C4 Therapeutics, Inc. presented clinical data from the ongoing Phase 1 dose escalation portion of its Phase 1/2 clinical trial of CFT7455, a MonoDAC?? degrader of IKZF1/3, for the potential treatment of multiple myeloma (MM) and non-Hodgkin's lymphomas (NHL). These data include results from CFT7455 as a monotherapy for relapsed/refractory (R/R) MM patients, which has completed dose escalation, and interim results from CFT7455 in combination with dexamethasone for R/R MM patients, which continues to enroll patients.

C4T also continues to enroll patients in the Phase 1 dose escalation trial exploring CFT7455 as a monotherapy for NHL patients. The goal of the CFT7455 Phase 1 dose escalation trial is to define the safety profile of CFT7455, determine the maximum tolerated or administered dose, and identify signs of anti-tumor activity in R/R MM and R/R NHL. The Phase 1 dose escalation portion of the trial includes three arms: CFT7455 as a monotherapy for R/R MM patients, which is complete; CFT7455 in combination with dexamethasone for R/R MM patients, which continues to advance through dose escalation; and CFT7455 as a monotherapy for NHL patients, which also continues to advance through dose escalation.

The Phase 1 dose escalation portion of the ongoing Phase 1/2 trial has utilized a 14 days on/14 days off dosing schedule within which both daily dosing and Monday/Wednesday/Friday (MWF) dosing were explored. Monotherapy dose escalation is complete. As of the November 28, 2023 data cutoff date, 22 patients had received CFT7455 as a monotherapy.

The maximum dose administered was 75 µg daily for 14 days on/14 days off. A maximum tolerated dose was not defined. Patients were heavily pretreated, with a median of seven prior therapies.

The majority of patients (n=12) received prior CAR-T or T-cell engager therapy. Clearance of CFT7455 is consistent with a 48-hour half-life. Daily dosing (14 days on/14 days off) resulted in deep IKZF1/3 degradation.

After day 14, as plasma concentrations of CFT7455 begin to decline, degraded proteins recover through day 28, enabling neutrophil recovery. CFT7455 was well tolerated. 22 patients were evaluable for safety.

The most common adverse events (AEs) Grade 3 or above were neutropenia (n=11), anemia (n=4) and leukopenia (n=4). No dose-limiting toxicities (DLTs) resulted in discontinuation of therapy. As of the November 28, 2023 data cutoff date, 20 patients were evaluable for evidence of anti-tumor effect.

Four patients received the maximum dose administered of 75 µg daily. Three patients were refractory to BCMA therapies. Responses were measured in accordance with the International Myeloma Working Group (IMWG) criteria for multiple myeloma.

All four patients achieved Stable Disease (SD) or better and one patient achieved a Partial Response (PR). CFT7455 induced CD8+ T-cell activation by increasing the effector memory T-cell subset, as required for effective adaptive immunity. T-cell activation was observed at well tolerated monotherapy doses, supporting the potential use of CFT7455 in combination with bi-specific T-cell engagers and monoclonal antibody therapies.

As of the November 28, 2023 data cutoff date, nine patients had received CFT7455 in combination with dexamethasone across two initial dose escalation cohorts (50 µg MWF for 14 days on/14 days off; or 37.5 µg daily for 14 days on/14 days off). Patients were heavily pretreated, with a median of six prior therapies. The majority of patients (n=5) received prior CAR-T or T-cell engager therapy.

This arm is ongoing; patients are currently enrolling in either the 62.5 µg escalation cohort or the 37.5 µg expansion cohort. CFT7455 in combination with dexamethasone is well tolerated to date. The most common AEs Grade 3 or above were consistent with the monotherapy safety signal.

No AEs have led to dose reductions, discontinuations or DLTs. All three patients evaluable for efficacy at 37.5 µg daily achieved SD or better according to IMWG criteria. These assessments include: One patient achieved a Stringent Complete Response (sCR), after initially achieving a Very Good Partial Response (VGPR).

This patient was refractory to BCMA therapies. One patient achieved a PR. This patient was refractory to BCMA therapies.

One patient achieved SD. C4T expects to present the following data on CFT7455 in 2024: Complete Phase 1 dose escalation data from the ongoing Phase 1/2 clinical trial in R/R MM. Complete Phase 1 dose escalation data from the ongoing Phase 1/2 clinical trial in NHL.