A Phase I/II Study to Assess the Safety and Tolerability of the Combination of Oral ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma
A Phase I/II Study to Assess the Safety and Tolerability of the Combination of Oral ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma
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.
ON 123300 (NARAZACICLIB) is a multi-targeted kinase inhibitor targeting cyclin-dependent kinases (CDK) 4 and 6, AMPK-related protein kinase 5 (ARK5), colony-stimulating factor 1 receptor (CSF1R), tyrosine-protein kinase kit (c-Kit), and fms-like tyrosine kinase (FLT)3 at low nM concentrations that can arrest the cell cycle and thus block tumor cell proliferation and inhibit the growth of cancer cells. As an apoptotic and antiproliferative agent, ON 123300 (NARAZACICLIB) modulates the levels and activities of regulatory proteins of the cell cycle, including cyclin D1 and inhibits retinoblastoma (Rb) protein binding. ON 123300 (NARAZACICLIB) inhibits cancer cell growth and suppresses deoxyribonucleic acid (DNA) synthesis by preventing CDK-mediated G1-S phase transition, followed by tumor cell death by induction of mitochondria-mediated apoptosis.
ON 123300 (NARAZACICLIB) is being investigated for potential treatment of patients with solid tumors and hematologic malignancies as a single agent and in combination with other anticancer therapies. This is supported by antiproliferative and cytotoxic effects that have been observed with ON 123300 (NARAZACICLIB) in a wide variety of malignant human cell lines in cell-based assay systems, and in mouse xenograft models of breast cancer, colon cancer, mantle cell lymphoma, multiple myeloma, and melanoma. Based on the nonclinical efficacy models, Onconova intends to study patients with solid tumors and hematologic malignancies.
As of the data cutoff date 05 January 2022, Onconova-sponsored Study 19-01 (United States [US]) is an ongoing exploratory Phase 1 dose escalation study to assess the safety, tolerability, and pharmacokinetics (PK) of ON 123300 (NARAZACICLIB) capsules administered orally as escalating daily doses in patients with advanced cancer relapsed or refractory to at least 1 prior line of therapy.
Enrolled patients 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. Treatment would be discontinued for Grade 4 or above toxicity. For Grade 2-3 toxicity, will challenge with the lower dose first before discontinuing. (Grading of toxicities per CTCAE version 5.0)
Inclusion Criteria:
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:
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
No active infections (including but not limited to HIV, Hepatitis B, Hepatitis C, tuberculosis) or chronic health conditions which may interfere in the study in the opinion of the investigator.
HIV: undetectable HIV viral load and CD4 counts >200 for >6 months on continuous antiretroviral therapy may be screened.
Hepatitis B: If HbcAb positive and HBV PCR-, may be screened
Hepatitis C: if completed anti-viral therapy and in sustained virological response >6 months, may be screened
Tuberculosis: Quantiferon or skin prick test positive but with negative chest imaging
(CXR or CT) and asymptomatic, may be screened
Note: A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a
combination of several drugs, or a planned sequential therapy of various regimens3.
A treatment is considered a new line of therapy if any one of the following three conditions are met:
Start of a new line of treatment after discontinuation of a previous line: if the treatment regimen is discontinued for any reason, and a different regimen is started, it should be considered a new line of therapy. A regimen is considered to have been discontinued if all the drugs in that given regimen have been stopped. The regimen is not considered to have been discontinued if some of the drugs of the regiment, but not all, have been discontinued.
The unplanned addition or substitution of one or more drugs in an existing regimen: Unplanned addition of a new drug, or switching to a different drug, or combination of drugs due to any reason, is considered a new line of therapy.
Stem cell transplant (SCT): In patients undergoing >1 SCT, except in the case of a planned tandem SCT with a predefined interval such as 3 months, each SCT (autologous or allogeneic, should be considered a new line of therapy, regardless of whether the conditioning regime used is the same or different.
Exclusion Criteria:
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:
Following cardiac conditions:
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.
Active pregnancy or breastfeeding females
Known chronic alcohol or drug abuse
Lack of capacity to sign consent and/or participate in the trial
Any other condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents.
Any altered mental status or any psychiatric condition that would interfere with the understanding of the informed consent or limit compliance with study requirements.
Prior or concurrent malignancy, except for the following:
Uncontrolled, untreated or active infections, including but not limited to HIV, Hepatitis B, Hepatitis C, tuberculosis.