The Food and Drug Administration (FDA) granted inotuzumab ozogamicin, an anti-CD11 antibody-drug conjugate, a priority review designation for the treatment of patients with relapsed or refractory acute lymphoblastic leukemia (ALL), based on recent findings from the phase 3 INO-VATE trial.
Under the priority review program, the FDA will decide on the biologics license application for inotuzumab ozogamicin within six months compared with the standard 10-month review. The accelerated review timeline follows a breakthrough therapy designation for ALL received by inotuzumab ozogamicin in October 2015. Under the Prescription Drug User Fee Act (PDUFA), the FDA will make its decision on the application in August 2017.
“ALL that has recurred after, or is refractory to, first-line therapy is a rapidly progressing and deadly disease,” Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development, the developer of the drug, said in a statement. “Based on the positive results of the INO-VATE 1022 phase 3 trial, we believe inotuzumab ozogamicin, if approved, represents a new treatment option for adult patients with relapsed or refractory B-cell precursor ALL.”
Inotuzumab ozogamicin is composed of a humanized IgG4 anti-CD22 antibody covalently linked to N-acetyl-gamma-calicheamicin dimethyl hydrazide (CalichDMH). Upon binding to B cell-specific CD22 receptors, the drug is internalized causing the release of CalichDMH within the cell. The cytotoxic agent CalichDMH causes double-strand DNA breaks and apoptosis.
A prior antibody-drug conjugate from Pfizer that included ozogamicin — Mylotarg (gemtuzumab ozogamicin) — was approved for acute myeloid leukemia and was subsequently withdrawn from the US market after the agent failed to show clinical benefit in confirmatory clinical trials. This agent was initially approved under the FDA's accelerated review program based on a surrogate endpoint. It was withdrawn in 2010. Pfizer is hopeful that a similar fate does not await inotuzumab ozogamicin.
In the open-label phase 3 trial that was instrumental in the priority review, the risk of progression or death was reduced by 55 percent with inotuzumab ozogamicin versus standard therapy. Overall survival was improved with inotuzumab ozogamicin versus chemotherapy; however, this improvement was not statistically significant.
In the phase 3 study, 326 patients were enrolled, with the first 218 selected for the primary analysis. One hundred and nine patients received inotuzumab ozogamicin at a starting dose of 1.8 mg/m2
each cycle, which consisted of a 0.8 mg/m2
dose on day one followed by 0.5 mg/m2
on day eight and day 15. In the chemotherapy arm, 109 patients received physicians’ choice of fludarabine plus cytarabine with G-CSF, high-dose cytarabine, or cytarabine plus mitoxantrone.
Most of the patients in the investigational arm were under the age of 55 years (61 percent). The clinical trial represented the first salvage therapy for 67 percent of patients in the inotuzumab ozogamicin arm versus 63 percent in the comparator. All patients enrolled in the phase 3 study were CD22-positive, which is expressed in most patients with B-cell ALL.
Inotuzumab ozogamicin demonstrated a complete response (CR) or CR with incomplete platelet recovery (CRi) rate of 80.7 percent versus 29.4 percent with chemotherapy. In those who achieved a CR/CRi, 78.4 percent were minimal residual disease (MRD)-negative with inotuzumab ozogamicin versus 28.1 percent for chemotherapy.
For patients who were receiving their first salvage therapy, the CR/CRi rate was 87.7 percent with inotuzumab ozogamicin versus 28.8 percent with chemotherapy. In the second salvage therapy setting, the CR/CRi rate with inotuzumab ozogamicin was 66.7 percent versus 30.6 percent with chemotherapy.
Adverse events (AEs) were assessed in 259 patients from the full study population. This analysis consisted of those who received ≥1 dose of inotuzumab ozogamicin (139 patients) or chemotherapy (120 patients). The median duration of treatment in the inotuzumab ozogamicin arm was 8.3 weeks versus 0.9 weeks with chemotherapy.
Eighty-three percent of patients in the inotuzumab ozogamicin arm discontinued treatment over the course of the study versus 89 percent in the chemotherapy arm. The most common cause of discontinuation in the inotuzumab ozogamicin arm was CR (35 percent) compared with resistant disease in the chemotherapy arm (40 percent). The number of patients receiving SCT was doubled in the inotuzumab ozogamicin arm (48 patients) compared with chemotherapy (20 patients).
The most frequently observed grade 3 or higher AEs in both arms were hematologic cytopenias. Grade 3 or higher hepatobiliary AEs were seen in 9 percent of patients treated with inotuzumab ozogamicin versus 3 percent with chemotherapy. All grade veno-occlusive liver disease (VOD) occurred in 15 patients (13 were grade 3 or higher) in the inotuzumab ozogamicin arm versus one in the chemotherapy arm. Most VOD cases were seen after SCT (10 patients). In total, there were two deaths associated with VOD in the inotuzumab ozogamicin arm.
Clinical trials continue to assess inotuzumab ozogamicin as a treatment for patients with hematologic malignancies. A phase 1/2 study is looking at the drug as a treatment for elderly patients with ALL (NCT01371630
). Additionally, another phase 1/2 study is exploring the agent in patients with CD22-positive lymphoid malignancies (NCT01664910