Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, MOR03087 (MOR202), Lenalidomide, Pomalidomide, CD38
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.
Interventions
DRUGMOR03087 phase 1 dose escalation
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.
DRUGMOR03087
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.
DRUGDexamethasone
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.
DRUGPomalidomide
Pomalidomide will be administered to patients orally 4 mg on days 1-21 of the 28-day cycle.
DRUGLenalidomide
Lenalidomide will be administered to patients orally 25 mg on days 1-21 of the 28-day cycle.
Sponsors
MorphoSys AG
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects 18 years and older 2. 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 3. 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 4. Absolute neutrophil count (ANC) ≥ 1,000 / mm3 5. Haemoglobin ≥ 8 g/dL 6. Ability to comply with all study related procedures, medication use and evaluations
Exclusion criteria
1. Primary refractory multiple myeloma 2. History of significant cerebrovascular disease or sensory or motor neuropathy of toxicity grade 3 or higher 3. Treatment with systemic investigational agent within 28 days prior to first study treatment 4. Solitary plasmacytoma or plasma cell leukaemia 5. Previous allogenic stem cell transplant (SCT) 6. 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 7. Active systemic infection 8. Systemic disease preventing study treatment 9. Multiple myeloma with central nervous system (CNS) involvement 10. 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) 11. Significant uncontrolled cardiovascular disease or cardiac insufficiency (New York Heart Association \[NYHA\] classes III, IV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Austria, Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: MOR03087 Biweekly Dose Escalation Treatment cycle 28 days, MOR03087 doses applied day 1 & 15, initial 0.01 mg/kg, max 16 mg/kg | 31 |
| Part B: MOR03087 Weekly Dose Escalation Treatment cycle 28 days, MOR03087 doses applied day 1, 8, 15 & 22 plus extra dose on day 4 of cycle 1, Initial MOR03087 dose 4 mg/kg, max 16 mg/kg | 4 |
| Part C: MOR03087 Plus Dexamethasone Treatment cycle 28 days, iv MOR03087 and oral dexamethasone (DEX) applied day 1, 8, 15 & 22 plus extra dose on day 4 of cycle 1, initial MOR03087 dose 4 mg/kg, max 16 mg/kg. DEX dose 40 mg (≤ 75 years old) or 20 mg (\> 75 years old) | 18 |
| Part D: MOR03087 Plus Pomalidomide + Dexamethasone Treatment cycle 28 days, iv MOR03087 and oral dexamethasone (DEX) applied day 1, 8, 15 & 22 plus extra dose on day 4 of cycle 1, initial MOR03087 dose 8 mg/kg, max 16 mg/kg. DEX dose 40 mg (≤ 75 years old) or 20 mg (\> 75 years old). Pomalidomide was administered to patients orally 4 mg on days 1-21 of the 28-day cycle. | 21 |
| Part E: MOR03087 Plus Lenalidomide + Dexamethasone Treatment cycle 28 days, iv MOR03087 and oral dexamethasone (DEX) applied day 1, 8, 15 & 22 plus extra dose on day 4 of cycle 1, initial MOR03087 dose 8 mg/kg, max 16 mg/kg. DEX dose 40 mg (≤ 75 years old) or 20 mg (\> 75 years old).
Lenalidomide was administered to patients orally 25 mg on days 1-21 of the 28-day cycle. | 17 |
| Total | 91 |
Baseline characteristics
| Characteristic | Part A: MOR03087 Biweekly Dose Escalation | Part B: MOR03087 Weekly Dose Escalation | Part C: MOR03087 Plus Dexamethasone | Part D: MOR03087 Plus Pomalidomide + Dexamethasone | Part E: MOR03087 Plus Lenalidomide + Dexamethasone | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 3 Participants | 11 Participants | 11 Participants | 9 Participants | 57 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 1 Participants | 7 Participants | 10 Participants | 8 Participants | 34 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 31 Participants | 4 Participants | 18 Participants | 21 Participants | 17 Participants | 91 Participants |
| Region of Enrollment Austria | 0 participants | 0 participants | 3 participants | 1 participants | 0 participants | 4 participants |
| Region of Enrollment Germany | 31 participants | 4 participants | 15 participants | 20 participants | 17 participants | 87 participants |
| Sex: Female, Male Female | 12 Participants | 0 Participants | 8 Participants | 8 Participants | 5 Participants | 33 Participants |
| Sex: Female, Male Male | 19 Participants | 4 Participants | 10 Participants | 13 Participants | 12 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 31 | 0 / 4 | 0 / 18 | 1 / 21 | 4 / 17 |
| other Total, other adverse events | 31 / 31 | 4 / 4 | 18 / 18 | 21 / 21 | 17 / 17 |
| serious Total, serious adverse events | 13 / 31 | 4 / 4 | 7 / 18 | 20 / 21 | 14 / 17 |
Outcome results
Primary
Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087
1. as monotherapy 2. in combination with dexamethasone 3. in combination with pomalidomide + dexamethasone 4. in combination with lenalidomide + dexamethasone
Time frame: First cycle of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087 | 16 mg/kg |
| Part B: MOR03087 Weekly Dose Escalation | Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087 | 16 mg/kg |
| Part C: MOR03087 Plus Dexamethasone | Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087 | 16 mg/kg |
| Part D: MOR03087 Plus Pomalidomide + Dexamethasone | Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087 | 16 mg/kg |
| Part E: MOR03087 Plus Lenalidomide + Dexamethasone | Determination of Maximum Tolerated Dose and / or Recommended Dose and Dosing Regimen of MOR03087 | 16 mg/kg |
Primary
Number of Participants Who Develop Anti-MOR03087 Antibodies
Number of participants who develop anti-MOR03087 antibodies, a measure of immunogenicity
Time frame: during treatment period, maximum 3 years after 1st dose
Population: all patients with available data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Number of Participants Who Develop Anti-MOR03087 Antibodies | 0 Participants |
| Part B: MOR03087 Weekly Dose Escalation | Number of Participants Who Develop Anti-MOR03087 Antibodies | 0 Participants |
| Part C: MOR03087 Plus Dexamethasone | Number of Participants Who Develop Anti-MOR03087 Antibodies | 0 Participants |
| Part D: MOR03087 Plus Pomalidomide + Dexamethasone | Number of Participants Who Develop Anti-MOR03087 Antibodies | 0 Participants |
| Part E: MOR03087 Plus Lenalidomide + Dexamethasone | Number of Participants Who Develop Anti-MOR03087 Antibodies | 0 Participants |
Secondary
Duration of Response
Duration of response (Kaplan Meier estimates)
Time frame: patients were observed up to 36 months
Population: Of the total 91 patients, 26 obtained a response: 5 in part C, 10 in part D and 11 in part E. Duration of response was calculated only in these patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Duration of Response | 16.7 months |
| Part B: MOR03087 Weekly Dose Escalation | Duration of Response | 21.2 months |
| Part C: MOR03087 Plus Dexamethasone | Duration of Response | 32.2 months |
Secondary
Overall Response Rate
number (#) of patients responding (# stringent complete response + # complete response + # very good partial response + # partial response)
Time frame: maximum 3 years after 1st dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Overall Response Rate | 0 Participants |
| Part B: MOR03087 Weekly Dose Escalation | Overall Response Rate | 0 Participants |
| Part C: MOR03087 Plus Dexamethasone | Overall Response Rate | 5 Participants |
| Part D: MOR03087 Plus Pomalidomide + Dexamethasone | Overall Response Rate | 10 Participants |
| Part E: MOR03087 Plus Lenalidomide + Dexamethasone | Overall Response Rate | 11 Participants |
Secondary
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
Time frame: 56 days
Population: Pharmakokinetics was analysed on all available data on patients receiving 4mg/kg weekly, 8mg/kg weekly and 16 mg/kg weekly irrespective in which part the patients were treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Pharmacokinetics: AUC Cycle 1+2 - Area Under the Time/Concentration Curve for MOR202 | 3307.57 mg*days/L | Standard Deviation 2332.07 |
| Part B: MOR03087 Weekly Dose Escalation | Pharmacokinetics: AUC Cycle 1+2 - Area Under the Time/Concentration Curve for MOR202 | 7970.15 mg*days/L | Standard Deviation 4289.21 |
| Part C: MOR03087 Plus Dexamethasone | Pharmacokinetics: AUC Cycle 1+2 - Area Under the Time/Concentration Curve for MOR202 | 18178.57 mg*days/L | Standard Deviation 8414.44 |
Secondary
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
Time frame: up to 7 days after last MOR202 dose
Population: Pharmakokinetics was analysed on all available data on patients receiving 4mg/kg weekly, 8mg/kg weekly and 16 mg/kg weekly irrespective in which part the patients were treated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Pharmacokinetics: Cmax - Maximum Observed Serum Concentration for MOR202 | 137.86 µg/mL | Standard Deviation 79.43 |
| Part B: MOR03087 Weekly Dose Escalation | Pharmacokinetics: Cmax - Maximum Observed Serum Concentration for MOR202 | 311.67 µg/mL | Standard Deviation 118.33 |
| Part C: MOR03087 Plus Dexamethasone | Pharmacokinetics: Cmax - Maximum Observed Serum Concentration for MOR202 | 681.53 µg/mL | Standard Deviation 226.69 |
Secondary
Progression-free Survival
Progression-free survival (Kaplan Meier estimates)
Time frame: patients were observed up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Progression-free Survival | 1.1 months |
| Part B: MOR03087 Weekly Dose Escalation | Progression-free Survival | 2.1 months |
| Part C: MOR03087 Plus Dexamethasone | Progression-free Survival | 8.4 months |
| Part D: MOR03087 Plus Pomalidomide + Dexamethasone | Progression-free Survival | 15.9 months |
| Part E: MOR03087 Plus Lenalidomide + Dexamethasone | Progression-free Survival | 26.7 months |
Secondary
Time to Progression
Time to Progression (Kaplan Meier estimate)
Time frame: patients were observed for up to 36 months
Population: safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: MOR03087 Biweekly Dose Escalation | Time to Progression | 1.1 months |
| Part B: MOR03087 Weekly Dose Escalation | Time to Progression | 2.1 months |
| Part C: MOR03087 Plus Dexamethasone | Time to Progression | 8.4 months |
| Part D: MOR03087 Plus Pomalidomide + Dexamethasone | Time to Progression | 15.9 months |
| Part E: MOR03087 Plus Lenalidomide + Dexamethasone | Time to Progression | 33.2 months |