ATRA and Carfilzomib in Plasma Cell Myeloma Patients
ConditionMultiple Myeloma
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorThe Methodist Hospital Research Institute
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age ≥ 18 years with relapsed/refractory multiple myeloma documented according to International Myeloma Working Group (IMWG) criteria.
Previously treated with at least three lines of therapy which would include Immunomodulatory drugs (IMiDs), Proteosome inhibitors (including carfilzomib), anti-CD 38 antibodies and failed to achieve a minor response after completing at least 2 cycles of carfilzomib-based therapy or are relapsed while on therapy.
Patient or legal guardian voluntarily can sign informed consent.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
Disqualifiers
Non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL M-protein in serum, <200 mg/24-hour urine M-protein, or disease only measured by serum free light chain.
Plasma Cell Leukemia (Previously treated Plasma Cell Leukemia can be included per PI discretion)
Concurrent light chain amyloidosis
Central nervous system involvement (patients with known brain metastases have poor prognosis and often develop progressive neurologic dysfunction that may confound the evaluation of neurologic and other Adverse Events while on ATRA).
Trial design
Design model
Sequential
Treatments tested in this trial
All-Trans Retinoic Acid (ATRA) Dose 0
DrugPatients will receive oral ATRA 25 mg/m2 per day in two divided doses with carfilzomib-based regimens. Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study. If a dose limiting toxicity occurs at 25 mg/m2, then the dose will be reduced by 50% to 15 mg/sq m daily in two divided doses.
All-Trans Retinoic Acid (ATRA) Dose -1
DrugPatients will receive oral ATRA 15 mg/m2 per day in two divided doses with carfilzomib-based regimens. Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.
All-Trans Retinoic Acid (ATRA) Dose 1
DrugPatients will receive oral ATRA 45 mg/m2 per day in two divided doses with carfilzomib-based regimens. Eligible patients will enter the study in cohorts of two with the first cohort treated at Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16 evaluable patients will be recruited and in the second phase a minimum of 26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be recruited in the study.
Treatment groups
42 Participants
are divided into 1 treatment groupGroup A: All-Trans Retinoic Acid (ATRA), Carfilzomib, and DexamethasoneExperimental treatment 3 interventions
Trial outcomes
Primary outcomes
1
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).
Time frame
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 outcomes
1
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.
Time frame
From date of initial treatment until progression, unacceptable toxicity, treating physician's discretion, or patient withdraws, whichever came first, assessed up to 7 months.2
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.
Time frame
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.3
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.
Time frame
The dose limiting toxicity period begins from date of initial treatment until 21 days after.4
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.
Time frame
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.Sponsors and contacts
Click on the lead sponsor to view all of their trials.
The Methodist Hospital Research Institute
Lead sponsor
Cancer Prevention Research Institute of Texas
Collaborator
Source ClinicalTrials.gov