A Phase 1b Study of Subcutaneous Daratumumab Regimens in Combination with Bispecific T Cell Redirection Antibodies for the Treatment of Subjects with Multiple Myeloma

Multiple myeloma is a malignant plasma cell dis order characterized by
osteolytic lesions, increased susceptibility to infections, and
renal failure, and is the third most common hematological malignancy. Treatment
options for multiple myeloma have substantially improved over time and vary
depending on the aggressiveness of the disease, underlying prognostic factors,
physical condition of the patient, and existing co-morbidities. Despite these
therapeutic achievements, the disease recurs and is associated with additional
risk factors such as comorbidities or increasing age. Thus, multiple myeloma
remains an incurable malignancy and an unmet medical need with significant
morbidity and mortality warranting
the need for novel therapeutic approaches.

The combination of daratumumab with talquetamab or teclistamab is based on the
following rationale. Daratumumab, in addition to its direct cytotoxicity to
myeloma cells, has been shown to increase helper and cytotoxic T cells and
deplete CD38+ immunoregulatory cells.2 In preclinical testing, the benefits of
such immune modulation were observed from in vivo pretreatment of multiple
myeloma patients with daratumumab, which increased the in vitro cell lysis of
multiple myeloma cells to a bispecific antibody targeting BCMA and CD3.16
Therefore, daratumumab in combination with talquetamab or teclistamab may lead
to enhanced
clinical responses in the treatment of relapsed or refractory multiple myeloma
through multiple mechanisms of action. By targeting CD38, daratumumab exhibits
conventional anti-tumor effects of CDC, ADCC, ADCP and apoptosis, as well as
immunomodulatory effects. By targeting either GPRC5D or BCMA with a bispecific
antibody, enhanced T cell-mediated cytotoxicity is expected through recruitment
of CD3-expressing T cells to the GPRC5D- or BCMA-expressing cells. By jointly
targeting different epitopes on multiple myeloma cells, effector T cells and NK
cells, as well as the bone marrow microenvironment through discrete and
complementary mechanisms of action, this combination may be an effective
therapeutic
approach in treating relapsed or refractory multiple myeloma.

This study has been transitioned to CTIS with ID 2023-503468-17-00 check the CTIS register for the current data.

Primary
- Part 1: To identify recommended Phase 2 doses and schedules (RP2Ds) for each
combination.
- Part 2: To characterize the safety of each RP2D for each combination

Secondary
- To characterize the pharmacokinetics and pharmacodynamics of each study
treatment
- To assess the immunogenicity of each study treatment
- To evaluate the antitumor activity of each combination

This is an open-label, multicenter, multi-cohort study of daratumumab in
combination with bispecific T cell redirecting antibodies in subjects with
multiple myeloma who have received prior therapy that included at least 3 prior
lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory
agent (IMiD) or who have disease that is double refractory to a PI and an IMiD.
These combinations will be tested concurrently, and enrollment will be
independent. The sponsor will allocate patients to each combination. The
following combinations will be studied:

• Combination 1 (SC-1): daratumumab (SC) & talquetamab (SC)
• Combination 2 (SC-2): daratumumab (SC) & teclistamab (SC)
• Combination 3 (SC-3): daratumumab (SC) & talquetamab(SC) en pomalidomide
• Combination 4 (SC-4): daratumumab (SC) & teclistamab(SC) en pomalidomide
The study of each combination will be conducted in 2 parts:
- Part 1: dose escalation to establish the RP2D(s) of each combination
- Part 2: dose expansion at the RP2D(s) for each combination
The aim of the study is to evaluate the safety of daratumumab in combination
with T cell redirectingantibodies, and to evaluate the antitumor activity of
each combination.

Daratumumab dosing: All subjects will receive daratumumab, administered
subcutaneously at a dose of 1800 mg in 28-day cycles as follows: weekly in
Cycles 1-2, biweekly in Cycles 3-6, and every 4 weeks thereafter.
Bispecific antibody dosing: talquetamab or teclistamab will be administered
subcutaneous in 28-day cycles.
Pomalidomide dosing: daily dosis of 4mg.

Please see document K6. Risk Benefit Analyse_20JUN2019:

Efficacy has been observed for IV daratumumab in combination with
chemoimmunotherapy in subjects with multiple myeloma. The efficacy and adverse
event profiles of SC daratumumab are consistent with those of IV daratumumab,
with a lower rate of IRRs. Nonclinical pharmacology
studies of talquetamab and teclistamab showed effective killing of target
malignant lymphocytes and suggest that these agents may result in decreased
tumor burden for subjects with multiple myeloma, which is supported by
preliminary efficacy data in the ongoing FIH Studies 64407564MMY1001 and
64007957MMY1001, respectively. Preliminary safety data in subjects with
multiple myeloma from
Studies 64407564MMY1001 and 64007957MMY1001 for talquetamab monotherapy and
teclistamab monotherapy demonstrate favorable safety profiles for each.