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

Phase 1

Completed

Conditions: Multiple Myeloma

Interventions: Drug: MOR03087 phase 1 dose escalation
Drug: MOR03087
Drug: Dexamethasone
Drug: Pomalidomide
Drug: Lenalidomide

Registration Number: NCT01421186

Lead Sponsor: MorphoSys AG

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 91

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1 dose escalation	MOR03087 phase 1 dose escalation	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.
Phase 2a confirmatory cohorts	MOR03087	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.
Phase 1 dose escalation	Pomalidomide	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.
Phase 1 dose escalation	Dexamethasone	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.
Phase 1 dose escalation	Lenalidomide	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.
Phase 2a confirmatory cohorts	Dexamethasone	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.
Phase 2a confirmatory cohorts	Lenalidomide	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.
Phase 2a confirmatory cohorts	Pomalidomide	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.

Primary Outcome Measures

Name	Time	Method
Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087	First cycle of treatment	1. as monotherapy 2. in combination with dexamethasone 3. in combination with pomalidomide + dexamethasone 4. in combination with lenalidomide + dexamethasone
Number of Participants Who Develop Anti-MOR03087 Antibodies	during treatment period, maximum 3 years after 1st dose	Number of participants who develop anti-MOR03087 antibodies, a measure of immunogenicity

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate	maximum 3 years after 1st dose	number (#) of patients responding (# stringent complete response + # complete response + # very good partial response + # partial response)
Time to Progression	patients were observed for up to 36 months	Time to Progression (Kaplan Meier estimate)
Progression-free Survival	patients were observed up to 36 months	Progression-free survival (Kaplan Meier estimates)
Duration of Response	patients were observed up to 36 months	Duration of response (Kaplan Meier estimates)
Pharmacokinetics: Cmax - Maximum Observed Serum Concentration for MOR202	up to 7 days after last MOR202 dose	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
Pharmacokinetics: AUC Cycle 1+2 - Area Under the Time/Concentration Curve for MOR202	56 days	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

Trial Locations

Locations (10): AKH (Allgemeines Krankenhaus der Stadt Wien), Abteilung für Klinische Onkologie, Universitätsklinik für Innere Medizin I
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Vienna, Austria
Medizinische Klinik II, Abt. Hämatologie, Onkologie,
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Tübingen, Germany
Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Studienambulanz für Hämatologie/Onkologie und Infektiologie
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Würzburg, Germany
Sektion für Stammzell- und Immuntherapie, II. Medizinischen Klinik,
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Kiel, Germany
Klinikum rechts der Isar/ Studien / III. Med. Klinik
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Munich, Germany
Charité - Universitätsmedizin Berlin, CBF: Campus Benjamin Franklin, CC 14: Tumormedizin, Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie
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Berlin, Germany
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus
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Dresden, Germany
Universitäsklinikum Heidelberg, Klin.-Pharmakologisches Studienzentrum
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Heidelberg, Germany
Medizinische Universitätsklinik, Abt. Innere Medizin I
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Freiburg, Germany
Medizinische Klinik 5 - Hämatologie und Internist. Onkologie, Universitätsklinikum Erlangen
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Erlangen, Germany