                                39 (35.8%)                      19 (17.4%) [26.8%-45.5%]                   [10.8%-25.9%]
2-sided p-value = 0.0022
CRib; n (%) [95% CI]                               49 (45.0%)                      13 (11.9%) [35.4%-54.8%]                    [6.5%-19.5%]
2-sided p-value < 0.0001
MRD negativityc for patients achieving               69/88 (78.4%)                    9/32 (28.1%) CR/CRi; rated (%) [95% CI]                          [68.4%-86.5%]                   [13.7%-46.7%] 2-sided p-value < 0.0001
BESPONSA                    HIDAC, FLAG, or
(N=164)                 MXN/Ara-C (N=162)
Median OS; months [95% CI]                                 7.7                             6.2 [6.0 to 9.2]                    [4.7 to 8.3]
Hazard ratio [95% CI] = 0.751 [0.588-0.959]
2-sided p-value = 0.0210
Median PFSe, f; months [95% CI]                            5.0                             1.7 [3.9-5.8]                       [1.4-2.1]
Hazard ratio [95% CI] = 0.450 [0.348-0.581]
Table 6.     Study 1: Efficacy results in patients ≥ 18 years of age with relapsed or refractory B-cell precursor ALL who received 1 or 2 prior treatment regimens for ALL 
2-sided p-value < 0.0001
Median DoRg; months [95% CI]                              3.7                           0.0 [2.8 to 4.6]                      [-,-]
Hazard ratio [95% CI] = 0.471 [0.366-0.606]
2-sided p-value < 0.0001
Abbreviations: ALL=acute lymphoblastic leukaemia; ANC=absolute neutrophil counts; Ara-C=cytarabine; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete haematological recovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high- dose cytarabine; HSCT=haematopoietic stem cell transplant; ITT=intent-to-treat; MRD=minimal residual disease; MXN=mitoxantrone; N/n=number of patients; OS=overall survival; PFS=progression-free survival.
a
CR, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukaemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 109/L and ANC ≥ 1 × 109/L) and resolution of any extramedullary disease.
b
CRi, per EAC, was defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukaemic blasts, partial recovery of peripheral blood counts (platelets < 100 × 109/L and/or ANC < 1 × 109/L) and resolution of any extramedullary disease.
c
MRD negativity was defined by flow cytometry as leukaemic cells comprising < 1 × 10-4 (< 0.01%) of bone marrow nucleated cells.
d
Rate was defined as number of patients who achieved MRD negativity divided by the total number of patients who achieved CR/CRi per EAC.
e
PFS was defined as the time from date of randomisation to earliest date of the following events: death, progressive disease (including objective progression, relapse from CR/CRi, treatment discontinuation due to global deterioration of health status), and start of new induction therapy or post-therapy HSCT without achieving CR/CRi.
f
In the standard definition of PFS, defined as the time from date of randomisation to earliest date of the following events: death, progressive disease (including objective progression and relapse from CR/CRi), the HR was 0.568 (2-sided p-value=0.0002) and median PFS was 5.6 months and 3.7 months in the BESPONSA and Investigator’s choice of chemotherapy arm, respectively.
g
Duration of remission was defined as the time since first response of CRa or CRib per Investigator’s assessment to the date of a PFS event or censoring date if no PFS event was documented. Analysis was based on the ITT population with patients without remission being given a duration of zero and considered an event.

Among the initial 218 randomised patients, 64/88 (73%) and 21/88 (24%) of responding patients per EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the BESPONSA arm. No additional patients achieved CR/CRi after Cycle 3 in the BESPONSA arm.

CR/CRi and MRD negativity findings in the initial 218 randomised patients were consistent with those seen in all 326 randomised patients.

Among all 326 randomised patients, the survival probability at 24 months was 22.8% in the BESPONSA arm and 10% in the Investigator’s choice of chemotherapy arm.

A total of 79/164 (48.2%) patients in the BESPONSA arm and 36/162 (22.2%) patients in the Investigator’s choice of chemotherapy arm had a follow-up HSCT. This included 70 and 18 patients in the BESPONSA and Investigator’s choice of chemotherapy arm, respectively, who proceeded directly to HSCT. In those patients who proceeded directly to HSCT, there was a median gap of 4.8 weeks (range: 1-19 weeks) between the last final dose of inotuzumab ozogamicin and HSCT. The
OS improvement for BESPONSA versus Investigator’s choice of chemotherapy arm was seen in patients who underwent HSCT. Although there was a higher frequency of early deaths post-HSCT (at Day 100) in the BESPONSA arm, there was evidence of a late survival benefit for BESPONSA. In patients who underwent a follow-up HSCT, the median OS was 11.9 months (95% CI: 9.2, 20.6) for BESPONSA versus 19.8 months (95% CI: 14.6, 26.7) for Investigator’s choice of chemotherapy. At month 24, the survival probability was 38.0% (95% CI: 27.4, 48.5) versus 35.5% (95% CI: 20.1, 51.3) for BESPONSA and Investigator’s choice of chemotherapy, respectively. Furthermore, at month 24, the survival probability was 38.0% (95% CI: 27.4, 48.5) for patients who underwent a follow-up HSCT compared to 8.0% (95% CI: 3.3, 15.3) for patients who did not undergo a follow-up HSCT in the BESPONSA arm.

BESPONSA improved OS versus Investigator’s choice of chemotherapy for all stratification factors including duration of first remission 12 months, Salvage 1 status, and age at randomisation <55 years. There was also a trend for better OS with BESPONSA for patients with other prognostic factors (Ph-, no prior HSCT,  90% leukaemic blasts CD22-positive at baseline, no baseline peripheral blasts, and baseline haemoglobin ≥ 10 g/dL, based on exploratory analyses). Patients with mixed-lineage leukaemia (MLL) gene rearrangements, including t (4;11), that generally have lower CD22 expression prior to treatment, had a worse OS outcome following treatment with BESPONSA or Investigator’s choice of chemotherapy.

For patient-reported outcomes, most functioning and symptom scores were in favour of BESPONSA compared to Investigator’s choice of chemotherapy. Patient-reported outcomes measured using the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) were significantly better for BESPONSA by estimated mean post-baseline scores (BESPONSA and Investigator’s choice of chemotherapy, respectively) for role functioning (64.7 versus 53.4, improvement grade small), physical functioning (75.0 versus 68.1, improvement grade small), social functioning (68.1 versus 59.8, improvement grade medium), and appetite loss (17.6 versus 26.3, improvement grade small) compared to Investigator’s choice of chemotherapy.
There was a trend in favour of BESPONSA, improvement grade small, for estimated mean post- baseline scores (BESPONSA and Investigator’s choice, respectively) in global health status/Quality of Life (QoL) (62.1 versus 57.8), cognitive functioning (85.3 versus 82.5), dyspnoea (14.7 versus 19.4), diarrhoea (5.9 versus 8.9), fatigue (35.0 versus 39.4). There was a trend in favour of BESPONSA for estimated mean post-baseline scores from the EuroQoL 5 Dimension (EQ-5D) questionnaire, (BESPONSA and Investigator’s choice of chemotherapy, respectively) for the EQ-5D index (0.80 versus 0.76, minimally important difference for cancer = 0.06).

Patients with relapsed or refractory ALL who have received 2 or more prior treatment regimens for ALL - Study 2

The safety and efficacy of BESPONSA were evaluated in a single-arm, open-label, multicentre Phase 1/2 study (Study 2). Eligible patients were ≥ 18 years of age with relapsed or refractory B-cell precursor ALL.

Of 93 screened patients, 72 patients were assigned to study drug and were treated with BESPONSA.
The median age was 45 years (range: 20-79 years); 76.4% were Salvage status ≥ 2; 31.9% had received a prior HSCT and 22.2% were Ph+. The most common reasons for treatment discontinuation were: disease progression/relapse (30 [41.7%]), resistant disease (4 [5.6%]); HSCT (18 [25.0%]), and adverse events (13 [18.1%]).

In the Phase 1 portion of the study, 37 patients received BESPONSA at a total dose of 1.2 mg/m2 (nN=3), 1.6 mg/m2 (nN=12), or 1.8 mg/m2 (nN=22). The recommended BESPONSA dose was determined to be 1.8 mg/m2/cycle administered at a dose of 0.8 mg/m2 on Day 1 and 0.5 mg/m2 on Days 8 and 15 of a 28-day cycle with a dose reduction upon achieving CR/CRi.

In the Phase 2 portion of the study, patients had to have received at least 2 prior treatment regimens for ALL and patients with Ph+ B-cell ALL had to have failed treatment with at least 1 TKI. Of the 9 patients with Ph+ B-cell ALL, 1 patient had received 1 previous TKI and 1 patient had received no prior TKIs.


Table 7 shows the efficacy results from this study.
Table 7.     Study 2: Efficacy results in patients ≥ 18 years of age with relapsed or refractory B-cell precursor ALL who received 2 or more prior treatment regimens for ALL 
BESPONSA
(N=35)
CRa/CRib; n (%) [95% CI]                                                       24 (68.6%) [50.7%-83.2%]
CRa; n (%) [95% CI]                                                        10 (28.6%) [14.6%-46.3%]
CRib; n (%) [95% CI]                                                       14 (40.0%) [23.9%-57.9%]
Median DoRf; months [95% CI]                                                       2.2 [1.0 to 3.8]
MRD negativityc for patients achieving CR/CRi;                                18/24 (75%) rated (%) [95% CI]                                                           [53.3%-90.2%] Median PFSe; months [95% CI]                                                       3.7 [2.6 to 4.7]
Median OS; months [95% CI]                                                         6.4 [4.5 to 7.9]
Abbreviations: ALL=acute lymphoblastic leukaemia; ANC=absolute neutrophil counts; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete haematological recovery; DoR=duration of remission; HSCT=haematopoietic stem cell transplant; MRD=minimal residual disease; N/n=number of patients; OS=overall survival; PFS=progression-free survival.
a, b, c, d, e, f
For definition, see Table 6 (with the exception that CR/CRi was not per EAC for Study 2) 
In the Phase 2 portion of the study, 8/35 (22.9%) patients had a follow-up HSCT.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with BESPONSA in one or more subsets of the paediatric population for the treatment of relapsed or refractory ALL (see section 4.2 for information on paediatric use).

Study ITCC-059 has been performed in compliance with the agreed Paediatric Investigation Plan (see section 4.2 for information on paediatric use).

Study ITCC-059 was a Phase 1/2 multicentre, single-arm, open-label study conducted in 53 paediatric patients ≥ 1 and < 18 years of age with relapsed or refractory CD22-positive B-cell precursor ALL to identify a recommended Phase 2 Dose (Phase 1) and to further evaluate the efficacy, safety, and tolerability of the selected BESPONSA dose as a monotherapy agent (Phase 2). The study also evaluated the Pharmacokinetics and Pharmacodynamics of BESPONSA as monotherapy (see section 5.2).

In the Phase 1 Cohort (N=25), two dose levels were examined (initial dose of 1.4 mg/m2 per cycle and an initial dose of 1.8 mg/m2 per cycle). In the Phase 2 Cohort (N=28), patients were treated at the initial dose of 1.8 mg/m2 per cycle (0.8mg/m2 on Day 1, 0.5mg/m2 on Days 8 and 15) followed by a dose reduction to 1.5mg/m2 per cycle for patients in remission. In both Cohorts, patients received a median of 2 cycles of therapy (range: 1 to 4 cycles). In the Phase 1 Cohort, the median age was 11 years (range: 1-16 years), and 52% of patients had second or greater relapsed B-cell precursor ALL. In the Phase 2 Cohort, the median age was 7.5 years (range: 1-17 years), and 57% of patients had second or greater relapsed B-cell precursor ALL.


Efficacy was evaluated on the basis of Objective Response Rate (ORR), defined as the rate of patients with CR+CRp+CRi. In the Phase 1 Cohort, 20/25 (80%) patients had CR, the ORR was 80% (95% CI: 59.3-93.2), and the median Duration of Response (DoR) was 8.0 months (95% CI: 3.9- 13.9). In the Phase 2 Cohort, 18/28 (64%) patients had CR, the ORR was 79% (95% CI: 59.0-91.7), and the DoR was 7.6 months (95% CI: 3.3-NE). In the Phase 1 Cohort, 8/25 patients (32%) and 18/28 (64%) in the Phase 2 Cohort had a follow-up HSCT.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
In patients with relapsed or refractory ALL treated with inotuzumab ozogamicin at the recommended starting dose of 1.8 mg/m2/cycle (see section 4.2), steady-state exposure was achieved by Cycle 4.
The mean (SD) maximum serum concentration (Cmax) of inotuzumab ozogamicin was 308 ng/mL (362). The mean (SD) simulated total area under the concentration-time curve (AUC) per cycle at steady state was 100 mcgh/mL (32.9).

Distribution

In vitro, the binding of the N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp). In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.

Biotransformation

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolised via nonenzymatic reduction. In humans, serum N-acetyl-gamma-calicheamicin dimethylhydrazide levels were typically below the limit of quantitation (50 pg/mL), but sporadic measurable levels of unconjugated calicheamicin up to 276 pg/mL occurred in some patients.

Elimination

Inotuzumab ozogamicin pharmacokinetics were well characterised by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h, and the terminal elimination half-life (t½) at the end of Cycle 4 was approximately 12.3 days. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was observed between Cycles 1 and 4.

Based on a population pharmacokinetic analysis in 765 patients, body surface area was found to significantly affect inotuzumab ozogamicin disposition. The dose of inotuzumab ozogamicin is administered based on body surface area (see section 4.2).

Pharmacokinetics in specific groups of subjects or patients

Age, race, and gender

Based on a population pharmacokinetic analysis, age, race, and gender did not significantly affect inotuzumab ozogamicin disposition.


Hepatic impairment
No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with hepatic impairment.

Based on a population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab ozogamicin in patients with hepatic impairment defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) category B1 (total bilirubin ≤ ULN and AST > ULN; nN=133) or B2 (total bilirubin > 1.0-1.5 × ULN and AST any level; nN=17) was similar to patients with normal hepatic function (total bilirubin/AST ≤ ULN; nN=611) (see section 4.2). In 3 patients with hepatic impairment defined by NCI ODWG category C (total bilirubin > 1.5-3 × ULN and AST any level) and 1 patient with hepatic impairment defined by NCI ODWG category D (total bilirubin > 3 × ULN and AST any level), inotuzumab ozogamicin clearance did not appear to be reduced.

Renal impairment

No formal pharmacokinetic studies of inotuzumab ozogamicin have been conducted in patients with renal impairment.

Based on population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab ozogamicin in patients with mild renal impairment (CLcr 60-89 mL/min; nN=237), moderate renal impairment (CLcr 30-59 mL/min; nN=122), or severe renal impairment (CLcr 15-29 mL/min; nN=4) was similar to patients with normal renal function (CLcr ≥ 90 mL/min; nN=402) (see section 4.2).
Inotuzumab ozogamicin has not been studied in patients with end-stage renal disease (see section 4.2).

Paediatric population

At the adult recommended dose, the median exposure in paediatric patients with ALL (aged ≥1 and < 18 years) was 25% higher than those in adults. The clinical relevance of the increased exposure is unknown.

Cardiac electrophysiology

Population pharmacokinetic/pharmacodynamic evaluation suggested a correlation between increasing inotuzumab ozogamicin serum concentrations and prolongation of QTc intervals in ALL and non-Hodgkin’s lymphoma (NHL) patients. The median (upper bound of the 95% CI) for the change in QTcF at a supratherapeutic Cmax concentration was 3.87 msec (7.54 msec).

In a randomised clinical study in patients with relapsed or refractory ALL (Study 1), maximum increases in QTcF interval of  30 msec and ≥ 60 msec from baseline were measured in 30/162 (19%) and 4/162 (3%) patients in the inotuzumab ozogamicin arm, respectively, versus18/124 (15%) and 3/124 (2%) in the Investigator’s choice of chemotherapy arm, respectively. Increases in QTcF interval of > 450 msec and > 500 msec were observed in 26/162 (16%) and none of the patients in the inotuzumab ozogamicin arm versus 12/124 (10%) and 1/124 (1%) patients in the Investigator’s choice of chemotherapy arm, respectively (see section 4.8).