A Study of OPD5 Followed by Autologous Stem Cell Transplant for Patients With Relapsed Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of a single infusion of OPD5 before Autologous Stem Cell Transplant in patients with RRMM. The study will evaluate increasing doses of OPD5 to find the best dose and to assess any side effects. Each patient will be assigned to a dose cohort of 3-6 patients to receive one single dose of OPD5. Each patient will be hospitalized for about 14 days from the OPD5 infusion and then have monthly visits to the clinic for 3 months and then every third month until disease progression or starting new myeloma treatment, maximum up to 2 years.

Official Title
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An Open-label Phase I, Dose Escalation Study of the Safety and Tolerability of OPD5 as Myeloablative Conditioning Regimen Followed by Autologous Stem Cell Transplant (ASCT) for Patients With Relapsed Refractory Multiple Myeloma (RRMM)

Conditions
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Relapse Multiple Myeloma, Multiple Myeloma

Intervention / Treatment
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* Drug: OPD5


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, between the ages of 18 years and 70 years at the planned time of study treatment; patients greater than 70 years of age may qualify on a case by case basis Diagnosis of multiple myeloma Received a previous Autologous Stem Cell Transplantation ( ASCT) (single or tandem) that resulted in disease progression within 24 months Received at least 2 prior lines of therapy Refractory to previous treatment with a Proteasome Inhibitor (PI), an immunomodulatory drug (IMiD) and an anti-Cluster of Differentiation 38 monoclonal antibody (anti-CD38 mAb) Male and women of childbearing potential agrees to use contraception during the treatment period and during a specified time period after the last dose Exclusion Criteria: Prior treatment with melphalan flufenamide (melflufen) or OPD5 Any medical condition that may interfere with safety or participation in this study Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance Prior allogeneic stem cell transplantation or prior salvage ASCT

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: Sequential Assignment
Interventional Model Description: A minimum of 3 and up to 6 evaluable patients will be enrolled per dose level. After the first cohort, the doses for the following dose cohorts will be adaptively escalated/de-escalated based on observed dose limiting toxicities in previous cohort.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose cohort 1<br>In dose cohort 1, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level of 30 mg/m2 (dose based on body surface area) | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|
| Experimental: Dose cohort 2<br>In dose cohort 2, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level decided based on the results from Dose Cohort 1 | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|
| Experimental: Dose cohort 3<br>In dose cohort 3, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level decided based on the results from Dose Cohort 2 | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|
| Experimental: Dose cohort 4<br>In dose cohort 4, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level decided based on the results from Dose Cohort 3 | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|
| Experimental: Dose cohort 5<br>In dose cohort 5, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level decided based on the results from Dose Cohort 4 | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|
| Experimental: Dose cohort 6<br>In dose cohort 6, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level decided based on the results from Dose Cohort 5 | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|
| Experimental: Dose cohort 7<br>In dose cohort 7, treatment with OPD5 solution will be given as one single i.v. infusion over 30 minutes at a dose level decided based on the results from Dose Cohort 6 | Drug: OPD5<br>* OPD5 solution for i.v. infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and grade of Treatment Emergent Adverse Events (TEAEs) | Including frequency and grade of defined Dose Limiting Toxicities | 30 days post OPD5 treatment with ASCT | 
| Incidence of clinically significant changes in clinical laboratory parameters |  | 30 days post OPD5 treatment with ASCT | 
| Magnitude of clinically significant changes in clinical laboratory parameters |  | 30 days post OPD5 treatment with ASCT | 
| Incidence of clinically significant adverse findings in vital signs |  | 30 days post OPD5 treatment with ASCT | 
| Severity of clinically significant adverse findings in vital signs |  | 30 days post OPD5 treatment with ASCT | 
| Incidence of clinically significant adverse findings in electrocardiograms (ECGs) |  | 30 days post OPD5 treatment with ASCT | 
| Severity of clinically significant adverse findings in electrocardiograms (ECGs) |  | 30 days post OPD5 treatment with ASCT | 
| Incidence of clinically significant adverse findings in other physical examination parameters |  | 30 days post OPD5 treatment with ASCT | 
| Severity of clinically significant adverse findings in other physical examination parameters |  | 30 days post OPD5 treatment with ASCT | 
| Incidence of mucositis |  | 30 days post OPD5 treatment with ASCT | 
| Severity of mucositis | Using World Health Organization (WHO) oral toxicity scale, from 0 (no change) to 4 (oral feeding is not possible) | 30 days post OPD5 treatment with ASCT | 
| The number of deaths not related to relapse or progression |  | 100 days post OPD5 treatment with ASCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response | Best response for a single patient. Best response will include the following categories: stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD) and Progressive Disease (PD) as assessed by the investigator according to International Myeloma Working Group Uniform Response Criteria (IMWG-URC) | 30 days post OPD5 treatment with ASCT | 
| Overall Response Rate (ORR) | Proportion of patients who achieve response of CR, sCR, VGPR or PR as their best response. | approximately 100 days post OPD5 treatment with ASCT | 
| Duration of response (DOR) | Time from the first confirmed response of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause | approximately 12 months | 
| Time to progression (TTP) | Time from the date of OPD5 administration to the date of the first documented confirmed PD | approximately 12 months | 
| Time to next treatment (TTNT) | Time from the date of OPD5 administration start to the start of first post study myeloma therapy (maintenance MM treatment not considered as new line of therapy) | approximately 12 months | 
| Progression Free Survival (PFS) | Time from the date of OPD5 dosing to the date of first documentation of confirmed progressive disease (PD) or death due to any cause | approximately 12 months | 
| Pharmacokinetics Area under the curve AUC(0-t) for OPD5 and the metabolites desethyl-melflufen and melphalan |  | Day -1 (the day of OPD5 infusion) | 
| Pharmacokinetics AUC(0-infinity) for OPD5 and the metabolites desethyl-melflufen and melphalan |  | Day -1 (the day of OPD5 infusion) | 
| Pharmacokinetics elimination half-life (t½) for OPD5 and the metabolites desethyl-melflufen and melphalan |  | Day -1 (the day of OPD5 infusion) | 
| Pharmacokinetics Cmax for OPD5 and the metabolites desethyl-melflufen and melphalan |  | Day -1 (the day of OPD5 infusion) | 
| Time to hematological recovery | defined as the return of Absolute Neutrophil Count (ANC) ≥ 0.5 x 10^9/L and platelets ≥ 20 x 10^9/L for two consecutive days | approximately Day 14 | 
| Time to myeloablation | defined as the first of at least two consecutive days with ANC < 0.5 x 10^9/L and platelets <20 x 10^9/L | approximately Day 14 | 
| Minimal Residual Disease (MRD) status by Next Generation sequencing (NGS) in patients that achieve a CR or VGPR. |  | approximately Day 100 |