MP0250 Combined with Bortezomib and Dexamethasone in Multiple Myeloma Patients Previoulsy Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

Background

MP0250 is a first-in-class selective tri-specific multi-DARPin® drug candidate neutralizing VEGF-Α and HGF as well as binding to human serum albumin to increase its plasma half-life. Preclinical studies have shown that MP0250 enhances sensitivity of Multiple Myeloma (MM) cells to bortezomib, inhibits tumor growth and reduces bone destruction. In this clinical phase 2 trial (NCT03136653), we are investigating the safety, tolerability and efficacy of the combination of MP0250 plus bortezomib and dexamethasone (dex) in patients (pts) with relapsed/refractory (RR) MM previously exposed to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD).

Aims

To study the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM.

Trial Design

This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. A dose-escalation phase (part 1) consisting of two cohorts will define a safe dose of the combination of MP0250 plus bortezomib + dex followed by a dose-expansion phase (part 2). Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone (dex) 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Up to 40 patients will be enrolled. Patients will receive treatment until there is documented disease progression or unacceptable toxicity.

Methods

The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, pharmacokinetics and potential biomarkers that include MM specific markers and cytokines monitoring bone homeostasis. The safety analysis set (SAF) is defined as patients who have received at least 1 dose of the combination of MP0250 plus bortezomib + dex.

Results

Data cut off was 21 July 2018. 8 pts have been treated in cohort 1 and 3 pts in cohort 2. Median time from initial diagnosis to first dose was 4.8 years (range, 1-10). Median number of prior therapies was 3 (range, 2-5). All 11 pts had prior exposure to IMiDs and PIs and 4 pts were considered PI refractory. Four patients received PI immediately prior to receive MP250 in combination. The most frequent drug-related grade ≥ 3 AEs: hypertension in 3 pts, thrombocytopenia in 6 pts, proteinuria in 2 pts and transient liver enzyme elevation in 1 patient. One dose-limiting toxicity has been reported in cohort 1 (grade 3 hypertension) and two in cohort 2 (grade 3 epistaxis, grade 3 proteinuria). There were no infusion-related reactions. Best response achieved in the 8 efficacy evaluable pts in cohort 1 was VGPR in 1 and PR in 4 for an overall response rate (ORR, ≥PR) of 62.5%. In cohort 2, 1 patient achieved Minimal Response (MR), 1 patient stable disease and 1 progressive disease. Three of four patients who were coming immediately from a PI based regimen achieved a response. Pharmacokinetics data in cohort 1 show sustained exposure over multiple cycles with a mean half-life of 11 days, and no indication of ADA mediated drug clearance was observed. Data from cohort 1 patients show accumulation of MP0250-HGF complexes over multiple cycles confirming the stable binding of MP0250 to HGF suggesting that all circulating HGF is neutralized.

Summary

Data from cohort 1 (8 mg/Kg q3w) suggest that MP0250 can be safely combined with bortezomib and dex in patients with relapsed and refractory MM. Durable responses were seen in patients who came from PI based pretreatment suggesting that MP0250 might be capable to reverse PI resistance.