ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

NCT06351644 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: STUDY-24-00244
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Multiple myeloma (MM) is a malignancy characterized by uncontrolled proliferation of plasma cells for which there is an urgent and unmet need to develop new, effective therapeutics. Onconova Therapeutics has developed a first-in-class oral inhibitor of CDK4 and ARK5 ON 123300 (NARAZACICLIB) which shows potent anti-myeloma activity in vitro and in vivo in preclinical models, and is undergoing evaluation in Phase 1-2 trials worldwide. In this study, the researchers will test the safety and preliminary efficacy of inhibition of CDK4 and ARK5 by ON 123300 (NARAZACICLIB) in combination with dexamethasone in myeloma patients in a Phase I/II clinical trial.

Conditions

Relapsed and/or Refractory Multiple Myeloma

Outcome Measures

Primary Outcomes (3)

• Phase I: The optimal biological dose (OBD) of the combination of ON 123300 (NARAZACICLIB) and dexamethasone

  Phase I: Determination of the optimal biological dose (OBD) of the combination of ON 123300 (NARAZACICLIB) and dexamethasone in relapsed MM patients - defined as the lowest safe dose with the highest rate of efficacy measured by the overall response rate (ORR).

  within first 2 cycles of treatment (1 cycle = 28 days)

• Phase I: Dose-Limiting Toxicity (DLT) rate

  Phase I: The DLT rate (within 2 cycles of combination therapy) at the OBD as well as all dose levels initiated. Toxicity is reached when a patient experiences a dose limiting toxicity (DLT) within 2 cycles of combination therapy. DLTs will be recorded and graded according to standard NCI CTC criteria.

  within first 2 cycles of treatment (1 cycle = 28 days)

• Phase II: Overall response rates (ORR)

  Phase II: Overall response rates (ORR) is achieved when a patient has partial response (PR) or better at 2 cycles of combination therapy according to IMWG criteria. ORR will be estimated as the proportion of patients that achieve PR or better according to IMWG criteria after 2 cycles of treatment among all patients enrolled in the study that were given at least one dose of ON 123300 (NARAZACICLIB).

  after 2 cycles of therapy (1 cycle = 28 days)

Secondary Outcomes (10)

• Number of Adverse events of Special Interest (AESI)

  Evaluated continuously until end of study, for a maximum up to 2 years after enrollment

• HbA1c

  Per Cycle/Every 28 Days for a maximum up to 2 years after enrollment

• Fasting insulin levels

  Per Cycle/Every 28 Days for a maximum up to 2 years after enrollment

• Lipid profiles

  Per Cycle/Every 28 Days for a maximum up to 2 years after enrollment

• Free fatty acids

  Per Cycle/Every 28 Days for a maximum up to 2 years after enrollment

Study Arms (1)

ON 123300 (NARAZACICLIB) + dexamethasone

EXPERIMENTAL

Participants will continue 28-day cycles of ON 123300 (NARAZACICLIB) + dexamethasone as long as the drug shows anti-myeloma activity with a disease response ≥PR (PR, VGPR, CR) and the patient does not exhibit any DLTs and the study is open. Patients will continue the regimen until disease progression/intolerable toxicity/death, withdrawal OR for a maximum up to 2 years after enrollment.

Drug: ON 123300; Drug: Dexamethasone

Interventions

ON 123300 DRUG

dosed starting at 200 mg of ON 123300 (NARAZACICLIB) daily for four weeks. Dose levels will be 160 mg, 200 mg, 240 mg, 280 mg, 320 mg. Treatment cycles will be four weeks long. ON 123300 (NARAZACICLIB) is available as an oral formulation ON 123300 (NARAZACICLIB) monolactate capsules (containing 40 mg free base) and is provided in 120 cc high-density polyethylene (HDPE) bottles with child-resistant closures containing 30 hard gelatin capsules. ON 123300 (NARAZACICLIB) is also available in tablet form. The tablets are 40 mm (oblong) and 120 mg (round). Either form, capsules or tablets, may be used in this study.

Also known as: NARAZACICLIB

ON 123300 (NARAZACICLIB) + dexamethasone

Dexamethasone DRUG

Weekly oral dexamethasone 20mg

Also known as: Decadron

ON 123300 (NARAZACICLIB) + dexamethasone

Eligibility Criteria

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

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Able to provide a signed Written Informed Consent: Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care
• Male or female patients ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Symptomatic MM having progressed on ≥2 prior line of therapies - including 1 proteasome inhibitor (bortezomib, carfilzomib etc.), 1 immunomodulatory drug (lenalidomide, pomalidomide, thalidomide etc.), and 1 CD38 targeting monoclonal antibody (daratumumab, isatuximab) either as monotherapy or in combination. Refractoriness (progression while on therapy or ≤60 days after discontinuation of therapy) to prior line of therapy is not required.
• Subjects who received BCMA-targeted immune-effector therapies like CAR-T cells and/or bispecific antibodies prior can be enrolled provided they are ≥60 days out of the treatment.
• Subjects must not be candidates for treatment regimens known to provide clinical benefit to be eligible for this study.
• Subjects must have measurable disease defined by at least 1 of the following 4 measurements:
• Serum M-protein \> 0.5 g/dL or Urine M-protein \> 200 mg/24 hours
• Light chain MM without measurable disease in serum or urine: Serum immunoglobulin free light chain assay: involved free light chain level \>10 mg/dL (\> 100 mg/L) provided the serum free light chain ratio is abnormal
• For oligo/non-secretory myeloma, measurable by standard imaging (PET/CT or MRI) ± bone marrow biopsy if myeloma biomarkers are inconclusive or non-contributory
• Able to swallow and absorb oral medication
• All previous therapies for cancer, including radiotherapy, major surgery and investigational therapies discontinued for ≥ 14 days before study entry, and all acute effects of any prior therapy resolved to baseline severity or Grade ≤ 1 Common Terminology Criteria for Adverse Events (CTCAE v5.0) excluding alopecia or fatigue.
• Adequate organ or marrow function
• CrCl (Cockcroft-Gault equation) ≥ 45ml/min

You may not qualify if:

• Active plasma cell leukemia at screening (\>5% plasma cells by standard differential), Waldenstroms macroglobulinemia, PEOMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes), known active or prior CNS involvement or exhibits meningeal signs (extradural skull or spinal mass causing extrinsic mass effect is not excluded) or clinically significant amyloidosis.
• History of allogeneic hematopoietic cell transplantation (HCT), or other cellular therapy product, within 60 days.
• Inability to tolerate oral medication, presence of poorly controlled gastrointestinal disease, or dysfunction that could affect study drug absorption including but not limited to:
• Diarrhea \> Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
• Following cardiac conditions:
• New York Heart Association (NYHA) stage III or IV congestive heart failure
• myocardial infarction or coronary artery bypass graft (CABG) \<6 months prior to enrollment
• History of clinically significant ventricular arrhythmia or unexplained syncope not believed to be vasovagal in nature or due to dehydration
• History of severe nonischemic cardiomyopathy e. Impaired cardiac function (LVEF \<45%) as assessed by echocardiogram or multi gated acquisition (MUGA) scan.
• Stroke or seizure within 6 months of enrollment
• Are at risk for Torsades de pointes (TdP): Patients who have a marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval \>470 msec) using Fredericia's QT correction formula, or who have a history of additional risk factors for TdP (eg, heart failure, hypokalemia, family history of Long QT Syndrome), or who are currently taking medications that prolong the QT/QTc interval.
• Are currently taking or within 5 half-lives of taking strong inducers and inhibitors of cytochrome P450 enzyme (CYP) 2C8 and CYP3A4.
• Have had major surgery within 14 days prior to screening to allow for postoperative healing of the surgical wound and site(s).
• Have received recent (within 28 days prior to screening) live attenuated vaccines.

Sponsors & Collaborators

• Adriana Rossi: lead

Study Sites (1)

Mount Sinai Health System

New York, New York, 10029, United States

Location

MeSH Terms

Interventions

ON123300; Dexamethasone; Calcium Dobesilate

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Adriana Rossi, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

• Samir Parekh, MBBS

  Icahn School of Medicine at Mount Sinai

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Model Details: This is a single arm optimal biologic dose finding phase I/II clinical trial.

Study Record Dates

• First Submitted: April 2, 2024
• First Posted: April 8, 2024
• Study Start: October 2, 2024
• Primary Completion: April 28, 2025
• Study Completion: April 28, 2025
• Last Updated: November 12, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: Beginning 9 months and ending 36 months following article publication.
• Access Criteria: Researchers who provide a methodologically sound proposal. To achieve aims in the approved proposal. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at (Link tbd).

Locations

US (1)