Phase IV trial of a fractionated dosing schedule of gemtuzumab ozogamicin

Gemtuzumab ozogamicin (GO), a CD33-directed antibody–drug conjugate that has been extensively covered on the AML Hub, is approved by the U.S Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed and relapsed/refractory (R/R) CD33-positive acute myeloid leukemia (AML).¹ GO is also approved by the European Commission as a combination therapy with daunorubicin and cytarabine for the treatment of patients aged ≥15 years with de novo CD33-positive AML.¹

While GO has been shown to be beneficial in patients with CD33-positive AML, it has also been associated with high rates of hematologic and liver toxicities.¹ Further studies, including the ALFA‑0701 study (NCT00927498), have shown that a fractionated dosing schedule may improve the safety profile of GO without reducing its efficacy.¹

Here, we summarize key findings from a phase IV clinical trial published by Montesinos et al.¹ in Cancer Chemotherapy and Pharmacology evaluating the effect of a fractionated dosing schedule of GO on the QT interval corrected for heart rate (QTc), safety, pharmacokinetics, and immunogenicity.

Study design and patient characteristics

• Single-arm, phase IV study (NCT03727750).
• 51 patients with R/R CD33-positive AML (Table 1).
• Key eligibility criteria:
  • Initial peripheral white blood cell count <30 × 10⁹/L
  • Eastern Cooperative Oncology Group performance status ≤2
  • Adequate renal and hepatic functions
• Key exclusion criteria:
  • Allogeneic hematopoietic stem cell transplantation (allo-HSCT) ≤2 months before enrollment
  • Receiving medications known to prolong the QT interval during the study
• Fractionated dosing regimen of GO 3 mg/m² on Days 1, 4, and 7 of Cycle 1
• Of 51 patients:
  • 98.0% received ≥1 dose of GO during Cycle 1
  • 92.0% received all doses in Cycle 1
  • 17.6% received further doses in Cycle 2
  • Following treatment, 35.3% of patients received ≥1 further systemic treatment and 3.9% received allo-HSCT
• Follow-up was until 12 months on the study or death.

Table 1. Baseline characteristics*

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European LeukemiaNET; WBC, white blood cell. *Adapted from Montesinos, et al.1 †N = 49.
Characteristic, % (unless otherwise stated)	All patients (N = 51)
Median age (range), years	67 (22–82)
Sex
Male	60.8
Female	39.2
ECOG PS
0	30.0
1	54.0
2	16.0
ELN risk
Favorable	15.7
Intermediate	43.1
Adverse	37.3
Median WBC count (range), × 109/L†	3.2 (0.3–25.8)
Prior induction regimens
1	52.9
2	21.6
3	15.7
>3	7.8
Time since the start of last induction
<3 months	19.6
3 to <6 months	17.6
6 to <12 months	19.6
≥12 months	41.2
Prior allo-HSCT	9.8

The primary endpoint was the mean change from baseline QTc. Secondary endpoints were pharmacokinetics, adverse events (AEs), incidences of antidrug antibodies (ADAs)/neutralizing antibodies (NAbs), overall survival, and response rate. Incidences of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) were recorded as serious AEs regardless of severity. While patients aged 12–17 years were included in the study, this analysis includes only adult patients with 12 months of follow-up.

Key findings

QT interval

• For all time points in Cycle 1, the upper limit of the two-sided 90% confidence interval (CI) for least squares mean differences in QTc using Fridericia’s formula (QTcF) was <10 ms.
• The greatest mean QTcF shift from baseline was 5.10 ms (90% CI, 2.2–8.1 ms).
• 89.8% of patients had a QTcF ≤450 ms.
• 93.9% of patients had a maximum increase from baseline of ≤30 ms.
• No patient had a postbaseline QTcF >480 ms or a baseline change of >60 ms.

Safety

• All causality treatment-emergent AEs (TEAEs) occurred in 98.0% of patients, with serious TEAEs recorded in 68.0% of patients (Table 2).
• 6.0% of patients temporarily discontinued and 4.0% of patients permanently discontinued GO due to TEAEs.
• VOD/SOS did not occur; however, treatment-related Grade 5 capillary leak syndrome was reported in 2.0% of patients.

Table 2. TEAEs reported in ≥10% of patients who received a fractionated dosing schedule of GO*

GO, gemtuzumab ozogamicin; TEAE, treatment-emergent adverse event. *Adapted from Montesinos, et al.1
TEAE, %	Patients who received a fractionated dosing schedule of GO (n = 50)
	All-causality		Treatment-related
	All grades	Grade 3–4	All grades	Grade 3–4
Any TEAE	98.0	54.0	50.0	30.0
Febrile neutropenia	40.0	36.0	12.0	12.0
Thrombocytopenia	22.0	18.0	14.0	10.0
Hypokalemia	18.0	2.0	4.0	0.0
Pyrexia	18.0	2.0	0.0	0.0
Nausea	16.0	0.0	6.0	0.0
Sepsis	14.0	6.0	0.0	0.0
Anemia	12.0	10.0	6.0	4.0
Vomiting	12.0	0.0	2.0	0.0
Neutropenia	10.0	10.0	10.0	10.0
Aspartate aminotransferase increased	10.0	2.0	10.0	2.0
Constipation	10.0	0.0	0.0	0.0
Diarrhea	10.0	0.0	2.0	0.0
Disease progression	10.0	0.0	0.0	0.0
Epistaxis	10.0	0.0	2.0	0.0
Headache	10.0	0.0	0.0	0.0
Hypomagnesemia	10.0	0.0	4.0	0.0

Pharmacokinetics

• Exposure measured by geometric mean area under the plasma concentration-time profile (AUC) from time zero to 336 h post-dose and maximum plasma concentration (C_max) were:
  • 461,500 pg h/mL and 11,740 pg/mL for conjugated calicheamicin
  • 1,639 pg h/mL and 58.8 pg/mL for unconjugated calicheamicin
  • 26,820 ng h/mL and 585.6 ng/mL for hP67.6 antibody

Immunogenicity

• At baseline, 24.0% of patients had positive ADAs against GO.
• Treatment-induced ADA was reported in 12.0% of patients, with infusion-related pyrexia observed in 33.3% of these patients.
• Infusion-related reactions were observed in 15.9% of patients who were negative for treatment-induced ADAs.
• No patients who were positive for ADAs against GO were positive for NAbs at baseline.
• 2.0% of patients had treatment-induced NAbs.

Efficacy

• The overall response rate was 9.8%.
• 3.9% of patients achieved complete remission, with 5.9% of patients achieving complete remission with incomplete count recovery.
• The median overall survival was 2.8 months (95% CI, 1.7–4.2 months).
• 88.2% of patients died, with disease progression reported as the most common cause of death (77.8% of patients).

Conclusion

In this study, a fractionated dosing schedule of GO had a negligible effect on QT interval prolongation in patients with R/R AML. The safety profile of the fractionated dosing schedule was aligned with the known safety profile of GO. While VOD/SOS was not observed, one patient experienced capillary leak syndrome. The likelihood of post-allo-HSCT VOD/SOS is difficult to estimate, as the number of patients who went on to receive allo-HSCT was low. The presence of ADAs were not linked to any safety concerns.