Trial Title:
ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma
NCT ID:
NCT06351644
Condition:
Relapsed and/or Refractory Multiple Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Dexamethasone
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
This is a single arm optimal biologic dose finding phase I/II clinical trial.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
ON 123300
Description:
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.
Arm group label:
ON 123300 (NARAZACICLIB) + dexamethasone
Other name:
NARAZACICLIB
Intervention type:
Drug
Intervention name:
Dexamethasone
Description:
Weekly oral dexamethasone 20mg
Arm group label:
ON 123300 (NARAZACICLIB) + dexamethasone
Other name:
Decadron
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.
Detailed description:
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)
Criteria for eligibility:
Criteria:
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:
- 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
- ALT/AST ≤2 times upper limit of normal
- Total bilirubin ≤2 times upper limit of normal (<3 x ULN for congenital
hyperbilirubinemia states like Gilbert Syndrome)
- Corrected serum calcium ≤12.5mg/dL or free ionized calcium ≤6.5mg/dL
- ANC ≥1 x 109/L (prior growth factor permitted but must be without support 7
days before screening test)
- Hemoglobin ≥8g/dL (without blood transfusion in 7 days prior to test,
recombinant erythropoietin permitted)
- Platelets ≥50 x 109/L
- 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:
- 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.
- 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:
- Adequately treated non-melanoma skin cancer (basal cell or squamous cell skin
carcinoma) ≥1 year
- Cervical carcinoma in situ adequately treated ≥1 year
- Adequately treated Stage I or II cancer from which the subject is currently in
complete remission ≥2 years
- Any other cancer from which the subject has been disease-free for ≥ 3 years
- Males or females of childbearing potential who do not agree to practice 2
highly effective methods of contraception. Highly effective method of
contraception has a failure rate of less than 1% per year when used
consistently and correctly, and agree to remain on a highly effective method of
contraception from the time of signing the informed consent form through 90
days after the last dose of study drug. For women, examples of highly effective
contraceptives include A) user independent methods: 1. implantable progesterone
only hormonal contraception 2. intrauterine device/intrauterine hormone
releasing system 3. vasectomized partner B) user dependent methods: 1. combined
estrogen and protestor hormonal contraception (oral intravaginal or
transdermal) 2. progesterone only hormone contraception (oral or injectable).
For men, highly effective barrier method of contraception include - condom with
spermicidal foam/gel/film/cream/suppository from the time of signing the ICF
until 90 days after receiving the last dose of treatment. Intercourse with a
pregnant woman must involve the use a condom. Women and men must agree not to
donate eggs or sperm while on the study drug or up to 90 days after the last
dose of drug.
- Uncontrolled, untreated or active infections, including but not limited to HIV,
Hepatitis B, Hepatitis C, tuberculosis.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Mount Sinai Health System
Address:
City:
New York
Zip:
10029
Country:
United States
Status:
Recruiting
Contact:
Last name:
Adriana Rossi, MD
Contact backup:
Last name:
Katherine Vandris
Email:
Katherine.Vandris@mssm.edu
Investigator:
Last name:
Adriana Rossi
Email:
Principal Investigator
Start date:
September 19, 2024
Completion date:
June 5, 2028
Lead sponsor:
Agency:
Adriana Rossi
Agency class:
Other
Source:
Icahn School of Medicine at Mount Sinai
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06351644
