Evaluation of Isatuximab, Evorpacept, and Dexamethasone in Relapsed or Refractory Multiple Myeloma: A Phase 1/2 Clinical Trial
- Trial ID
- 2024-514993-38-00
- Protocol
- ACT16482-06
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 1/2 clinical trial is to evaluate the efficacy of **isatuximab** in combination with evorpacept and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM). Specifically, Part 1 aims to determine or confirm the recommended dose of novel agents when combined with isatuximab, with or without dexamethasone. Part 2 seeks to demonstrate the clinical benefit of these novel agents in terms of achieving a very good partial response (VGPR) or better. This is clinically relevant as it may provide a new therapeutic option for patients with RRMM, potentially improving response rates and outcomes.
Secondary objectives include: - Assessing the overall response rate (ORR) in each treatment arm during both the dose-finding and expansion phases. - Evaluating the very good partial response (VGPR) in the dose-finding phase. - Determining the clinical benefit rate (CBR) and duration of response (DOR) in each treatment arm. - Measuring the time to first response (TT1R) and time to best response (TTBR). - Assessing safety and tolerability, progression-free survival (PFS), and overall survival (OS). - Evaluating the potential immunogenicity and pharmacokinetics (PK) of isatuximab and novel agents. - Assessing disease and treatment-related symptoms, health-related quality of life, and the global impact of side effects, as well as confirming clinically meaningful change scores for clinical outcome assessments (COAs).
Participants
The clinical trial involves a total of **29 participants** diagnosed with **cancer**, specifically focusing on individuals with relapsed or refractory multiple myeloma (RRMM). The study population includes both male and female subjects who are **18 years of age or older**. Participants were selected based on their prior treatment history, having received at least two prior lines of therapy for multiple myeloma, including proteasome inhibitors and immunomodulatory drugs. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have measurable disease, as defined by specific criteria for serum and urine M protein levels or serum free light chain levels. Lifestyle considerations include the requirement for participants of childbearing potential to agree to use contraception. The trial also includes a vulnerable population, as indicated by the selection criteria. The study does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **isatuximab** in combination with evorpacept and **dexamethasone** in patients with relapsed or refractory multiple myeloma (RRMM). This study is structured as a Phase 1/2 trial, incorporating both dose-finding and expansion phases. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial extends until September 2028, with recruitment anticipated to commence in June 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and prior treatment history. The primary inclusion criteria require participants to be 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and a history of at least two prior lines of therapy for multiple myeloma. The screening visit will also confirm measurable disease status through specific laboratory assessments.
Following the screening, participants will be enrolled in either Part 1 or Part 2 of the trial. Part 1 focuses on determining the recommended dose of novel agents when combined with isatuximab, while Part 2 aims to demonstrate the clinical benefit in terms of the rate of very good partial response (VGPR) or better. Participants will attend regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments of clinical benefit rate, duration of response, progression-free survival, and overall survival, among other endpoints.
The end-of-study visit will occur upon completion of the treatment regimen or in the event of disease progression or unacceptable toxicity. The expected length of participant involvement will vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with study procedures, or the occurrence of serious adverse events. Throughout the trial, data on immunogenicity, pharmacokinetics, and quality of life will be collected to provide a comprehensive evaluation of the treatment's impact.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Dexamethasone** is utilized in two formulations: **Dexamethason 8 mg JENAPHARM®** and **Dexamethason 4 mg JENAPHARM®**. Both are provided in tablet form for oral use. The active substance, dexamethasone, is of chemical origin. The tablets are repackaged and relabeled for clinical supplies. The frequency of administration and specific dosing schedules are determined based on the trial protocol, with compliance monitored through standard clinical trial procedures.
**Isatuximab** is administered as a solution for infusion, with two separate product entries under the same name. The active substance, isatuximab, is a protein of other origin. The solution is delivered intravenously, and the dosing schedule is aligned with the trial's objectives to determine the recommended dose when combined with other agents. Participant compliance is monitored through infusion records and clinical assessments.
**ALX148** is another investigational product used in this trial, provided as an injection for intravenous administration. The active substance, ALX148, is also a protein of other origin. This product is designated as an orphan drug, indicating its use in treating a rare condition. The administration schedule is designed to evaluate its efficacy in combination with other trial medications, with compliance tracked through infusion logs and participant monitoring.
Throughout the trial, the combination of these medications aims to assess their efficacy in treating relapsed or refractory multiple myeloma. The trial includes both dose-finding and expansion phases to establish the clinical benefit of these novel agents. Compliance with the dosing regimen is crucial and is ensured through rigorous monitoring and documentation practices inherent in clinical trial protocols.
Efficacy
The efficacy of the clinical trial evaluating the combination of isatuximab, evorpacept, and **dexamethasone** in patients with relapsed or refractory multiple myeloma (RRMM) will be assessed through a series of primary and secondary endpoints. The primary endpoints include the determination of the recommended dose of novel agents in combination with isatuximab during Part 1 of the trial, and the rate of Very Good Partial Response (VGPR) or better during Part 2. Secondary endpoints encompass a range of measures, including Overall Response Rate (ORR), Clinical Benefit Rate (CBR), Duration of Response (DOR), Time to First Response (TT1R), Time to Best Response (TTBR), and Progression-Free Survival (PFS). Additionally, Overall Survival (OS) and the immunogenicity of isatuximab and novel agents will be evaluated.
Patient-reported outcomes will be assessed using validated instruments such as the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30) and the EORTC multiple myeloma module (QLQ-MY20) questionnaire. The global impact of side effects will be measured using the Functional Assessment of Cancer Therapy (FACT-G) (GP5). Pharmacokinetic parameters, including the concentration of novel agents and isatuximab, will be monitored, with specific attention to the time to reach maximum concentration (tmax) and the area under the concentration versus time curve (AUC) for evorpacept in Substudy 06. These assessments will provide a comprehensive evaluation of the clinical benefit and safety profile of the treatment regimen in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be 18 years of age inclusive or older
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Participants with relapsed or refractory MM who have received at least 2 prior lines of therapy for MM, including PIs and IMiDs (eg, Induction regimen with autologous stem cell transplant followed by maintenance is considered one line).
- RRMM with measurable disease: Serum M protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis and/or
- RRMM with measurable disease: Urine M protein ≥200 mg/24 hours measured using urine protein immunoelectrophoresis and/or
- RRMM with measurable disease: Serum free light chain (sFLC) MM without measurable M protein in serum or urine per previous criteria (serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa lambda free light chain ratio <0.26 or >1.65)
- Men or woman or childbearing potential should agree to use contraception.
- Substudy 06: Anti-CD38 therapy naïve or prior exposure to such drugs with a wash out of at least 12 months after the last dose. “Exposure” is defined as at least 2 cycles of therapy.
Exclusion Criteria
- Primary systemic amyloid light chain amyloidosis, plasma cell leukemia, monoclonal gammopathy of undetermined significance, or smoldering myeloma
- Uncontrolled infection within 14 days prior to first study intervention administration.
- Clinically significant cardiac (including valvular) or vascular disease within 3 months prior to first study intervention administration., eg, myocardial infarction, unstable angina, coronary (eg, coronary artery bypass graft, percutaneous coronary intervention) or peripheral artery revascularization, left ventricular ejection fraction <40%, heart failure New York Heart Association Classes III and IV, stroke, transient ischemic attack, pulmonary embolism, other thromboembolic event, or cardiac arrhythmia (Grade 3 or higher by NCI CTCAE Version 5.0).
- Known acquired immunodeficiency syndrome-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A.
- Uncontrolled or active hepatitis B virus (HBV) infection.
- Active hepatitis C virus (HCV) infection.
- Any of the following within 3 months prior to first study intervention administration: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease.
- Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma, unless they are successfully treated with curative intent for more than 3 years before first study intervention administration.
- Any anti-MM drug treatment within 14 days before first study intervention administration, including dexamethasone
- Participants with a contraindication to treatment.
- Vaccination with a live vaccine 4 weeks before the start of the study.
- Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
- Hemoglobin <8 g/dL.
- Platelets <50 × 10^9/L.
- Absolute neutrophil count <1.0 × 10^9/L.
- Creatinine clearance <30 mL/min/1.73m2.
- Total bilirubin >1.5 × ULN, except for known Gilbert syndrome in which direct bilirubin should be ≤2.5 × ULN
- Aspartate aminotransferase and/or alanine aminotransferase >3 × ULN.
- Patients with grade 3 or 4 hypercalcemia.
- Substudy 06:History of active autoimmune disorders.
- Substudy 06:History of autoimmune hemolytic anemia or autoimmune thrombocytopenia.
- Substudy 06:Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD.
- Substudy 06:Prior allogenic hematopoietic stem cell transplant (allo-HSCT).
- Substudy 06:Participants with chronic active EBV infection.
- Substudy 06:Participants with known history of HLH.
- Substudy 06:Hemoglobin < 9 g/dL.
- Substudy 06:Prior therapy with any anti-CD47 or anti signal regulatory protein alpha agent.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 04 Jun 2024 | 3 |
 Germany | Recruiting | 04 Jun 2024 | 2 |
 Greece | Recruiting | 04 Jun 2024 | 4 |
 Italy | Recruiting | 04 Jun 2024 | 4 |
 Norway | Recruiting | 04 Jun 2024 | 4 |
 Portugal | Not Recruiting | 04 Jun 2024 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Dexamethason 4 mg JENAPHARM® | Test | TABLET | ORAL USE | — | — | PRD988426 |
evorpacept | Test | INJECTION | INTRAVENOUS | — | — | PRD8805872 |
Isatuximab | Test | SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD10653334 |
Dexamethason 8 mg JENAPHARM® | Test | TABLET | ORAL USE | — | — | PRD988427 |
Isatuximab | Test | SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD10652636 |