A Phase 1/2a Study of Human Anti-CD 38 Antibody MOR03087 (MOR202) in Relapsed/Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This is an open-label, multicentre, dose escalation study to characterize the safety and preliminary efficacy of the human anti-CD38 antibody MOR03087 (MOR202), in adult subjects with relapsed/refractory multiple myeloma, as monotherapy and in adult subjects with relapsed/refractory multiple myeloma in combination with standard therapy.

Detailed Description
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The study enrolled patients aged 18 years or older with relapsed or refractory multiple myeloma and Karnofsky performance status of 60% or higher. Patients were assigned to the different treatment regimens with MOR202 ranging between 0·01 mg/kg and 16 mg/kg in a 3 + 3 design. Dose-escalation and expansion was done either with MOR202 intravenous infusions alone (MOR202 q2w [twice a week] and q1w [weekly] groups) or in combination with dexamethasone (MOR202 with dexamethasone group), with dexamethasone plus pomalidomide (MOR202 with dexamethasone plus pomalidomide group) or plus lenalidomide (MOR202 with dexamethasone plus lenalidomide group). Primary endpoints were safety, MOR202 maximum tolerated dose (or recommended dose) and regimen, and immunogenicity.

Official Title
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A Phase 1/2a, Open-Label, Multicentre, Dose-Escalation Study to Evaluate the Safety and Preliminary Efficacy of the Human Anti-CD 38 Antibody MOR03087 as Monotherapy and in Combination With Standard Therapy in Subjects With Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: MOR03087 phase 1 dose escalation
* Drug: MOR03087
* Drug: Dexamethasone
* Drug: Pomalidomide
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 years and older Relapsed or refractory multiple myeloma defined as: Parts A, B and C: (i) Failure of at least 2 previous therapies which must have included an immunomodulatory agent and a proteasome inhibitor (either together or part of different therapies) (ii) All subjects must have documented progression during or after their last prior therapy for multiple myeloma Part D: (i) At least 2 previous therapies including lenalidomide and a proteasome inhibitor (ii) All subjects must have documented progression during or within 60 days after their last prior therapy for multiple myeloma Part E: (i) Received at least one previous therapy (ii) All subjects must have documented progression during or after their last prior therapy for multiple myeloma Presence of serum M-protein ≥ 0.5 g per 100 mL (≥ 5 g/L) and / or urine M-protein ≥ 200 mg per 24-hour period Absolute neutrophil count (ANC) ≥ 1,000 / mm3 Haemoglobin ≥ 8 g/dL Ability to comply with all study related procedures, medication use and evaluations Exclusion Criteria: Primary refractory multiple myeloma History of significant cerebrovascular disease or sensory or motor neuropathy of toxicity grade 3 or higher Treatment with systemic investigational agent within 28 days prior to first study treatment Solitary plasmacytoma or plasma cell leukaemia Previous allogenic stem cell transplant (SCT) Prior therapy with other monoclonal antibodies targeting the CD38 antigen or prior therapy with other IgG monoclonal antibodies within 3 months prior to first study treatment, or IgM monoclonal antibodies within 1 month prior to first study treatment Active systemic infection Systemic disease preventing study treatment Multiple myeloma with central nervous system (CNS) involvement Previous treatment with cytotoxic chemotherapy or large field radiotherapy or other myeloma specific therapy within 28 days prior to first study treatment (radiation to a single site as concurrent therapy is allowed) Significant uncontrolled cardiovascular disease or cardiac insufficiency (New York Heart Association [NYHA] classes III, IV)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 dose escalation<br>Part A: MOR03087 dose escalation; biweekly treatment Part B: MOR03087 dose escalation; weekly treatment Part C: MOR03087 dose escalation (weekly treatment) + dexamethasone Part D: MOR03087 weekly treatment in combination with pomalidomide + dexamethasone Part E: MOR03087 weekly treatment in combination with lenalidomide + dexamethasone For all parts, patients will be treated until disease progression (PD) or until a maximum of 3 years after first treatment. | Drug: MOR03087 phase 1 dose escalation<br>* Treatment cycles will be 28 days. Initial MOR03087 doses will be 0.01 mg/kg in part A, 4 mg/kg in parts B and C and 8 mg/kg in parts D and E; in all parts MOR03087 doses will be escalated to a maximum of 16 mg/kg. In part A, patients will receive a biweekly intravenous infusion of MOR03087 which will be administered on days 1 and 15 of the cycle. In parts B to E patients will receive a weekly intravenous infusion of MOR03087 which will be administered on days 1, 8, 15, and 22 of the cycle. In all parts a loading dose of MOR03087 will be additionally administered on day 4 of cycle 1.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered to patients orally; 40 mg (≤ 75 years old) or 20 mg (> 75 years old) on days 1, 8, 15, and 22 of the 28-day cycle. An additional dose will be administered in cycle 1 on day 4.<br>Drug: Pomalidomide<br>* Pomalidomide will be administered to patients orally 4 mg on days 1-21 of the 28-day cycle.<br>Drug: Lenalidomide<br>* Lenalidomide will be administered to patients orally 25 mg on days 1-21 of the 28-day cycle.<br>|
| Experimental: Phase 2a confirmatory cohorts<br>Confirmatory cohorts of MOR03087 monotherapy (plus or minus dexamethasone), in combination with pomalidomide plus dexamethasone, and in combination with lenalidomide plus dexamethasone. Following completion of Parts A, B, and C (dose escalation of MOR03087 biweekly and weekly schedules), the Maximum Tolerated Dose (MTD) or recommended dose and dosing regimen will be confirmed in a minimum of 6 subjects. Following completion of Parts D (dose escalation of MOR03087 in combination with pomalidomide + dexamethasone) and E (dose escalation of MOR03087 in combination with lenalidomide + dexamethasone), the MTD and/or recommended dose in each part will be confirmed in a minimum of 6 subjects. For all parts, patients will be treated until PD or until a maximum of 3 years after first treatment. | Drug: MOR03087<br>* MOR03087 will be administered according to the Maximum Tolerated Dose (MTD) or recommended dose and dosing regimen for MOR03087 from parts A-E of the phase I dose escalation. The biweekly MOR03087 regimen as described in part A; the weekly regimen as described for parts B-E.<br>Drug: Dexamethasone<br>* Dexamethasone will be administered to patients orally; 40 mg (≤ 75 years old) or 20 mg (> 75 years old) on days 1, 8, 15, and 22 of the 28-day cycle. An additional dose will be administered in cycle 1 on day 4.<br>Drug: Pomalidomide<br>* Pomalidomide will be administered to patients orally 4 mg on days 1-21 of the 28-day cycle.<br>Drug: Lenalidomide<br>* Lenalidomide will be administered to patients orally 25 mg on days 1-21 of the 28-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087 | as monotherapy in combination with dexamethasone in combination with pomalidomide + dexamethasone in combination with lenalidomide + dexamethasone | First cycle of treatment | 
| Number of Participants Who Develop Anti-MOR03087 Antibodies | Number of participants who develop anti-MOR03087 antibodies, a measure of immunogenicity | during treatment period, maximum 3 years after 1st dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | number (#) of patients responding (# stringent complete response + # complete response + # very good partial response + # partial response) | maximum 3 years after 1st dose | 
| Time to Progression | Time to Progression (Kaplan Meier estimate) | patients were observed for up to 36 months | 
| Progression-free Survival | Progression-free survival (Kaplan Meier estimates) | patients were observed up to 36 months | 
| Duration of Response | Duration of response (Kaplan Meier estimates) | patients were observed up to 36 months | 
| Pharmacokinetics: Cmax - Maximum Observed Serum Concentration for MOR202 | PK analysis for MOR202 4, 8 and 16 mg/kg IV once weekly dose groups only, since serum concentrations of MOR202 were substantially affected by target mediated drug disposition effects for remaining dose groups | up to 7 days after last MOR202 dose | 
| Pharmacokinetics: AUC Cycle 1+2 - Area Under the Time/Concentration Curve for MOR202 | PK analysis for MOR202 4, 8 and 16 mg/kg IV once weekly dose groups only, since serum concentrations of MOR202 were substantially affected by target mediated drug disposition effects for remaining dose groups | 56 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, MOR03087 (MOR202), Lenalidomide, Pomalidomide, CD38