ATRA and Carfilzomib in Plasma Cell Myeloma Patients

NCT06536413 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: PRO00037762 (HMCC-HM22-001)
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Multiple Myeloma

Outcome Measures

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).

  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 (4)

• Efficacy of combination therapy of ATRA, Carfilzomib, and Dexamethasone in resistant Multiple Myeloma

  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

  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

  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.

  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.

Study Arms (1)

All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone

EXPERIMENTAL

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.

Drug: All-Trans Retinoic Acid (ATRA) Dose 0; Drug: All-Trans Retinoic Acid (ATRA) Dose -1; Drug: All-Trans Retinoic Acid (ATRA) Dose 1

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), Carfilzomib, and Dexamethasone

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.

All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Adequate organ function defined as:
• Hemoglobin ≥8 g/dL (baseline or after Peripheral Red Blood Cell transfusion), Platelet count \>75,000 and Absolute Neutrophil Count \>1000/ micro liter.
• Left Ventricular Ejection fraction ≥50%
• Creatinine Clearance ≥ 30 ml/min
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 × ULN
• Measurable disease requiring treatment defined as patients having one or more of the criteria below:
• Serum M protein ≥ 0.5 g/dL or
• Urine M-protein ≥ 200 mg/24 hours or
• Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum
• kappa lambda ratio.

You may not qualify if:

• 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).
• Pregnant or breast feeding
• Severe, active, recurrent, or intercurrent infection (viral, bacterial, fungal), or diagnosis of neutropenia and fever within one week of C1D1.
• History of Allogeneic hematopoietic cell transplantation or solid organ transplantation.
• Unstable angina pectoris, cardiac arrhythmia or \> New York Heart Failure association class II cardiac failure, defined as comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• Patient has a significant history of renal, neurologic (peripheral neuropathy), psychiatric, endocrinologic (diabetes mellitus), metabolic, immunologic, cardiovascular, pulmonary, hepatic disease, or significant social situation within the past 6 months that, in the opinion of the investigator, would impede his/her ability to fully participate in the study. For patients who have required an intervention for the above diseases within the past 6 months, a case-by-case discussion with the investigator must occur.
• On investigational therapies within 12 weeks of enrollment.
• Previous allergic reaction or intolerance to a proteasome inhibitor, including carfilzomib, bortezomib, or ixazomib.
• Or deemed unfit for the study on evaluation by Investigator.

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Cancer Prevention Research Institute of Texas: collaborator

Study Sites (1)

Houston Methodist Neal Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Related Publications (44)

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• Perel G, Bliss J, Thomas CM. Carfilzomib (Kyprolis): A Novel Proteasome Inhibitor for Relapsed And/or Refractory Multiple Myeloma. P T. 2016 May;41(5):303-7. No abstract available.

  PMID: 27162470 BACKGROUND

Related Links

• Bayesian Optimal Interval Designs for Phase I Clinical Trials
• Continued Improvement in Survival of Patients with Newly Diagnosed Multiple Myeloma (MM)

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Tretinoin

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors

Study Officials

• Sai Ravi Pingali, MD

  Houston Methodist Neal Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sai Ravi Pingali, MD

CONTACT

713-441-0566; spingali@houstonmethodist.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hematologist-Oncologist

Study Record Dates

• First Submitted: June 27, 2024
• First Posted: August 5, 2024
• Study Start: July 29, 2024
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2030
• Last Updated: April 8, 2025

Record last verified: 2025-03

Locations

US (1)