Onvansertib for Chronic Myelomonocytic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Mayo Clinic
Must not be taking: Strong CYP3A4 inhibitors
Disqualifiers: Active CNS disease, Heart failure, others
No Placebo Group
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests onvansertib, a drug taken by mouth, for patients with chronic myelomonocytic leukemia that has returned or doesn't respond to other treatments. Onvansertib blocks an enzyme needed for cancer cells to grow, aiming to stop their growth and cause them to die.
Will I have to stop taking my current medications?
The trial allows the continuation of hydroxyurea for the first 28 days, but other anticancer chemotherapy or biologic therapy must be stopped at least 2 weeks before joining the trial. If you are taking hydroxyurea beyond the first cycle, it must be discussed with the study's Sponsor/Principal Investigator.
What makes the drug Onvansertib unique for treating Chronic Myelomonocytic Leukemia?
Onvansertib is unique because it is a novel treatment option for Chronic Myelomonocytic Leukemia, a condition with limited standard treatments. It works by targeting specific proteins involved in cancer cell division, offering a new approach compared to existing therapies.
12345Eligibility Criteria
Adults with chronic myelomonocytic leukemia that's returned or isn't responding to treatment, who've had specific prior treatments and have a certain level of health (good organ function, no severe concurrent illnesses). They must be able to consent, complete questionnaires, provide samples for research, and agree to use effective contraception.Inclusion Criteria
Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (obtained =< 14 days prior to pre-registration)
Platelet count >= 20,000/mm^3 (obtained =< 14 days prior to pre-registration)
Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
+13 more
Exclusion Criteria
I have a type of blood disorder that is not CMML.
Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: Pregnant persons, Nursing persons, Persons of childbearing potential who are unwilling to employ adequate contraception, Increased risk of Torsade des Pointes (TdP) defined as follows: A marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval > 480 msec [CTCAE Grade >= 2] using Fredericia's QT correction formula), A history of additional risk factors for TdP (eg. heart failure, family history of long QT syndrome)
I have been treated with a PLK1 inhibitor before.
+16 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Dose-escalation
Patients receive onvansertib orally once daily to determine the maximum tolerated dose
8-12 weeks
Weekly visits (in-person) for dose adjustments and monitoring
Dose-expansion
Patients continue receiving onvansertib at the determined dose to evaluate efficacy and safety
Up to 4 years
Monthly visits (in-person) for monitoring and assessments
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
2 visits (in-person)
Participant Groups
The trial is testing Onvansertib's safety and optimal dose. It involves collecting biological specimens and performing bone marrow biopsies plus ultrasound imaging. Onvansertib targets an enzyme in cancer cells to stop their growth and cause cell death.
1Treatment groups
Experimental Treatment
Group I: Treatment (onvansertib)Experimental Treatment4 Interventions
Patients receive onvansertib PO QD on study. Patients also undergo bone marrow aspiration and biopsy, collection of blood samples, and ultrasound imaging during screening and throughout the trial.
Onvansertib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Onvansertib for:
- Acute Myeloid Leukemia (AML) - Orphan Drug Designation
🇪🇺 Approved in European Union as Onvansertib for:
- Acute Myeloid Leukemia (AML) - Orphan Drug Designation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in RochesterRochester, MN
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. [2022]Chronic myeloid leukemia (CML) is caused by reciprocal translocation between chromosomes 9 and 22, forming BCR-ABL, a constitutively activated tyrosine kinase. Imatinib mesylate, a selective inhibitor of BCR-ABL, represents current frontline therapy for CML; however, emerging evidence suggests that drug resistance to imatinib may limit its long-term success. To improve treatment options, dasatinib (BMS-354825) was developed as a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. To date, dasatinib has shown promising anti-leukemic activity in preclinical models of CML and in phase I/II clinical studies in patients with imatinib-resistant or imatinib-intolerant disease.
Olverembatinib in chronic myeloid leukemia. [2022]The introduction of tyrosine kinase inhibitors (TKIs) represents a new era in the management of chronic myeloid leukemia (CML). Despite their long clinical success, point mutations emerging before or during TKI treatment remain an obstacle for several cases. T315I is one of these point mutations in the tyrosine kinase domain of BCR::ABL1. It is a major cause of resistance against first- and second-generation TKIs and therefore lowers survival rates of a small group of patients. Olverembatinib (HQP-1351, formerly GZD-824) is a novel, orally active TKI, which acts through targeting the ATP-binding site of the BCR::ABL1 tyrosine kinase. In recent studies, olverembatinib appears to be an effective and safe treatment option for CML patients harboring T315I mutation. This article mainly focuses on the efficacy and safety data of olverembatinib along with other clinically available and potentially active drugs against T315I-mutated CML.
Cost-effectiveness of dasatinib versus high-dose imatinib in patients with Chronic Myeloid Leukemia (CML), resistant to standard dose imatinib--a Swedish model application. [2015]Chronic myeloid leukemia (CML) is a progressive disease, consisting of three phases, chronic, accelerated and blast phase. Treatment with imatinib has demonstrated high response rates and improved prognosis for patients with CML. The emergence of imatinib resistance is a major concern. Dasatinib is an oral kinase inhibitor of BCR-ABL that has been developed for treating CML patients across all phases of disease who are resistant or intolerant to imatinib.
Managing resistance in chronic myeloid leukemia. [2017]Chronic myeloid leukemia (CML) is a myeloproliferative disorder that affects 5000 new patients per year in the United States. Prior to 10 years ago, durable remission was rare and patients often underwent bone marrow transplantation with substantial morbidity and mortality. Fortunately, CML has been the epicenter of exciting advances in cancer therapy with the discovery of the Bcr-Abl gene fusion and the subsequent development of imatinib mesylate, a small molecule tyrosine kinase inhibitor, to target the kinase activity of the bcr-abl protein product. Despite unprecedented durability for complete hematologic, cytogenetic, and molecular responses seen with front-line imatinib therapy, many patients require alternative therapy because of drug intolerance, suboptimal response, primary resistance, secondary resistance, or progression to advanced phase disease. Further, up to 5% of patients present with advanced disease that does not sustain a durable response to tyrosine kinase inhibitors. Thus, up to one third of CML patients require alternate therapy. Chronic myeloid leukemia has become an exemplary model system for understanding molecular targeting and overcoming mechanisms of drug resistance. This review will discuss potential mechanisms of resistance and ongoing research into novel targets and agents for CML resistant to standard of care.
Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. [2022]Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm, driven by the KIT D816V mutation in >90% of patients. Avapritinib, a potent, highly selective D816V-mutant KIT inhibitor, is approved for treatment of adults with AdvSM by the US Food and Drug Administration, regardless of prior therapy, and the European Medicines Agency for patients with prior systemic therapy, based on EXPLORER (#NCT02561988; clinicaltrials.gov) and PATHFINDER (#NCT03580655; clinicaltrials.gov) clinical studies. We present latest pooled efficacy and safety analyses from patients who received ≥1 systemic therapy prior to avapritinib in EXPLORER/PATHFINDER. Overall response rate in response-evaluable patients (n = 31) was 71% (95% confidence interval: 52% to 86%; 22/31), including 19% (6/31) with complete remission (CR)/CR with partial recovery of peripheral blood counts (CRh). Median time to response was 2.3 months, median time to CR/CRh was 7.4 months, and median duration of response (DOR) was not reached. Reductions ≥50% in bone marrow mast cell infiltration (89%), KIT D816V variant allele fraction (66%), serum tryptase (89%), and reductions ≥35% in spleen size (70%) occurred in most patients. Median OS was not reached (median follow-up 17.7 months). Avapritinib was effective in all AdvSM subtypes, regardless of number/type of prior therapies or poor prognostic somatic mutations. Treatment-related adverse events (TRAEs) were observed in 94% of patients, most commonly grade 1/2; 57% had TRAEs of at least grade 3; 81% remained on treatment at 6 months. Avapritinib in adults with AdvSM who received prior systemic therapy was generally well tolerated, with high response rates regardless of prior systemic therapy.