P-225: A first-in-human study of FOR46 in patients with triple refractory Multiple Myeloma

Background Cluster of differentiation 46 (CD46) is highly expressed in multiple myeloma, especially in patients (pts) with gain of chromosome 1q and in the refractory setting. In vitro studies show upregulation and enhanced cytotoxicity upon treatment with pomalidomide, dexamethasone or lenalidomide. FOR46, an anti-CD46 antibody-drug conjugate with vc-MMAE, recognizes a tumor selective epitope of CD46 and is taken up by malignant cells by macropinocytosis, which is a relatively tumor selective uptake mechanism. Methods Pts with MM were enrolled who had progressed on proteasome inhibitors, immunomodulatory drugs and CD38-targeted therapies. An accelerated titration followed by 3+3 dose escalation design was used. FOR46, at protocol specified doses, was infused intravenously over 30-60 minutes on Day 1 of 21-day cycles. Following excess toxicity (neutropenia and fatigue) in a patient (pt) with high body mass index (BMI), dosing was changed from actual weight (AW) to adjusted body weight (ABW). G-CSF secondary prophylaxis was required for pts experiencing grade (gr) ≥ 3 neutropenia during a previous treatment cycle. The initial protocol had 2.4 mg/kg AW as the highest dose. When the MTD was not defined using ABW dosing, escalation was held pending protocol amendment to allow a higher dose and expansion to 10 patients at 2.4 mg/kg ABW began. Safety was evaluated using CTCAE v5.0 and efficacy was evaluated per IMWG criteria. Dexamethasone was only allowed for infusion reaction prophylaxis. CD46 antigen density was determined on patient MM cells via flow cytometry. Results Fifteen pts were enrolled at 6 pre-defined dose levels from 0.1 to 2.4 mg/kg with 1 patient each at the 0.1, 0.3 and 0.6 mg/kg dose levels, 3 at 1.2 and 1.8 mg/kg and 6 at 2.4 mg/kg. Median age was 68 (range 33 – 79) with 4 females. Gain 1q was present in 9 pts, absent in 5 pts and unknown in 1. The median number of prior lines of therapy was 6 (range 3-17). The only dose-limiting toxicity (DLT) was gr 4 neutropenia in 1 high BMI patient dosed by AW. This was the only DLT among 6 pts at 2.4 mg/kg dosed by a mix of AW (n=3) and ABW (n=3). One of 3 at 2.4 mg/kg ABW had non-dose limiting gr 4 neutropenia. The most common related adverse event was gr 4 neutropenia in 3 pts (20%). One patient (6.7%) had gr 4 thrombocytopenia and 1 each (6.7%) had gr 3 AST elevation, neutropenia, anemia, nausea, and peripheral neuropathy (PN). Of the 6 response-evaluable pts in the 1.8 and 2.4 mg/kg cohorts, 3 had partial responses (PRs) lasting 21, 30, and 15 weeks, respectively. Of the PRs, 1 pt did not have gain of 1q21. In addition to the fifteen pts in dose escalation cohorts, 10 have been enrolled in an expansion cohort at 2.4 mg/kg by ABW. Conclusion FOR46 demonstrates an acceptable toxicity profile using ABW dosing. There is encouraging evidence of efficacy in triple refractory MM. A protocol amendment allowing additional dose escalation to 2.7 mg/kg by ABW has been approved. NCT03650491 Cluster of differentiation 46 (CD46) is highly expressed in multiple myeloma, especially in patients (pts) with gain of chromosome 1q and in the refractory setting. In vitro studies show upregulation and enhanced cytotoxicity upon treatment with pomalidomide, dexamethasone or lenalidomide. FOR46, an anti-CD46 antibody-drug conjugate with vc-MMAE, recognizes a tumor selective epitope of CD46 and is taken up by malignant cells by macropinocytosis, which is a relatively tumor selective uptake mechanism. Pts with MM were enrolled who had progressed on proteasome inhibitors, immunomodulatory drugs and CD38-targeted therapies. An accelerated titration followed by 3+3 dose escalation design was used. FOR46, at protocol specified doses, was infused intravenously over 30-60 minutes on Day 1 of 21-day cycles. Following excess toxicity (neutropenia and fatigue) in a patient (pt) with high body mass index (BMI), dosing was changed from actual weight (AW) to adjusted body weight (ABW). G-CSF secondary prophylaxis was required for pts experiencing grade (gr) ≥ 3 neutropenia during a previous treatment cycle. The initial protocol had 2.4 mg/kg AW as the highest dose. When the MTD was not defined using ABW dosing, escalation was held pending protocol amendment to allow a higher dose and expansion to 10 patients at 2.4 mg/kg ABW began. Safety was evaluated using CTCAE v5.0 and efficacy was evaluated per IMWG criteria. Dexamethasone was only allowed for infusion reaction prophylaxis. CD46 antigen density was determined on patient MM cells via flow cytometry. Fifteen pts were enrolled at 6 pre-defined dose levels from 0.1 to 2.4 mg/kg with 1 patient each at the 0.1, 0.3 and 0.6 mg/kg dose levels, 3 at 1.2 and 1.8 mg/kg and 6 at 2.4 mg/kg. Median age was 68 (range 33 – 79) with 4 females. Gain 1q was present in 9 pts, absent in 5 pts and unknown in 1. The median number of prior lines of therapy was 6 (range 3-17). The only dose-limiting toxicity (DLT) was gr 4 neutropenia in 1 high BMI patient dosed by AW. This was the only DLT among 6 pts at 2.4 mg/kg dosed by a mix of AW (n=3) and ABW (n=3). One of 3 at 2.4 mg/kg ABW had non-dose limiting gr 4 neutropenia. The most common related adverse event was gr 4 neutropenia in 3 pts (20%). One patient (6.7%) had gr 4 thrombocytopenia and 1 each (6.7%) had gr 3 AST elevation, neutropenia, anemia, nausea, and peripheral neuropathy (PN). Of the 6 response-evaluable pts in the 1.8 and 2.4 mg/kg cohorts, 3 had partial responses (PRs) lasting 21, 30, and 15 weeks, respectively. Of the PRs, 1 pt did not have gain of 1q21. In addition to the fifteen pts in dose escalation cohorts, 10 have been enrolled in an expansion cohort at 2.4 mg/kg by ABW. FOR46 demonstrates an acceptable toxicity profile using ABW dosing. There is encouraging evidence of efficacy in triple refractory MM. A protocol amendment allowing additional dose escalation to 2.7 mg/kg by ABW has been approved. NCT03650491