BiTE Antibodies Show Encouraging Activity in Myeloma, AML

Max S. Topp, MD

Data from 2 early-stage trials of bispecific T-cell engager (BiTE) antibody constructs in relapsed/refractory hematologic malignancies demonstrated antitumor activity and early evidence of tolerability, investigators reported at the 2018 ASH Annual Meeting.

The BiTE candidates are AMG 420, which binds to the antigen BCMA that is expressed on multiple myeloma cells, and AMG 330, which binds to CD33 to treat relapsed/refractory acute myeloid leukemia (AML). Both BiTEs also attach to CD3 on T cells.

In a phase I study evaluating AMG 420, 7 of 10 patients with heavily pretreated multiple myeloma who were administered a 400-µg/day dose had responses, including 4 with a complete response (CR).¹ Four patients with CRs and 1 with a partial response (PR) had no minimal residual disease.

Six of the 7 responders at 400 µg/day were still responding at 7.5 months of follow-up. Response duration at the 400 µg/day dose was for up to 7 cycles, with 4 patients still on treatment, reported Max S. Topp, MD, from University Hospital Würzburg, Germany.

While investigators observed responses at lower dose levels, Topp added that the majority of patients developed robust responses starting at 400 µg/day.

He presented data from a first-in-human phase I dose escalation study of AMG 420 for up to 10 cycles, depending on response. Single-patient cohorts were treated with 0.2 to 1.6 µg/day during a run-in phase, followed by cohorts of 3 to 6 patients treated with 3.2 to 800 µg/day. Patients were treated in 6 four-week cycles followed by 2 weeks off. A total of 42 patients were enrolled.

Eleven patients had objective responses at the datacut. Investigators recorded 2 more responses after the cutoff, for an overall objective response rate (ORR) of 31% (13/42). The ORR for patients in the 400-µg/day cohort was 70%.

In addition to the 4 CRs at the 400-µg/day dose, 3 other patients had a CR (1 each at 6.5, 100, and 200 µg/day). There were 4 PRs in the overall cohort at datacut and an additional 2 PRs after the datacut. The median time to any response was 1.4 months and the median time to best response was 2.8 months.

The maximum-tolerated dose was 400 µg/day.

To be eligible, patients had to have progressed after at least 2 prior lines of treatment, which included at least 1 proteasome inhibitor (PI) and at least 1 immunomodulatory agent. They were treated for up to 5 cycles or until disease progression or investigator decision; 5 more cycles could be given for was perceived benefit.

Patients enrolled had multiple myeloma for a median of 5.2 years during which they received a median of 4 prior therapies (range, 2-10). Eleven (26%) had prior daratumumab and 4 (10%) had prior elotuzumab (Empliciti). Thirty-five patients (83%) had prior autologous stem cell transplant. Some 55% were refractory to immunomodulatory therapy, 45% to a PI, and 31% to both. Twenty-one percent were refractory to daratumumab and 10% to elotuzumab.

One (2%) dose-limiting toxicity (DLT), peripheral polyneuropathy, occurred in the 400-µg/d arm, which returned to baseline after IV immunoglobulin and corticosteroid treatment. At the 800-µg/d dose, 2 of 3 patients experienced DLTs; a grade 3 cytokine release syndrome (CRS) and grade 3 peripheral polyneuropathy.

“To our surprise, it took us many, many cohorts…until we hit the ceiling in defining DLTs,” said Topp. “In this study, 800 µg was deemed to be intolerable for the patients.”

Nearly half (48%) of patients experienced serious adverse events (AEs), including 17 who required hospitalization, and 4 had a prolonged hospitalization. Treatment-related serious AEs included 2 cases of grade 3 peripheral polyneuropathy and 1 case of grade 3 edema. Investigators observed CRS in 16 patients, 13 of which were grade 1. There were no grade 3/4 central nervous system toxicities

AMG 330: Anti-CD33 BiTE

Infections were observed in 12 of 42 patients; 3 were grade 2, 7 were grade 3. Pneumonia (7%) and central line infections (7%) were the most common serious infections. One patient developed adenovirus infection and another developed aspergillus/influenza that led to death, neither of which were deemed to be related to the study drug. Two other patients died due to progressive disease. In December 2018, the FDA granted a fast track designation to AMG 420 based on the results from this dose escalation study. The fast track process is designed to facilitate the development and expedite the review of drugs that fill an unmet medical need for treatment of serious conditions.AMG 330 was evaluated in a multicenter phase I dose escalation study of 40 adults with relapsed/refractory AML with >5% blasts in their bone marrow. CD33 is expressed in about 99% of patients with AML, explained lead investigator Farhad Ravandi, MD, from MD Anderson Cancer Center in Houston.

Five of the 40 patients had a response: 2 CRs, 2 CRs with incomplete count recovery (CRi), and 1 morphologic leukemia-free state.² All 5 had their best response within 1 cycle of starting treatment

“The majority of the responses occurred at the higher doses,” said Ravandi. “Two CRs occurred at a target dose of 240 μg/day and 1 CRi and another CRi occurred at target doses of 120 and 240.

“There was a higher likelihood of occurrence of response if patients had a lower peripheral blood CD33-positive AML blasts or even lower CD33-positive and CD33- negative blasts.”

Although the patient population was small and the response rate was low, investigators observed an association between achieving a response and a higher effector-to-target cell ratio, as well as higher number of CD4-positive and CD8-positive T cells at baseline.

“These early data show encouraging evidence of tolerability and anti-leukemic activity of AMG 330 in patients with released refractory AML,” he said. “The study is still ongoing with dose escalation and adjustment of the schedule, and the current cohort has a step-up dose with a target dose of 360 μg/day.”

AMG 330 was administered by continuous IV infusion for 2 to 4 weeks, depending on the cohort, followed by 1 to 4 weeks off therapy. Single cohorts were treated for the first 3 doses followed by cohorts of 3 to 6 patients each, up to a target of 480 μg/day. Duration of therapy was up to 6 cycles if no DLT was encountered in the first cycle.

Pretreatment with a single dose of dexamethasone was instituted as risk mitigation for CRS after dose 5 (30 μg/day). At cohort 11, AMG 330 was given as 10 μg/day for 3 days, 60 μg/day for 4 days, and 240 μg/day for 21 days. At cohort 12, the step ups were to 60 μg/day for 2 days and then 240 μg/day for 23 days.

Mean patient age was 58.5 years. The median number of prior therapies was 4 (range, 1-15) and 43% had prior stem cell transplant.

Thirty-five patients discontinued treatment, 27 (68%) due to disease progression. Three (8%) patients completed at least 5 cycles of therapy. Two (5%) AEs leading to discontinuation were directly attributed to AMG 330, said Ravandi.

The DLT was considered to be 480 μg/day, occurring in 2 of 6 patients. CRS occurred in 11 (28%), patients, 2 were grade 3 and 2 were grade 4. There were 2 DLTs, persistent grade 2 CRS and grade 4 ventricular fibrillation, at the target dose of 480 μg/day. Treatment-related neurologic AEs were observed in 19 patients including 1 patient with grade 2 seizure, 2 patients with grade 2 somnolence, and 1 with grade 1 speech disturbance.

References

1. Ravandi F, Stein AS, Kantarjian HM, et al. A Phase 1 first-in-human study of AMG 330, an anti-CD33 bispecific T-cell engager (BiTE®) antibody construct, in relapsed/refractory acute myeloid leukemia (R/R AML). Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 25.
2. Topp MS, Duell J, Zugmaier G, et al. Treatment with AMG 420, an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE®) antibody construct, induces minimal residual disease (MRD) negative complete responses in relapsed and/or refractory (R/R) multiple myeloma (MM) patients: results of a first-in-human (FIH) phase 1 dose escalation study. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 1010.