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Phase 1 study of IMGN853, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) in patients (Pts) with epithelial ovarian cancer (EOC) and other FRA-positive solid tumors.
Background: IMGN853 (mirvetuximab soravtansine) is a FRα-targeting ADC comprising a FRα-binding antibody and potent maytansinoid, DM4. Methods: This Phase 1 trial is being conducted to determine safety, pharmacokinetics (PK), pharmacodynamics, maximum tolerated dose, recommended phase 2 dose (RP2D) and evidence of activity of IMGN853 in pts with EOC or other FRa-positive solid tumors. As previously reported, the occurrence of ocular adverse events (AEs) was associated with peak drug exposure and pt weight. Dosing by adjusted ideal body weight (AIBW) instead of total body weight (TBW) was implemented to decrease PK variability. Two dosing schedules are being evaluated; (A) once every 3 weeks and (B) Days 1, 8, and 15, every 4 weeks. Results: Fifty nine pts enrolled to dose escalation to date, 44 (30 TBW; 14 AIBW) pts in A, 16 (AIBW) in B. RP2D for A was determined to be 6.0 mg/kg, while dose finding in B continues. Exposure to IMGN853 increased with an increase in dose in a more than dose-proportional manner indicating non-linear PK. AIBW dosing enabled better control of drug exposure, with more pts treated within a clinically relevant therapeutic window. The majority of AEs have been CTCAE grade 1 or 2, generally similar across both schedules: included GI events, ocular events, cough, fatigue, and neuropathy in > = 20% of patients. Nausea, vomiting and headache may be more common on schedule B. Diarrhea may be more common on schedule A. Preliminary evidence of clinical benefit (CB) (partial PR or complete CR response, CA125 response, SD ≥ 6 cycles) has been observed with both schedules during escalation. In A, CB was observed in 11/44 pts: 4 PRs; 2 confirmed CA125 responses; 5 SD, 2 for 10 cycles. In B, 5/15 evaluable pts had CB: 1 PR; 4 SD, 3 with confirmed CA125 response; six pts remain on study. Benefit was seen in epithelial and transitional cell ovarian cancer, endometrial cancer and NSCLC. Conclusions: With both schedules,IMGN853 demonstrates encouraging clinical activity in heavily pretreated patients during dose escalation with a manageable AE profile. A RP2D has been identified for schedule A, while schedule B continues dose finding. Clinical trial information: NCT01609556
Abstracts by Hossein Borghaei:
A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian population who had progressed on crizotinib (NP28761).Meeting: 2015 ASCO Annual Meeting | Abstract No: 8019
First-in-human, dose-escalation, safety, and PK study of a novel 5T4-ADC in patients with advanced solid tumors.Meeting: 2015 ASCO Annual Meeting | Abstract No: TPS2603
First-line monotherapy with nivolumab (NIVO; anti-programmed death-1 [PD-1]) in advanced non-small cell lung cancer (NSCLC): Safety, efficacy and correlation of outcomes with PD-1 ligand (PD-L1) expression.Meeting: 2015 ASCO Annual Meeting | Abstract No: 8025