ATRA and Carfilzomib in Plasma Cell Myeloma Patients

Conditions

• Multiple Myeloma

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• All-Trans Retinoic Acid (ATRA) Dose 0 — DRUG
  Patients 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 — DRUG
  Patients 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 — DRUG
  Patients 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.

Study Details

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.

Key Dates

Start date

Jul 29, 2024

Status verified

Mar 2026

Primary completion

Jul 31, 2029

Completion

Jul 31, 2030

Study Design

Enrollment

42 participants (estimated)

Allocation

NA

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Arms

• Experimental: All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone
  Carfilzomib will be given at Cycle 1 (20 mg/m2 on Days 1, 70 mg/m2 on Days 8 and 15) and Cycles 2 - onward (70 mg/m2 on Days 1, 8, and 15) as a 30-minute intravenous (IV) infusion to evaluate tolerability to treatment. Dexamethasone will be given \[20 mg, PO/IV\] on the days of carfilzomib treatment. ATRA will be given for 3 weeks (21 days) out of every 4 weeks (28 days) up to a maximum of 24 weeks (6 cycles). Only for Cycle 1, patients will start oral ATRA 25 mg/m2 7 days prior to Cycle 1 Day 1 through Cycle 1 Day 21 for a total of 28 days of dosing. 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.

Primary Outcome Measure

Safety and Tolerability of ATRA in combination with Carfilzomib/ Dexamethazone and RP2D [ 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. ]

Central Contacts

• Sai Ravi Pingali, MD
  713-441-0566
  [email protected]

Locations (1)

Find similar trials in Houston, TX

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