Selumetinib + Azacitidine for Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Chicago
Must not be taking: MEK inhibitors
Disqualifiers: Active malignancy, Cardiac conditions, Ophthalmologic conditions, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This is a phase I, open-label, dose-escalation study to determine the MTD of selumetinib when combined with the standard dose of azacitidine. Treatment will begin within 28 days of screening procedures. Treatment will continue indefinitely, provided that the patient continues to derive benefit. A patient will be taken off study for reasons described in detail in section 3.12 including disease progression, unacceptable toxicity, inter-current illness, withdrawal of consent, or at the discretion of the investigator. Patients will be followed for 12 weeks after the last dose of study drug, until any study treatment related toxicities have stabilized, or until death. The total duration of the study is expected to be approximately 24 months.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot have received any anti-cancer therapy within 14 days before starting the study, except for hydroxyurea, which can be continued if needed.
What data supports the effectiveness of the drug Azacitidine for leukemia?
Azacitidine has been shown to be effective and safe in treating higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), including in older patients, by prolonging overall survival compared to conventional care. It is recommended as the first-line treatment for most patients with higher-risk MDS.
12345What safety data exists for Azacitidine in humans?
Azacitidine, used for myelodysplastic syndromes and acute myeloid leukemia, has shown adverse events like blood-related issues and infections in clinical trials.
678910What makes the drug Selumetinib + Azacitidine unique for treating leukemia?
The combination of Selumetinib and Azacitidine is unique because it combines a MEK inhibitor (Selumetinib) with a hypomethylating agent (Azacitidine), potentially offering a novel approach to targeting leukemia cells by affecting different pathways involved in cancer cell growth and survival.
1351112Eligibility Criteria
Adults with high-risk chronic blood cancers like Myeloid Leukemia, who haven't been treated with MEK inhibitors before, can join. They should have certain levels of disease severity and organ function, no recent cancer treatments except possibly hydroxyurea, and not be pregnant or breastfeeding. Participants must use effective birth control.Inclusion Criteria
My myelofibrosis is high risk, and I can't tolerate or didn't respond to JAK inhibitor therapy.
I can take care of myself and do some daily activities.
My liver tests are within the required range.
+9 more
Exclusion Criteria
Any uncontrolled concurrent illness that may put the patient at undo risk
Pregnant or lactating patients
I haven't taken any cancer treatments in the last 14 days, except hydroxyurea.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive azacitidine subcutaneously on days 1-7 and selumetinib on days 8-21 in 28-day cycles
Indefinite, as long as benefit is derived
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
Long-term follow-up
Participants are monitored for long-term outcomes and survival
Up to 100 months
Participant Groups
The trial is testing the combination of Selumetinib and Azacitidine to find the maximum tolerated dose. It's an early-phase study where patients receive treatment within 28 days after screening and continue indefinitely if beneficial, unless they experience unacceptable side effects or choose to leave.
1Treatment groups
Experimental Treatment
Group I: Azacitidine and selumetinibExperimental Treatment2 Interventions
Subjects will receive azacitidine subcutaneously on days 1-7. Selumetinib will be administered on days 8-21. Subjects will continue on this schedule in cycles of 28 days duration in the absence of disease progression.
Azacitidine is already approved in European Union, United States, Canada, Japan, Australia for the following indications:
🇪🇺 Approved in European Union as Vidaza for:
- Acute myeloid leukemia
- Chronic myelomonocytic leukemia
- Myelodysplastic syndromes
🇺🇸 Approved in United States as Vidaza for:
- Myelodysplastic syndromes
- Chronic myelomonocytic leukemia
🇨🇦 Approved in Canada as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
🇯🇵 Approved in Japan as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
🇦🇺 Approved in Australia as Vidaza for:
- Myelodysplastic syndromes
- Acute myeloid leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The University of ChicagoChicago, IL
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Who Is Running the Clinical Trial?
University of ChicagoLead Sponsor
References
Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]Azacitidine (Vidaza *) is approved in Europe for treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20-30% bone marrow (BM) blasts, and chronic myelomonocytic leukemia (CMML) with 10-29% BM blasts and no myeloproliferative syndrome (i.e.
Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed.
Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. [2022]Label="PURPOSE">Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (mIDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.
Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]Label="OBJECTIVE" NlmCategory="OBJECTIVE">Azacitidine (Vidaza® ) is the standard treatment for patients with higher-risk myelodysplastic syndromes (MDS) not eligible for allogeneic stem cell transplantation. In the noninterventional study PIAZA, we evaluated the effectiveness and safety of azacitidine treatment in 149 patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) in routine clinical practice.
Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties. In pivotal, international, phase 3 trials, subcutaneous azacitidine was an effective and well tolerated treatment in patients with higher-risk MDS or AML, including older patients with AML with >30 % BMB, with extensive evidence from the real-world setting confirming its efficacy and safety in these patient populations. Azacitidine is the only approved hypomethylating agent that has been shown to prolong overall survival compared with conventional care regimens and thus, it is recommended as the first-line hypomethylating agent for most patients with higher-risk MDS. Hence, azacitidine remains and important agent for use in the treatment of higher-risk MDS and AML, including in older patients with AML with >30 % BMB.
Characteristics of adverse event reporting of Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to the US Food and Drug Administration. [2023]BACKGROUND: On September 9, 2021, the US Food and Drug Administration (FDA) issued a drug safety communication and required revisions to the Boxed Warning for Xeljanz/Xeljanz XR (tofacitinib), Olumiant (baricitinib), and Rinvoq (upadacitinib) to include information about the risk of serious heart-related events, cancer, blood clots, and death. The Boxed Warning was based on a large safety randomized clinical trial of tofacitinib, but neither baricitinib nor upadacitinib has been studied in similar large safety clinical trials. OBJECTIVE: To evaluate characteristics of adverse event (AE) reporting of tofacitinib/XR, baricitinib, and upadacitinib to the FDA. METHODS: We analyzed the public FDA's Adverse Event Reporting System data to examine reported AEs that were related to any of the 3 drugs between January 1, 2019, and September 30, 2021. Both brand and generic names of these drugs were used to identify these AEs. Frequencies of AE reports were evaluated by patient demographics (age and sex), type of reporter, reporter region, seriousness, and reactions related to death, cardiovascular, cancer, and blood clots. Chi-square tests were used to compare the proportion of characteristics of AEs between these drugs at P < 0.05. RESULTS: We identified 56,833 AE reports of tofacitinib/XR, 2,318 reports of baricitinib, and 5,359 reports of upadacitinib. Higher proportions of patients reporting AEs for tofacitinib/XR were older and female than for baricitinib and upadacitinib. Higher proportions of tofacitinib/XR and baricitinib AEs were reported by health professionals than for upadacitinib. Higher proportions of upadacitinib AEs were in the United States and more serious than those of tofacitinib/XR and baricitinib AEs (all group and paired comparisons at P < 0.05). Regarding reactions, baricitinib AEs had highest proportions of death (7.2%) and cancer-related (4.1%) events, whereas tofacitinib/XR AEs had the highest proportions of cardiovascular-related (14.1%) and blood clot-related (14.8%) events. CONCLUSIONS: Although baricitinib and upadacitinib are in the same drug class as tofacitinib/XR, their risk of serious cardiovascular events, cancer, blood clots, and death might not be similar. Findings from this hypothesis-generating study suggest that there may be differential AEs between Janus kinase inhibitors, and therefore, future research for robust comparative safety is warranted.
Sunitinib adverse events in metastatic renal cell carcinoma: a meta-analysis. [2021]Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated survival benefit in patients with metastatic renal cell carcinoma (mRCC); however, significant adverse events (AEs) have been associated with its use. The significant variation in the reported incidences of AEs has prompted this meta-analysis to quantify the risk and explore associated predictors.
A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma. [2022]To provide an updated review of adverse events associated with sunitinib, pazopanib, bevacizumab, temsirolimus, axitinib, everolimus and sorafenib and their management.
Use of "Real-World" data to describe adverse events during the treatment of metastatic renal cell carcinoma in routine clinical practice. [2021]Insights into the experience of metastatic renal cell carcinoma (mRCC) patients are needed to optimize patient care. A retrospective, multicenter registry of mRCC patients treated at academic (Duke) and community (ACORN) practices was developed to fill this need. Treatment data were collected on 466 patients who received first-line therapy from 2007 to 2011. Clinically significant adverse events (AEs) were abstracted from medical records and compared to clinical trials. Two hundred and seventy patients received first-line therapy with sunitinib, 60 temsirolimus, 53 sorafenib, 25 pazopanib, and 58 "other." A total of 85.8 % of all patients experienced at least one AE: fatigue (56.7 %), vomiting (40.1 %), diarrhea (33.7 %), asthenia (32.8 %), and mucosal inflammation (20.8 %). When comparisons were made between patients >65 versus
Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database. [2023]Azacitidine is a useful drug for myelodysplastic syndromes and acute myeloid leukemia. In clinical trials, hematologic toxicity and infection have been observed as adverse events (AEs) of this drug. However, information on the time to onset of high risk AEs and subsequent outcomes, as well as differences in the frequency of AEs due to the route of administration is lacking. In this study, we investigated azacitidine-induced AEs comprehensively using the Japanese Adverse Event Reporting Database (JADER) published by the Pharmaceuticals and Medical Devices Agency, with disproportionate analysis of AE incidence trends, time to onset, and subsequent outcomes. In addition, we analyzed the differences in AEs by route of administration and the number of days until the occurrence of AEs and generated hypotheses.
Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]Azacitidine (Vidaza) is a pyrimidine nucleoside analogue of cytidine. Subcutaneous azacitidine was recently approved in the EU for the treatment of adults who are not eligible for haematopoietic stem cell transplantation and who have intermediate-2-risk or high-risk myelodysplastic syndromes (MDS) [according to International Prognostic Scoring System (IPSS) criteria], chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, or acute myeloid leukaemia (AML) with 20-30% blasts and multilineage dysplasia (according to the WHO classification). Subcutaneous azacitidine is the only drug shown to significantly prolong survival in patients with higher-risk MDS or WHO-defined AML, compared with conventional care (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). In addition, azacitidine is associated with a lower risk of AML progression and higher rates of complete remission, partial remission, haematological improvement and red blood cell (RBC) transfusion independence. Azacitidine has an acceptable tolerability profile; peripheral cytopenias are the most commonly occurring adverse event. Thus, azacitidine is a valuable option for the first-line treatment of patients with higher-risk MDS/AML.
Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. [2022]Azacitidine (Vidaza®) is a pyrimidine nucleoside analogue of cytidine. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), as well as summarizing its pharmacological properties. The randomized, multicentre Cancer and Leukemia Group B 9221 trial compared the efficacy of subcutaneous azacitidine with that of supportive care alone in patients with MDS fulfilling French-American-British (FAB) classification criteria. The overall response rate, the complete response rate and the complete plus partial response rate were significantly higher in patients receiving azacitidine than in those receiving supportive care alone. The randomized, open-label, multicentre AZA-001 trial compared the efficacy of subcutaneous azacitidine with that of conventional care in adults with higher-risk (i.e. International Prognostic Scoring System intermediate-2-risk or high-risk classification) MDS/AML. Prior to randomization, investigators preselected patients to the conventional care strategy considered most appropriate (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). The median duration of overall survival was significantly prolonged by 9.4 months in patients with higher-risk MDS receiving azacitidine versus those receiving conventional care. The survival benefit seen with azacitidine versus conventional care was maintained across various patient subgroups (e.g. in patients aged ≥75 years, in those who did not achieve complete remission and in patients with WHO-defined AML). The efficacy of subcutaneous or intravenous azacitidine was also shown in a noncomparative trial in Japanese patients with MDS fulfilling FAB classification criteria, and registry programmes in various countries support the efficacy of azacitidine in patients with MDS. Azacitidine was generally well tolerated in patients with MDS, including in the elderly. Across trials, peripheral cytopenias were the most commonly occurring adverse event in azacitidine recipients, with gastrointestinal adverse events (e.g. nausea, vomiting and diarrhoea) and injection-site reactions among the most commonly occurring non-haematological adverse events. In conclusion, azacitidine is an important agent for use in the treatment of patients with MDS/AML.