mercaptopurine

P2, N=80, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P3, N=1033, Active, not recruiting, University College, London | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2, N=98, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting

P2, N=0, Withdrawn, National Cancer Institute (NCI) | N=154 --> 0 | Not yet recruiting --> Withdrawn

P3, N=560, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Nov 2028 --> Nov 2034

P2, N=145, Not yet recruiting, St. Jude Children's Research Hospital

Reduction in 6-MP dose intensity was observed in patients with both rs73189762 and known no-function variants in the NUDT15 and TPMT genes. This finding supports the initial observation and suggests that 6-MP dose reduction might be beneficial for individuals with this genotype combination.

P2; Trial primary completion date: May 2028 --> May 2025

This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.

P2, N=53, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P2, N=171, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Jul 2024

P2, N=154, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Aug 2024

P3; Initiation date: Apr 2024 --> Jul 2024

P3, N=310, Suspended, Alliance for Clinical Trials in Oncology | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P1, N=130, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1

P3, N=1895, Active, not recruiting, National Cancer Institute (NCI)

The mercaptopurine dose intensity was considerably low in NUDT15 rs116855232 TT genotype compared with CT and CC. The dosage of mercaptopurine should be adjusted according to the NUDT15 genotype in pediatric patients with ALL.

P2, N=500, Recruiting, National University Hospital, Singapore

It is revealed that increased tetrahydrofolate consumption via histidine catabolism partially explains the re-sensitization ability of histidine. More importantly, this work provides fresh insights into that desuccinylation mediated by SIRT5 is an indispensable and synergistic requirement for histidine combination therapy against 6-MP resistance, which is undisclosed previously and demonstrates a rational strategy to ameliorate chemoresistance and protect pediatric patients with B-ALL from disease progression or relapse.

P2, N=171, Not yet recruiting, National Cancer Institute (NCI)

P3; Initiation date: Jan 2024 --> Apr 2024

P1/2, N=90, Recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Aug 2024 --> Aug 2025

P3, N=4997, Recruiting, Children's Oncology Group | Trial completion date: Jun 2029 --> Mar 2030 | Trial primary completion date: Jun 2029 --> Mar 2030

P1/2, N=27, Recruiting, The First Affiliated Hospital with Nanjing Medical University

Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model...Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.

P2, N=154, Not yet recruiting, National Cancer Institute (NCI)

We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism.

P1/2, N=48, Not yet recruiting, Haukeland University Hospital

P1/2, N=90, Recruiting, Tanja Andrea Gruber | Not yet recruiting --> Recruiting

P3, N=488, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Jun 2023

To test the possibility that HBB acted in generating a persistor cell phenotype, cell lines were placed in mercaptopurine and prednisone for 10-14 days at two different concentrations and counted throughout drug exposure and for an additional 10-14 days following removal of drug. The increased clonal potential upon overexpression of HBB could be indicative of the ability to reconstitute a tumor from a small subpopulation following treatment. Additionally, our data suggests that protein is not required for increased clonal growth leading us to hypothesize that catalytic RNA is responsible. We are also currently analyzing RNAseq data from the cell lines and will compare differential gene expression between the empty vector and HBB expressing cells to discover downstream pathways impacted by HBB.

Background: Severe myelosuppression secondary to thiopurines such as 6-Mercaptopurine (6-MP) in patients with acute leukemia undergoing maintenance therapy is frequently attributed to inherited genetic polymorphisms of Thiopurine Methyltransferase (TPMT); however, this is rare in the Asian population...positive B-ALL was treated with BFM + Ponatinib, and one High-risk APML was treated with the APML 4 protocol... The prevalence of NUDT15 polymorphisms was high in our study population. Based on a meta-analysis, the prevalence of NUDT15 in the South Indian population was 16. 5%, and in patients with adverse effects, the pooled prevalence of NUDT15 polymorphisms was 49.

P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026

P3, N=1033, Active, not recruiting, University College, London | Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1x10 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm). In future studies, we aim to apply this method to investigate TPMT activity in patients' leukocytes.

P3; N=680; Not yet recruiting; Sponsor:National Cancer Institute (NCI)

ACHM-025 was designed to improve drug specificity and minimize toxicity observed with currently used DNA alkylating agents, such as cyclophosphamide (CPM), a prodrug which is activated systemically via liver enzymes...For the consolidation therapy comparison, ACHM-025 (IP Days 0, 7) or CPM (IP Days 0, 7) combined with cytarabine (Ara-C; IP Days 0-4, 7-11) and 6-mercaptopurine (6MP; IP Days 0-4, 7-11) were assessed against a T-ALL PDX derived from a patient at relapse... ACHM-025 exerted profound in vivo efficacy against T-ALL PDXs and eradicated the disease in 7 aggressive T-ALL PDXs. ACHM-025 was significantly more effective than CPM both as a single agent and when used in combination with Ara-C/6MP. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo.

In this study, bortezomib and vorinostat were incorporated into an ALL chemotherapy backbone containing dexamethasone, mitoxantrone, and pegasparaginase during induction and reinduction chemotherapy cycles...Following induction intensification with cyclophosphamide, cytarabine, and mercaptopurine, 77% and 66% of all patients and KMT2Ar patients respectively were MRD negative at the time of count recovery...Although the study was not powered to evaluate outcomes, EFS and OS in KMT2Ar patients suggest a clinical signal worth pursuing given the low proportion of patients transplanted in first remission. The successor study, TINI 2 (NCT05848687), will build upon the bortezomib/vorinostat backbone by incorporating 2 cycles of blinatumomab and the menin inhibitor ziftomenib in combination with chemotherapy during reinduction.

Patients received mini-Hyper-CVD (mHCVD, cyclophosphamide 150mg/m2 q12h D1-3, dexamethasone 20mg daily D1-4, 11-14, and vincristine 2mg D1, 8 alternating with methotrexate (MTX) 250mg/m2 D1 & cytarabine 500mg/m2 q12h D2, 3) for up to 8 cycles. Eight doses of intrathecal (IT) MTX /cytarabine were given for CNS prophylaxis; patients with CNS disease had IT hydrocortisone, MTX, and cytarabine twice weekly till CNS clearance, then weekly x4. Eight doses of rituximab 375mg/m2 were given on D1, 8 of C1-4 if CD20 was ≥20% by flow cytometry...Ursodeoxycholic acid was given to all patients...Maintenance was initially with vincristine 2mg D1, prednisolone 50mg daily D1-5, 6-mercaptopurine 50mg BID & MTX 10mg/m2 weekly (POMP) for three years...Conclusion Older patients with ND Ph-negative ALL treated with mHCVD plus InO, with or without blina had excellent response rates and deep remissions. However, further adjustment of the regimen is needed, especially in patients ≥70 years.

Among 21 drugs, seven showed significant differences in overall LC50 between children and adults (P<0.05 after Bonferroni correction): children displayed higher sensitivity to asparaginase, prednisolone, mercaptopurine, daunorubicin, and inotuzumab, while adults showed higher sensitivity to dasatinib and nelarabine...In the KMT2A subtype, cases in C-a exhibited an over-representation of the KMT2A::AFF1 fusion, and resistance to mercaptopurine (P=0.029), prednisolone (P=0.0039), vincristine (P=0.046) and cytarabine (P=0.0037)...In conclusion, these studies have revealed important new insights into the pharmacogenomic basis of age-related differences in B-ALL treatment response. These results indicate that both inter- and intra-subtype heterogeneity contribute to inferior prognosis in adults with ALL, but also point to therapeutic opportunities to improve their outcomes.

Introduction: Current COG protocols for childhood ALL recommend increasing 6-mercaptopurine (6MP) and methotrexate (MTX) dose intensity (DI=prescribed therapy dose/ planned protocol dose) to >100% during maintenance for patients exhibiting inadequate myelosuppression (surrogate for systemic exposure to 6MP/MTX). High antimetabolite dose intensity in children with ALL who adhere to oral 6MP during maintenance therapy is associated with higher odds of hematologic toxicities as well as increased hazard of relapse. These findings inform clinicians about the issues related to dose escalation beyond protocol doses, especially among adherent patients.