A Phase I Pharmacokinetic (PK) and Safety Study of Trph-222 in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL): Dose-Escalation Results

Background: TRPH-222 is an antibody-drug conjugate (ADC) comprised of a humanized anti-CD22 monoclonal antibody and maytansine, a potent anti-mitotic agent, joined by a novel linker-conjugation technology (SMARTag™). This approach enables site-specific conjugation of the maytansine payload while tightly controlling drug:antibody ratio (DAR), resulting in a highly stable anti-CD22 ADC resistant to MDR1-mediated efflux and does not mediate bystander killing. The primary objectives of study TRPH-222-100 are to determine the safety, tolerability, and pharmacokinetics (PK) of TRPH-222 monotherapy in patients with R/R NHL.

Methods: TRPH-222-100 is an open-label, multicenter dose-escalation study comprised of a dose-escalation stage followed by a dose-expansion stage. TRPH-222 was administered IV once every 3 wks to the treatment population which included patients with DLBCL, FL, MCL, and MZL in dose-escalation. Single patient cohorts received doses of TRPH-222 starting at 0.6 mg/kg until a dose-limiting toxicity (DLT) or grade >2 non-hematologic adverse event (AE) occurred, at which time the protocol converted to a 3+3 design. Data are reported here for the completed dose-escalation stage.

Results: As of 30Jun2020: 22 patients were enrolled (1 patient each at 0.6, 1.2, 2.0, and 3.0 mg/kg; 7 patients at 4.2 mg/kg, 4 patients each at 5.6 and 7.5 mg/kg, 3 patients at 10 mg/kg); 11 indolent (10 FL, 1 MZL) and 11 aggressive histology patients (8 DLBCL, 2 transformed FL, 1 MCL); median age 68 yrs, median number prior therapies 4 (range 1-8) including 5 patients receiving prior hematopoietic stem cell transplant and 4 receiving prior CAR-T treatment. Two DLTs (Grade 3 and 4 transaminase elevations; one each at 4.2 and 10 mg/kg) have occurred. Other treatment-related grade ≥ 3 AEs include (see table below):

No treatment-related Grade 5 toxicities or serious AEs have occurred. Two instances of peripheral neuropathy have been reported; one Grade 2 event increased from baseline Grade 1 (end of Cycle 4), and one Grade 1 event (Cycle 1) in a patient with a history of neuropathic pain. Ten patients (2.0 to 10 mg/kg) have experienced Grade 1 or 2 ocular events, most frequently presenting in Cycles 1-3 as blurred vision and/or dry eyes, which have resolved to ≤ Grade 1 with dose interruptions and reductions, and lubricant eye drops. The PK profile of TRPH-222 showed a long serum half-life (~5-10 days after first dose), with no unconjugated maytansine detected in samples assessed to date (up to 7.5 mg/kg, assay detection limit 100 pg/mL). No anti-drug antibodies have been detected in samples analyzed to date. Peripheral B-cells were reduced 50-75% after TRPH-222 administration at all dose levels, and 100% CD22 receptor occupancy (assessed in peripheral blood mononuclear cells) was observed at all dose levels. Eleven of the 22 patients remain on study; study discontinuations have been due to progressive disease (n=7; 3 DLBCL, 2 TFL, 2 FL), DLT (n=2; 1 FL, 1 DLBCL), and investigator decision (n=2; 1 DLBCL, 1 FL). Five complete responses (CR: 3 FL, 1 DLBCL, 1 MCL) and one partial response (PR: FL) have been observed at doses from 0.6 to 5.6 mg/kg at the end of cycle 6. Four patients with CRs confirmed at the end of cycle 9 are now off treatment and continuing to be followed for safety and response durability. Remaining patients on study at the data cutoff were in Stable Disease or not yet evaluated for response; data will be updated at the time of presentation.

Conclusions: TRPH-222 monotherapy is well tolerated through dose-escalation to 10 mg/kg, with a low incidence of AEs commonly associated with ADCs such as thrombocytopenia, neutropenia, and peripheral neuropathy. The most common AEs included low grade and manageable ocular findings consistent with known epithelial keratopathy of ADCs bearing microtubule inhibitors. These data, together with 100% CD22 receptor occupancy observed at all dose levels, and CRs/PRs observed at doses levels less than 10 mg/kg, support further assessment of TRPH-222 monotherapy in an expansion cohort currently enrolling R/R FL and DLBCL patients. These results support further clinical studies of TRPH-222, including combinations with other antitumor agents in B-cell lymphoma patients.