Clinical Trials

The purpose of this study is to evaluate the safety and tolerability of AO-176, including dose-limiting toxicities (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) when administered as monotherapy, and in combination with dexamethasone (AO-176+DEX) in adult patients with Relapsed/Refractory Multiple Myleoma (R/R MM).

Prior clinical experience with CD38-targeting antibodies, including daratumumab, establish this molecule as an important therapeutic target in multiple myeloma. CD38 is a type II transmembrane glycoprotein with both ectoenzymatic and signal transductionfunctions. CD38 dimerization is required for its catalytic activity (Desphande et al, 2017).Dimeric CD38 possesses both ADP ribosyl cyclase and cADPR hydrolyase activities; the former generates cyclic ADP ribose (cADPR) from NAD+ and the latter generates ADPR. CD38-mediated cADPR generation enables calcium release from intracellular stores, leading to a variety of cell type-specific physiological outcomes (Schuber and und, 2004; Lee and Aarhus, 1991). A distinct mode of CD38-dependent signal transduction involved in the regulation of proliferation and survival requires interactions with other cell surface molecules (Deshpande et al, 2017; Deaglio et al, 2007; Konopleva et al, 1998). In B- lymphocytes for example, CD38-dependent signal transduction activity utilizes interactions with CD19 and CD31/PECAM-1, the latter of which is the sole identified ligand for CD38 (Deaglio et al, 2007). Importantly, AMG 424 binding to CD38 on target cells results in redirection of T cell mediated cytotoxicity but should not modulate CD38 enzymatic activity or CD38-dependent signal transduction, based on expected serum concentrations in our proposed dosing scheme and significanty reduced binding affinity compared to a monoclonal antibody that does inhibit CD38 activity (Deckert et al., 2014).For this first-in-human study, relapsed/refractory multiple myeloma has been chosen as the indication for clinical investigation of AMG 424 because of the nearly uniform high expression of CD38 on plasma cells observed at the protein level, using flow cytometry (Lin et al, 2004). Although low level CD38 expression is widespread in different tissue types, including hematopoietic cells, plasma cells express CD38 protein at signficantly higher levels than other cell types (Malavasi et al, 2008 and Section 3 of AMG 424 IB).

The purpose of this study is to treat patients with drugs targeted to affect specific genes that are mutated as part of the disease. Mutations in genes can lead to uncontrolled cell growth and cancer. Patients with a greater than 30% mutation to any of the following genes; CDKN2C, FGFR3, KRAS, NRAS, BRAF V600E, IDH2 or T(11;14) can be enrolled to one of the treatment arms. These arms have treatments specifically directed to the mutated genes. Patients that do not have a greater than 30% mutation to the genes listed can be enrolled to a non-actionable treatment arm. The genetic sequencing of the patient's tumor is required via enrollment to the MMRF002 study: Clinical-grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies. (NCT02884102).

This phase I/II trial studies the side effects and best dose of ixazomib and to see how well it works when given together with pomalidomide and dexamethasone in treating patients with relapsed or relapsed/refractory multiple myeloma. Ixazomib may stop the growth of cancer by interfering with proteasomes (the protein breakdown mechanism in the cells). Pomalidomide and dexamethasone can modify and regulate the immune system and may stop cancer cells from growing. Giving ixazomib with pomalidomide and dexamethasone may be an effective treatment for relapsed or relapsed/refractory multiple myeloma.

The purpose of the phase 1 portion of this research study is to find out more about the side effects of belantamab and what doses of belantamab are safe for people when combined with lenalidomide and daratumumab, and to find the right dose for the phase 2 portion of the trial. 

This trial is exploring the use of a new drug called belantamab to be used in combination with daratumumab and lenalidomide and not using the same doses of dexamethasone as has been done with previous combinations. Belantamab is an anti-B-cell maturation antigen (BCMA) antibody-drug conjugate. This will be given along with 2 with two other drugs, lenalidomide and daratumumab.  Lenalidomide is an immunomodulatory drug (altering the immune effects on the tumor cell). Daratumumab is a drug that is a monoclonal antibody that is directed towards a protein on the myeloma cell. The proposed  belantamab-mafodotin combinations are novel therapies with unknown additional benefits over individual drugs and may pose additional risks.

The primary objective of the study is to determine the safety and tolerability of I-131-CLR1404, with and without concurrent weekly dexamethasone, in patients with relapsed or refractory multiple myeloma who have previously been treated with, or are intolerant of, an immunomodulator and a proteasome inhibitor.

The purpose of this study is to evaluate the safety, clinical pharmacology and clinical activity of TNB-383B, a T-cell engaging bispecific antibody, in subjects with relapsed or refractory MM who have received at least 3 prior lines of therapy. The study consists of 2 portions, a monotherapy dose escalation (Arm A) and a monotherapy dose expansion (Arm B). Arm A will evaluate the safety, tolerability, PK and PD profiles of escalating doses of single-agent TNB-383B ranging from 25 micrograms to 40 milligrams per dose, administered once every 3 weeks (Q3W), in approximately 24 subjects. Once the maximum tolerated dose (MTD) or recommended phase 2 dose, (RP2D) is identified in Arm A, Arm B will be initiated to further characterize the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the MTD/RP2D dose of TNB 383B monotherapy in approximately 48 subjects.

The purpose of this study is to evaluate the safety and effectiveness of venetoclax plus dexamethasone (VenDex) compared with pomalidomide plus dexamethasone (PomDex) in participants with t(11;14)-positive Relapsed or Refractory Multiple Myeloma.

Determine the preexisting and therapy-emergent germline and somatic variants associated with an increased risk of clonal and non-clonal cytopenia following CAR-T cell therapy.

The phase 1 primary objectives of this study are to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and recommended phase 2 dose (RPTD) of ABT-199 (venetoclax) when administered in subjects with relapsed or refractory multiple myeloma. This study will also assess the safety profile and PK of venetoclax in combination with dexamethasone in subjects with t(11;14)-positive multiple myeloma. The phase 2 primary objective is to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in subjects with t(11;14)-positive multiple myeloma and to evaluate patient reported outcomes.