Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: L01XC05
Gemtuzumab ozogamicin is a CD33-targeted ADC. Gemtuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognises human CD33. The antibody portion binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of myeloid leukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic stem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product. N-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4-(4-acetylphenoxy) butanoic acid) linker. Non-clinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumour cells, followed by internalisation of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukaemic blast cells. Several single agent studies measured target (CD33) saturation post-MYLOTARG dose in patients with relapsed and refractory AML. Across all studies, near maximal peripheral CD33 saturation was observed post-MYLOTARG dose at all dose levels of 2 mg/m² and above, suggesting that a low dose of gemtuzumab ozogamicin is sufficient to bind all available CD33 sites.
The efficacy and safety of MYLOTARG were evaluated in a multicentre, randomised, open-label Phase 3 study comparing the addition of MYLOTARG to a standard chemotherapy induction regimen of daunorubicin and cytarabine (DA) versus DA alone. Eligible patients were between 50 and 70 years of age with previously untreated de novo AML (Study ALFA-0701). Patients with acute promyelocytic leukaemia (APL, AML3) and patients with AML arising from myelodysplastic syndrome (MDS) or secondary AML were excluded from the study.
The primary endpoint was event-free survival (EFS). The secondary endpoints included CR and CRp rates, relapse-free survival (RFS), overall survival (OS), and safety of the combination DA with or without MYLOTARG.
In total, 271 patients were randomised in this study with 135 to induction treatment of 3+7 DA plus fractionated 3 mg/m² × 3 doses of MYLOTARG and 136 to 3+7 DA alone (see section 4.2). A second course of induction therapy with DA but without MYLOTARG, regardless of the randomisation arm, was allowed. Patients in either arm who did not receive the second course of induction therapy and did not achieve a CR after induction could receive a salvage course comprised of idarubicin, AraC, and granulocyte colony-stimulating factor (G-CSF).
Patients with CR or CRp received consolidation therapy with 2 courses of treatment including DNR and AraC with or without MYLOTARG according to their initial randomisation. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of MYLOTARG and transplantation was recommended.
Overall, the median age of patients was 62 years (range 50 to 70 years) and most patients (87.8%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender as a higher percentage of males were enrolled in the MYLOTARG arm (54.8%) than in the DA alone arm (44.1%). Overall, 59.0% and 65.3% of patients had documented favourable/intermediate-risk disease by the National Comprehensive Cancer Network (NCCN) and European LeukaemiaNet (ELN) 2010 risk classifications, respectively. CD33 expression on AML blasts by flow cytometry harmonised from local laboratory results was determined in 194/271 (71.6%) patients overall. Few patients (13.7%) had low CD33 expression (less than 30% of blasts).
The trial met its primary objective of demonstrating that MYLOTARG added in fractionated doses (3 mg/m² × 3) to standard induction chemotherapy for patients with previously untreated de novo AML resulted in a statistically significant and clinically meaningful improvement in EFS. Median EFS was 17.3 months (95% CI: 13.4, 30.0) in the MYLOTARG arm versus 9.5 months (95% CI: 8.1, 12.0) in the DA alone arm; hazard ratio (HR) 0.562 (95% CI: 0.415, 0.762); 2-sided p=0.0002 by log-rank test. Efficacy data from ALFA-0701 study are summarised in Table 8, and the Kaplan-Meier plot for EFS is shown in Figure 1.
Table 8. Efficacy results from study ALFA-0701 (mITT population):
| MYLOTARG + daunorubicin + cytarabine | daunorubicin + cytarabine | |
|---|---|---|
| Event-free survival (by Investigator) | N=135 | N=136 |
| Number of events, n (%) | 73 (54,1) | 102 (75,0) |
| Median EFS in months [95% CI]a | 17,3 [13,4, 30,0] | 9,5 [8,1, 12,0] |
| 2-year EFS probability[95% CI]b | 42,1 [32,9, 51,0] | 18,2 [11,1, 26,7] |
| 3-year EFS probability [95% CI]b | 39,8 [30,2, 49,3] | 13,6 [5,8, 24,8] |
| Hazard ratio [95% CI]c | 0,562 [0,415, 0,762] | |
| p-valued | 0,0002 | |
| Relapse-free survival (by Investigator) | N=110 | N=100 |
| Number of events, n (%) | 49 (44,5) | 66 (66,0) |
| Median RFS in months [95% CI]a | 28,0 [16,3, NE] | 11,4 [10,0, 14,4] |
| Hazard ratio [95% CI]c | 0,526 [0,362,0,764] | |
| p-valued | 0,0006 | |
| Overall survival | N=135 | N=136 |
| Number of deaths, n (%) | 80 (59,3) | 88 (64,7) |
| Median OS in months [95% CI]a | 27,5 [21,4, 45,6] | 21,8 [15,5, 27,4] |
| Hazard ratio [95% CI]c | 0,807 [0,596, 1,093] | |
| p-valued | 0,1646 | |
| Response rate (by Investigator) | N=135 | N=136 |
| Overall response % [95% CI]e | 81,5 [73,89, 87,64] | 73,5 [65,28, 80,72] |
| CR | 70,4 | 69,9 |
| CRp | 11,1 | 3,7 |
| Risk differenceυ [95% CI]f | 7,95 [-3,79, 19,85] | |
| p-valueg | 0,1457 |
Based on the primary definition of EFS: event dates (induction failure, relapse, or death) determined by investigator assessment. T he mIT T population included all patients who were randomised, unless withdrawal of consent prior to start of treatment and were analysed according to initial randomisation arm.
Abbreviations: CR=complete remission; CRp=complete remission with incomplete platelet recovery; CI=confidence interval; EFS=event-free survival; mIT T =modified intent-to-treat; n=number; N=number; NE= not estimable; OS=overall survival; RFS=relapse-free survival.
a Median estimated by Kaplan-Meier method; CI based on the Brookmeyer-Crowley method with log-log transformation.
b Estimated from Kaplan-Meier curve. Probability (%) calculated by the product-limit method; CI calculated from the log- log transformation of survival probability using a normal approximation and the Greenwood formula.
c Based on the Cox proportional hazards model Versus daunorubicin + cytarabine.
d 2-sided p-value from the log-rank test.
e Response defined as CR+CRp.
f Overall response difference; CI based on Santner and Snell method.
g Based on Fisher’s exact test.
Figure 1. Kaplan-Meier plot of event-free survival by investigator assessment from study ALFA-0701 (mITT population):
In subgroup analyses in ALFA-0701, the addition of MYLOTARG to standard combination chemotherapy did not improve EFS in the subgroup of patients having adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63, 1.95). EFS and OS analysed by cytogenetic risk classification and cytogenetic/molecular risk classification are presented in Table 9 and Table 10 below.
Table 9. Event-free survival by investigator assessment by AML risk classifications from study ALFA-0701 (mITT Population):
| MYLOTARG + daunorubicin + cytarabine | daunorubicin + cytarabine | |
|---|---|---|
| Cytogenetics (favourable/intermediate), N | 94 | 95 |
| Number of events, n (%) | 44 (46,8) | 68 (71,6) |
| Median EFS in months [95% CI]a | 22,5 [15,5-NE] | 11,6 [8,3-13,7] |
| Hazard ratio [95% CI]b | 0,460 [0,313-0,676] | |
| p-valuec | <0,0001 | |
| Cytogenetics (unfavourable), N | 27 | 30 |
| Number of events, n (%) | 23 (85,2) | 26 (86,7) |
| Median EFS in months [95% CI]a | 4,5 [1,1-7,4] | 2,8 [1,6-8,7] |
| Hazard ratio [95% CI]b | 1,111 [0,633-1,949] | |
| p-valuec | 0,7151 | |
| ELN (favourable/intermediate), N | 86 | 91 |
| Number of events, n (%) | 40 (46,5) | 63 (69,2) |
| Median EFS in months [95% CI]a | 22,5 [15,5-NE] | 12,2 [8.5-14,3] |
| Hazard ratio [95% CI]b | 0,485 [0,325-0,724] | |
| p-valuec | 0,0003 | |
| ELN (poor/adverse), N | 37 | 36 |
| Number of events, n (%) | 27 (73,0) | 32 (88,9) |
| Median EFS in months [95% CI]a | 7,4 [3,7-14,3] | 4,0 [1,7-8,6] |
| Hazard ratio [95% CI]b | 0,720 [0,430-1,205] | |
| p-valuec | 0,2091 |
The ALFA-0701 trial was not designed to prospectively evaluate the benefit of MYLOT ARG in subgroups; analysis are presented for descriptive purposes only. Based on the primary definition of EFS: event dates (induction failure, relapse, or death) determined by investigator assessment.
The mIT T population included all patients who were randomised, unless withdrawal of consent prior to start of treatment and were analysed according to initial randomisation arm.
Abbreviations: AML =acute myeloid leukaemia; CI=confidence interval; EFS=event-free survival; ELN=European LeukaemiaNet; mIT T =modified intent-to-treat; n=number; N=number; NE=not estimable.
a Median estimated by Kaplan-Meier method; CI based on the Brookmeyer and Crowley Method with log-log transformation.
b Based on the Cox Proportional Hazards Model Versus daunorubicin+cytarabine.
c 2-sided p-value from the log-rank test.
Table 10. Overall survival by AML risk classifications from study ALFA-0701 (mITT Population):
| MYLOTARG + daunorubicin + cytarabine | daunorubicin + cytarabine | |
|---|---|---|
| Cytogenetics (favourable/intermediate), N | 94 | 95 |
| Number of deaths, n (%) | 51 (54,3) | 57 (60,0) |
| Median OS in months [95% CI]a | 38,6 [24,4, NE] | 26,0 [18,9, 39,7] |
| Hazard ratio [95% CI]b | 0,747 [0,511,1,091] | |
| p-valuec | 0,1288 | |
| Cytogenetics (unfavourable), N | 27 | 30 |
| Number of deaths, n (%) | 24 (88,9) | 24 (80,0) |
| Median OS in months [95% CI]a | 12,0 [4,2, 14,2] | 13,5 [9,4, 27,3] |
| Hazard ratio [95% CI]b | 1,553 [0,878, 2,748] | |
| p-valuec | 0,1267 | |
| ELN (favourable/intermediate), N | 86 | 91 |
| Number of deaths, n (%) | 44 (51,2) | 53 (58,2) |
| Median OS in months [95% CI]a | 45,6 [25,5, NE] | 26,9 [19,3,46,5] |
| Hazard ratio [95% CI]b | 0,730 [0,489, 1,089] | |
| p-valuec | 0,1216 | |
| ELN (poor/adverse), N | 37 | 36 |
| Number of deaths, n (%) | 31 (83,8) | 29 (80,6) |
| Median OS in months [95% CI]a | 13,2 [7,0, 18,5] | 13,5 [10,8, 19,8] |
| Hazard ratio [95% CI]b | 1,124 [0,677, 1,867] | |
| p-valuec | 0,6487 |
The ALFA-0701 trial was not designed to prospectively evaluate the benefit of MYLOT ARG in subgroups; analysis are presented for descriptive purposes only.
The mIT T population included all patients who were randomised, unless withdrawal of consent prior to start of treatment and were analysed according to initial randomisation arm.
Abbreviations: AML=acute myeloid leukaemia; CI=confidence interval; ELN=European LeukaemiaNet; mIT T =modified intent-to-treat; n=number; N=number; NE=not estimable; OS=Overall Survival
a Median estimated by Kaplan-Meier method; CI based on the Brookmeyer and Crowley Method with log-log transformation.
b Based on the Cox Proportional Hazards Model Versus daunorubicin + cytarabine.
c 2-sided p-value from the log-rank test.
In a randomised study (COG AAML0531) that evaluated standard chemotherapy alone or combined with MYLOTARG in 1,063 newly diagnosed children with AML (93.7% of patients <18 years of age), and young adults (6.3% of patients); mean age was 8.9 years (range: 0-29 years), patients with de novo AML were randomly assigned to either standard 5-course chemotherapy alone or to the same chemotherapy with 2 doses of MYLOTARG (3 mg/m²/dose) administered once in induction Course 1 and once in intensification Course 2. The study showed that addition of MYLOTARG to intensive chemotherapy improved EFS (3 years: 50.6% versus 44.0%; HR 0.838; 95% CI: 0.706, 0.995; p=0.0431) in de novo AML owing to a reduced relapse risk, with a trend towards longer OS in the MYLOTARG arm which was not statistically significant (3 years: 72.4% versus 67.6%; HR 0.904; 95% CI: 0.721, 1.133; p=0.3799). However, it was also found that increased toxicity (post-remission toxic mortality) was observed in patients with low-risk AML which was attributed to the prolonged neutropenia that occurred after receiving gemtuzumab ozogamicin during intensification Course 2 (see sections 4.2 and 4.8). Overall, 29 (5.5%) of patients in the MYLOTARG arm and 15 (2.8%) patients in the comparator arm died during remission. Thus, the optimal dose of gemtuzumab ozogamicin for paediatric patients was not established (see section 4.2).
A systematic literature review of studies was conducted to evaluate MYLOTARG in paediatric patients with relapsed or refractory AML, which included 454 patients receiving MYLOTARG either as a monotherapy (single or fractionated dosing) or combination therapy from 16 published papers plus the US Expanded Access Study (see section 4.8). The median study size was 15 patients, with a range of 5-105 patients. The overall minimum and maximum ages range from 0 years to 22.3 years, with an overall median age of 8.7 years at the time of treatment.
Most studies were in the compassionate use setting (70.6%). MYLOTARG was given as monotherapy in 47.1%, part of a combination in 23.5%, and in both settings in 29.4% of the studies. Total dosing of MYLOTARG ranged from 1.8 mg/m² to 9 mg/m². When MYLOTARG was given in combination, a cytarabine based regimen was used in 8 of the 9 studies. In 23.5% of the studies the majority of patients received fractionated (3 mg/m² on Day 1, 4, 7) doses of MYLOTARG, while in 35.3% of the studies doses higher than 3 mg/m² were given. MYLOTARG was given as induction treatment in most studies (82.4%).
With MYLOTARG monotherapy, the response rate (CR/CRp/CRi; weighted average across studies) was 33.3% with fractionated dosing (1 study) and 24.3% with non-fractionated dosing (9 studies). In the combination setting, the response rate was 49.0% with non-fractionated MYLOTARG (3 studies) and 38.8% with fractionated MYLOTARG (2 studies).
Safety information on myelosuppression, infections, VOD overall and VOD post-HSCT, and death, which are known adverse events for MYLOTARG (see section 4.8 and Table 7), was obtained from literature.
Limitations of this analysis include the small sample size of some studies, heterogeneity of the studies, and the lack of control data in this setting.
Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of CD33-directed monoclonal antibody (hP67.6) that is covalently linked to the cytotoxic agent N-acetyl-gamma calicheamicin. The pharmacokinetics (PK) of gemtuzumab ozogamicin is described by measuring PK characteristics of the antibody (hP67.6) as well as total and unconjugated calicheamicin derivatives. Given that the hP67.6 portion renders target selectivity on the intact molecule, and that gemtuzumab ozogamicin dosages are reported in terms of milligrams of protein (hP67.6), the hP67.6 concentration results are reported as the primary PK measures. After gemtuzumab ozogamicin binds to the target it is internalised and N-acetyl calicheamicin is released by hydrolytic cleavage. Determination of PK parameters for unconjugated calicheamicin was limited due to the low systemic concentration levels.
No clinical PK data have been collected using the fractionated regimen; however, the PK have been simulated using the population PK model. Although the total dose of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 18 mg/m²), the predicted total AUC of hP67.6 over the course of treatment is 25%, and Cmax is 24%, of the values for original 9 mg/m² dosing regimen, since the PK is nonlinear. When gemtuzumab ozogamicin is administered at 3 mg/m² on Days 1, 4, and 7, the Cmax of hP67.6, which would occur at the end of infusion, is predicted to be 0.38 mg/L following the first dose and increased to 0.63 mg/L after the third dose.
In vitro, the binding N-acetyl gamma calicheamicin dimethyl hydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is a substrate of P-glycoprotein (P-gp). In patients, the total volume of distribution of hP67.6 antibody (sum of V1 [10 L] and V2 [15 L]) was found to be approximately 25 L.
The primary metabolic pathway of gemtuzumab ozogamicin is anticipated to be hydrolytic release of N acetyl gamma calicheamicin dimethyl hydrazide. In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolised, primarily via nonenzymatic reduction of the disulphide moiety. The activity (cytotoxicity) of the resultant metabolites is expected to be significantly attenuated. In patients, unconjugated calicheamicin plasma levels were typically low, with a predicted mean Cmax of 1.5 ng/mL following the third dose.
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolised via nonenzymatic reduction. Therefore, coadministration of gemtuzumab ozogamicin with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolising enzymes are unlikely to alter exposure to N-acetyl gamma calicheamicin dimethyl hydrazide.
Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with hydroxyurea, DNR, and AraC is not predicted to cause clinically meaningful changes in the PK of hP67.6 or unconjugated calicheamicin.
Effect on CYP substrates: In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to inhibit the activities of CYP1A2, CYP2A6 (tested only using gemtuzumab ozogamicin), CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to induce the activities of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.
Effect on UGT substrates: In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations.
Effect on drug transporter substrates: In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance associated protein (MRP) 2, multidrug and toxin extrusion protein (MATE)1 and MATE2K, organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)1 and OCT2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.
Effect on co-administered chemotherapeutic agents: Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with DNR and AraC is not predicted to cause clinically meaningful changes in the PK of these agents.
Based on Population PK analyses, the predicted clearance (CL) value of hP67.6 from plasma was 3 L/h immediately after the first dose and then 0.3 L/h. The terminal plasma half-life (t1⁄2) for hP67.6 was predicted to be approximately 160 hours for a typical patient at the recommended dose level (3 mg/m²) of MYLOTARG.
Based on a population PK analysis, age, race, and gender did not significantly affect gemtuzumab ozogamicin disposition.
No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with hepatic impairment.
Based on a population PK analysis, the clearance of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is not expected to be affected by mild hepatic impairment status, as defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG). The analysis included 405 patients in the following NCI ODWG impairment status categories: mild (B1, n=58 and B2, n=19), moderate (C, n=6), and normal hepatic function (n=322) (see section 4.2).
No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with renal impairment.
Based on a population PK analysis in 406 patients, the clearance of gemtuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr ] 60-89 mL/min; n=149) or moderate renal impairment (CLcr 30-59 mL/min; n=47), was similar to patients with normal renal function (CLcr ≥90 mL/min; n=209). The PK of gemtuzumab ozogamicin has not been studied in patients with severe renal impairment.
The results of the population modelling showed that the PK behaviour of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is similar between adult and paediatric AML patients following the 9 mg/m² dosing regimen.
The main toxicities occurred in the liver, bone marrow and lymphoid organs, haematology parameters (decreased RBC mass and WBC counts, mainly lymphocytes), kidney, eye and male and female reproductive organs. Effects on liver, kidney and male reproductive organs in rats, and on lymphoid tissues in monkeys (approximately 18 times for rats, and 36 times for monkeys, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168) were not reversible. Effects on female reproductive organs and the eye in monkeys were adverse in the 12-week study (approximately 193 and 322 times, respectively, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). The relevance of the irreversible animal findings to humans is uncertain. Nervous system effects have not been observed in animals after administration of MYLOTARG. Nervous system alterations were identified in rats with other antibody-calicheamicin conjugates.
Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics. N-acetyl gamma calicheamicin DMH (the released cytotoxin) was found to be mutagenic and clastogenic.
Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. In toxicity studies, rats developed preneoplastic lesions (minimal to slight oval cell hyperplasia) in the liver approximately 54 times, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). There were no preneoplastic or neoplastic lesions observed in monkeys up to approximately 115 times the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). The relevance of these animal findings to humans is uncertain.
In a female rat fertility study slightly lower numbers of corpora lutea and increased embryolethality were observed in the presence of maternal toxicity (approximately 9.7 times, the human clinical exposure after the third human dose of 3 mg/m² based on AUC168). Effects on the reproductive tract of female monkeys were observed in the 12-week study (atrophy of the ovary, oviduct, uterus, and cervix; approximately 193 times the human clinical exposure after the third dose of 3 mg/m²).
In a male fertility study, effects on male reproduction included lower spermatogonia and spermatocytes, decreases in testicular spermatids and epididymal sperm, vacuolation of the nucleus in spermatids, and/or appearance of giant cells. Additional findings included effects on the testes, epididymides and mammary gland as well as fertility. When male rats were mated again after a 9-week non-dosing period, effects on sperm and fertility were worse but there was partial recovery of the lower spermatogonia and spermatocytes in the testes. Effects on male rat reproductive organs were partially reversible or not reversible (see section 4.6). Male reproductive effects (testes, epididymides, seminal vesicles) in monkeys were observed at approximately 66 times the human clinical exposure after the third dose of 3 mg/m²).
In an embryo-foetal toxicity study lower foetal body weight, higher incidence of foetal wavy ribs, and lower incidence of foetal skeletal ossification were observed. Increased embryolethality and foetal morphological anomalies included digital malformations, absence of the aortic arch, anomalies in the long bones in the forelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae. Increased embryolethality was also observed in the presence of maternal toxicity. The lowest dose with embryo-foetal effects correlated with 9.7 times the human clinical exposure after the third human dose of 3 mg/m², based on AUC168 (see section 4.6).
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