EHA 2018| Phase I/IIa study of MOR202 used in combination treatments

The 23^rd Congress of the European Hematology Association (EHA) took place in Stockholm from 14–17 June 2018. On Saturday 16 June, an oral session took place during which, Marc S. Raab, head of the Max-Eder Research Unit “Experimental Therapies for Hematologic Malignancies”, which is jointly affiliated with the Heidelberg University Medical Center and the German Cancer Research Center (DFKZ) in Heidelberg, Germany, presented results of a phase I/IIa clinical trial on the safety and efficacy of MOR202.

MOR202 is a fully human monoclonal IgG1 antibody which targets CD38. MOR202 mediates the killing of cancer cells by inducing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, because it does not trigger complement activation, the action of MOR202 does not involve complement dependent cytotoxicity (CDC).

The primary objective of the study was to assess the safety profile and determine the recommended dose of MOR202 as a monotherapy and in combination with other agents, in relapsed and refractory multiple myeloma (RRMM) patients. The following combination treatments were studied: MOR202/dexamethasone (dex); MOR202/dex/pomalidomide (pom); MOR202/dex/lenalidomide (len). The current session focused on results from the combination treatments only.

Data is given as MOR202/dex vs MOR202/pom/dex vs MOR202/len/dex

Study Design

• Total number of patients (pts) = 56
• Secondary end points: efficacy, pharmacokinetics and pharmacodynamics
• Standard dose escalation (3 + 3 design)
• 28-day cycle
• MOR202 infusion time = 2 hr
• MOR202 dose escalation among treatment groups = 4; 8; 16 vs 8; 16 vs 8; 16 mg/kg (weekly intravenous infusion on days 1, 8, 15 and 22 of the cycle; a loading dose is additionally administered on day 4 of cycle 1)
• Pom = 4 mg (orally on days 1–21)
• Len = 25 mg (orally on days 1–21)
• Dex = 40 mg, or 20 mg (if aged >75 years) (orally on days 1, 8, 15, and 22 of the cycle; an additional dose is administered on day 4 of cycle 1)

Key Data

• Pts = 18 vs 21 vs 17
• Median age = 67 vs 65 vs 66 years
• Median prior lines of treatment = 3 vs 3 vs 2
• Infusion Related Reactions (IRR) = 11% (all grade ≤ 2)
• Most common hematological treatment emergent adverse events (TEAEs), grade ≥ 3: leukopenia = 11% vs 57% vs 47%; lymphopenia = 39% vs 48% vs 59%; neutropenia = 22% vs 76% vs 53%
• Most common non-hematological TEAEs, grade > 3  = hypertension, 11% vs 19% vs 12%; pneumonia, 6% vs 24% vs 6%
• Discontinued treatment due to TEAEs = two pts: one with grade 4 thrombocytopenia; one with serious grade 3 bacterial infection, complicated by acute kidney failure
• Overall response rate (ORR) = 28% vs 48% vs 65%
• Complete response (CR) = 0% vs 10% vs 12%; very good partial response (VGPR) = 11% vs 19% vs 12%; partial response (PR) = 17% vs 19% vs 41%
• PFS = 8.4 vs 17.5 months vs not reached (data cut off for analysis: December 2017)

Conclusions

This phase I/IIa study of MOR202, in combination with dex alone or pom/dex or len/dex, determines the safety of MOR202 in RRMM patients. MOR202 is well-tolerated with a low incidence of IRRs and low infusion time (30 minutes > < 2 hr). This study paves the way for expanded trials using MOR202 in this treatment combination.

Questions and Answers

Q1. The tolerability profile seems very good, with low incidence of IRR and also the infusion time is shorter than the most commonly used monoclonal antibody, which is daratumumab (dara). At the same time, the single agent activity is similar but maybe the patients are a bit less ‘treated’ compared to the dara treated patients. Can you comment on this?

A1. The lack of complement activation might contribute to a “less deeper” response, as we see fewer CRs compared to results from trials using dara. However, it does not seem to affect the long-term outcome such as progression-free survival. It seems that the CDC affects deepness of response but the ADCC and ADCP seem to contribute to the duration of response.

Q2. Were you able to look at some MRD results?

A2. No

Q3. There seems to be no dose response. At 8 mg/kg you have very good responses. Could that be the final dose?

A3. In terms of PK studies, 16 mg/kg is where we have the best saturation but in terms of response, we don’t see a clear response curve. Therefore, the extension cohorts were based on 16 mg/kg.