ATRA and Carfilzomib in Plasma Cell Myeloma Patients
NCT Number: NCT06536413
Acronym: ATRA
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1|PHASE2
Conditions: Multiple Myeloma
Interventions: DRUG: All-Trans Retinoic Acid (ATRA) Dose 0|DRUG: All-Trans Retinoic Acid (ATRA) Dose -1|DRUG: All-Trans Retinoic Acid (ATRA) Dose 1
Sponsor: The Methodist Hospital Research Institute
Collaborators: Cancer Prevention Research Institute of Texas
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 42
Study Design: Allocation: NA|Intervention Model: SEQUENTIAL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-07-29
Completion Date: 2030-07
Locations: Houston Methodist Neal Cancer Center, Houston, Texas, 77030, United States

Summary:
This is a Phase IB/II trial that will investigate the safety, tolerability and efficacy of combination therapy using All-Trans Retinoic Acid (ATRA) with Carfilzomib based therapies in plasma cell myeloma also commonly referred as Multiple Myeloma (MM), in patients considered refractory to proteasome inhibitors (PIs). Multiple myeloma is an incurable clonal plasma cell disorder that comprises 10% of all hematologic malignancies. Over the past 30 years the global prevalence of multiple myeloma has risen to 126%, with 85% of diagnoses occurring in patients \>55 years of age. In the past 15 years, survival has improved considerably, which is attributed to the development of multiple different classes of medications, including proteasome inhibitors. Proteasome inhibitors are the foundation of many multiple myeloma treatments in both transplant eligible and ineligible patients for the past 2 decades. While proteasome inhibitors have improved both progression free survival (PFS) and overall survival (OS), many patients eventually develop disease progression arising from resistance to therapies. As a result, there is an unmet need to overcome resistance and find ways to enhance multiple myeloma sensitivity to proteasome inhibitor toxicity. Carfilzomib, a modified peptide epoxyketone that selectively targets intracellular proteasome enzymes, is approved in combination with dexamethasone in patients that have received ≥1 line of therapy or in combination. There are few studies assessing ways to enhance carfilzomib-mediated multiple myeloma toxicity. All-Trans Retinoic Acid (ATRA) is an oxidative metabolite of retinol (vitamin A) and plays an important role in the regulation of cellular proliferation and differentiation. In a recent pre-clinical study, ATRA was found to enhance sensitivity of carfilzomib-mediated apoptosis in vitro via an interferon beta (IFN-β) response pathway. In the clinical setting, ATRA is a well-tolerated drug that has shown little change in the rate of adverse events in early clinical trials with multiple myeloma. The investigators hypothesize that ATRA enhances sensitivity of multiple myeloma to carfilzomib therapy.

Primary Outcome Measures: Safety and Tolerability of ATRA in combination with Carfilzomib/ Dexamethazone and RP2D, To determine safety and tolerability of ATRA in combination with carfilzomib/dexamethasone and determine the recommended phase II dose (RP2D). The RP2D will be defined as the highest dose administered at which 6 patients are treated with with no more than 2 experiencing dose limiting toxicity (DLT) (determined by diseases progression, unacceptable toxicity, physician's discretion)., From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws from the study, whichever came first, assessed up to 7 months.
Secondary Outcome Measures: Efficacy of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma, Overall Response Rate (percentage of patients with complete response \[CR\] or partial response \[PR\]), as defined by International Myeloma Working Group (IMWG) criteria., From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever came first, assessed up to 7 months.|Duration of Response of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma, Duration of response rate as defined by the duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease., From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease, whichever came first, assessed up to 7 months after initial treatment date.|Number of participants with treatment-related adverse events as assessed by CTCAE v5.0, Toxicity and safety, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0., The dose limiting toxicity period begins from date of initial treatment until 21 days after.|Disease response as measured by serum, viable cryopreserved peripheral blood mononuclear cells, and bone marrow myeloma plasma cells., To characterize the disease response of the ATRA and carfilzomib/dexamethasone combination as measured by serum, viable cryopreserved peripheral blood mononuclear cells, and bone marrow myeloma plasma cells., Correlative samples will be collected at Baseline, Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1. Cycles are 28 days in length.