Early Data Show CC-93269 has Activity in Multiple Myeloma

Interim results from a phase 1 trial show CC-93269 has activity in highly refractory, heavily pretreated patients with multiple myeloma, with an acceptable safety profile, according to a presentation at the virtual 25th Congress of the European Hematology Association.

Among patients receiving a 10-mg dose of CC-93269 (n = 9), the overall response rate (ORR) was 88.9% with a with stringent CR (sCR)/complete response (CR of 44.4%. In the total patient population (n = 30), ORR was 43.3% with a sCR/CR of 16.7%.

The median time to response was 4.1 weeks (range, 4.0-13.1), and 11 responses were ongoing with duration of response ranging from 5.3 to 40.6 weeks. Five of 30 patients (16.7%) achieved MRD-negative sCR/CR. The maximum tolerated dose, non-tolerated dose, and/or recommended phase 2 dose (RP2D) have not yet been reached.

“The safety profile of CC-93269 supports further development, and enrollment is ongoing to define recommended the phase 2 dose,” said investigator Luciano Costa, MD, PhD, with the division of Hematology and Oncology at the University of Alabama at Birmingham.

Investigators conducted this phase 1 dose-finding study (NCT03486067) to assess the safety and tolerability of CC-93269 in patients with relapsed/refractory multiple myeloma.

CC-93269 is a humanized 2+1 IgG1-based TCE that binds to B-cell maturation antigen (BCMA) on myeloma cells and to CD3ε on T cells, enabling specific BCMA binding. CC-93269 induces tumor regression in animal models of myeloma and promotes myeloma cell death in primary patient bone marrow aspirates.

Costa presented findings from Part A of the trial, which included dose escalation in two stages: fixed doses and step up in dose on cycle 1 on day 8. Primary endpoint was safety, including adverse events, maximum tolerated dose, and non-tolerated dose. Secondary endpoint was preliminary efficacy including pharmacokinetics and pharmacodynamics. It is administered by intravenous (IV) infusion or subcutaneous (SC) injection on a 28-day cycle.

Median age was 64 years (range 42-78), with a median of 5.9 years (range 1.4-16.6) since initial diagnosis. Median number of prior regimens was 5 (range 3-13) and included treatment with autologous stem cell transplantation (SCT; 77%), allogeneic SCT (10%), lenalidomide (100%), pomalidomide (87%), bortezomib (100%), carfilzomib (77%), and daratumumab (93%).

CC-93269 doses ranged from 0.15 to 10 mg; median duration of treatment was 14.0 weeks (range 1.6–46.0) with patients receiving a median of 3.5 cycles (range 1-12). Patients received cycles 1-3 on days 1, 8, 15, and 22. Cycles 4-6 were dosed on days 1 and 15. Cycles 7 onward were dosed on day 1.

With regard to pharmacodynamics, CC-93269 induces rapid redistribution of peripheral blood immune cells and rapid transient and cytokine release and blunted with the second infusion. With regard to pharmacokinetics, exposure increased in a dose related manner. Continuous exposure over the weekly dosing interval was measurable at doses at 3 mg and higher. “We did not receive responses in 3 mg or less,” Costa said.

Nearly all patients had a treatment-emergent adverse event, Costa said. “There were 4 deaths within 35 days of the last dose of the agent. One was due to cytokine release syndrome (CRS), and therefore, related to CC-93269. Others were not suspected to be related to the treatment.”

Cytokine release syndrome (CRS) was reported in 23 (76.7%) patients, but 73.3% of cases were grade 1/2 and occurred most frequently with the first or second dose (81%).

CRS prophylaxis was implemented with dexamethasone for first dose and dose increases in patients receiving ≥6 mg. 22 (73%) pts received dexamethasone and 13 (43%) patients received tocilizumab for the management of CRS.

Other grade 3 or higher treatment-emergent adverse events were reported in 22 (73.3%) patients; those occurring in 2 or more patients included neutropenia (43.3%), anemia (36.7%), infections (30.0%), thrombocytopenia (16.7%), general physical health deterioration (10%), and pyrexia (7%).

Reference

Costa L, Wong SW, Bermúdez A, et al. First clinical study of the B-cell antigen 2+1 T cell engager CC-93269 in patients with relapsed/refractory multiple myeloma: interim results of a phase I multicenter trial. Presented at: the 2020 European Hematology Congress: Virtual. June 11-21, 2020. Abstract #S205.