sapacitabine (CYC682) / Daiichi Sankyo - LARVOL DELTA

Olaparib + Sapacitabine in BRCA Mutant Breast Cancer (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Oct 2025 ➔ Oct 2026

Trial completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2

A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated metastatic breast cancer. (PubMed, Clin Cancer Res) - "Sapacitabine with olaparib produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of response in some patients suggest possible combinatorial benefit. Further exploration of olaparib with different sapacitabine schedules or substitution of a PARP1-selective inhibitor to potentially decrease hematological toxicity is warranted."

Journal • P1 data • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD

Olaparib + Sapacitabine in BRCA Mutant Breast Cancer (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Jun 2025 ➔ Oct 2025

Trial completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2

Construction and clinical significance of prognostic risk markers based on cancer driver genes in lung adenocarcinoma. (PubMed, Clin Transl Oncol) - "This study identified 11 effective biomarkers, DE-CDGs, which can predict LUAD prognosis and explored the biological significance of CDGs in LUAD prognosis, immunotherapy, and treatment."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Genome Mining and Genetic Manipulation Reveal New Isofuranonaphthoquinones in Nocardia Species. (PubMed, Int J Mol Sci) - "CS682 and to evaluate their potential therapeutic applications...In addition, a flexible methyltransferase substrate, ThnM3, was found to be involved in terminal methylation of NOC-IBR1, which was confirmed by in vitro enzyme assays. Thus, this study supports the importance of genome mining and genome editing approaches for exploring new specialized metabolites in a rare actinomycete called Nocardia."

Journal • Oncology

Efficacy Study of Oral Sapacitabine to Treat Acute Myeloid Leukemia in Elderly Patients (clinicaltrials.gov) - P2 | N=105 | Completed | Sponsor: Cyclacel Pharmaceuticals, Inc. | N=408 ➔ 105

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

New Hydroxyphenylacetic Acids and α-Pyrone Derivative from the Deep-Sea Cold Seep Sediment-Derived Fungus Penicillium corylophilum CS-682. (PubMed, Chem Biodivers) - "Their structures and stereo configurations were determined by detailed spectroscopic analysis of NMR and MS data, chiral HPLC analysis, J-based configuration analysis, and quantum chemical calculations of ECD, specific rotation, and NMR (with DP4+ probability analysis). Compound 3 showed inhibitory activity against some strains of pathogenic bacteria."

Journal

Functional characterization of a naphthalene-O-methyltransferase from Nocardia sp. CS682. (PubMed, Enzyme Microb Technol) - "The products were confirmed using high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopic analyses. Therefore, this study is the first to amplify, express the thnM3 (gene), and functionally characterize theThnM3, which exhibits the regioselective modifications of 1,8-dihydroxynaphthalene."

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Identification of 1,3,6,8- Tetrahydroxynaphthalene Synthase (ThnA) from Nocardia sp. CS682. (PubMed, J Microbiol Biotechnol) - "In this study, we report the heterologous expression of the type III polyketide synthase thnA in S. lividans TK24 and the identification of THN production in a mutant strain. We also compared the transcription level of thnA in S. lividans TK24 and S. lividans pIBR25-thnA and found that thnA was only transcribed in the mutant."

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Advances in Breast Cancer From AACR 2023 (Medscape) - "Notable advances in breast cancer, presented at the American Association for Cancer Research Annual Meeting 2023, are discussed by Dr Kathy Miller....Dr Miller next discusses the combination of olaparib and the novel agent sapacitabine in BRCA-mutated breast cancer. Although hematologic toxicities were an issue in this small trial, some patients experienced prolonged benefits."

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A phase Ib study of sapacitabine (sapa) and olaparib (ola) in patients (pts) with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer (MBC) (AACR 2023) - "Sapa/ola produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of 3+ years in 2 pts suggest possible combinatorial benefit. Further exploration with different sapa schedules or with substitution of a PARP1-selective inhibitor to decrease hematologic toxicity is warranted."

Clinical • Metastases • P1 data • Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • FANCD2 • HER-2 • MRE11A • PIK3CA • PTEN • RAD51

Prediction of Early Mortality with Non-Intensive Acute Myeloid Leukemia (AML) Therapies: Analysis of 1336 Patients from MRC/NCRI and SWOG (ASH 2021) - "Treatments included: Low dose Ara-C (LDAC) alone, sapacitabine alone and LDAC in combination with vosaroxin, tosedostat or ganetespib (MRC/NCRI); Azacytidine (AZA) alone, tipifarnib alone, and AZA in combination with mylotarg, midostaurin, and nivolumab (SWOG). Our ability to predict early death in older patients treated with lower intensity AML therapies is limited with routinely available clinical variables. Inclusion of cytogenetic risk, FLT3-ITD, and NPM1 mutation status minimally improved the prognostic accuracy as did some of the QLQ-C30 subscales. Our data highlight the difficulties in predicting outcomes with non-intensive AML therapy with routinely available baseline clinical information."

Clinical • Acute Myelogenous Leukemia • Anorexia • Fatigue • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • NPM1

A Phase I/II Study of Sapacitabine and Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia (ASH 2021) - "Previous studies of sapacitabine alone and alternating with decitabine (DAC) have demonstrated activity in acute myeloid leukemia (AML). In a heavily pretreated population of patients with R/R AML, the combination of sapacitabine and VEN was well tolerated and feasible to be administered as a completely oral, outpatient regimen. Most patients had multiple prior cycles of nucleoside analogue containing regimens and the only notable responder had only prior DAC. Further study of this well-tolerated combination in less heavily pretreated patients may be considered."

IO biomarker • P1/2 data • Acute Myelogenous Leukemia • Dermatology • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Neutropenia • Pneumonia • Renal Disease • Respiratory Diseases • Septic Shock • ASXL1 • NRAS • TET2 • TP53 • WT1

Cyclacel Pharmaceuticals Reports Third Quarter 2022 Financial Results and Provides Business Update (GlobeNewswire) - "The Company will not be pursuing further development of sapacitabine and has advised Daiichi Sankyo Co., Ltd., the licensor, that it wishes to terminate their license agreement for commercial reasons with the termination expected to be effective as of March 23, 2023."

Discontinued • Licensing / partnership • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

A Randomized Phase II Study of Oral Sapacitabine in Patients With Advanced Cutaneous T-cell Lymphoma (clinicaltrials.gov) - P2; N=16; Terminated; Sponsor: Cyclacel Pharmaceuticals, Inc.; N=32 ➔ 16

Clinical • Enrollment change • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Functional Characterization of a Regiospecific Sugar-O-Methyltransferase from Nocardia. (PubMed, Appl Environ Microbiol) - "strain CS682, was analyzed and functionally characterized...We demonstrated that ThnM1 is a promiscuous enzyme with regiospecific activity at the 2'-OH of rhamnose. As regiospecific methylation of sugars by chemical synthesis is a challenging step, ThnM1 may fill the gap in the potential diversification of natural products by methylating the rhamnose moiety attached to them."

Journal • Oncology

Olaparib + Sapacitabine in BRCA Mutant Breast Cancer (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting | Phase classification: P1/2 ➔ P1 | N=64 ➔ 10

Enrollment change • Enrollment closed • Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2

A Study of Oral Sapacitabine and Oral Seliciclib in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1; N=103; Completed; Sponsor: Cyclacel Pharmaceuticals, Inc.; Recruiting ➔ Completed

Clinical • Trial completion • Breast Cancer • Oncology • Solid Tumor • BRCA

Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells. (PubMed, J Exp Clin Cancer Res) - "Intrinsic and acquired resistance to CNDAC and related nucleoside analogues are driven by different mechanisms. The lack of cross-resistance between SAMHD1/ DCK substrates and non-substrates provides scope for next-line therapies after treatment failure."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DCK • SAMHD1

An Oral Combination Study of Novel Nucleoside Analogue Sapacitabine and BCL2 Inhibitor Venetoclax to Treat Patients with Relapsed or Refractory AML or MDS (ASH 2019) - P1/2; "Cytarabine (Ara-C) is the most active drug against AML; azacitidine and decitabine are active treatments of myelodysplastic syndrome (MDS) and AML...The combination of CNDAC (2’-C-cyano-2’-deoxy-1-β-D-arabino-pentafuranosylcytosine), the active metabolite of sapacitabine, and BCL2 inhibitor ABT737 was studied in AML cell line MV-411...Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess responses according to standard criteria."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

Expansion cohort of Phase I study of oral sapacitabine and oral seliciclib in patients with metastatic breast cancer and BRCA1/2 mutations (AACR 2019) - "The combination of sapacitabine and seliciclib was safe and led to durable clinical benefit in some patients with metastatic breast cancer and BRCA1/2 mutations. Prior progression on PARP inhibitors predicted resistance to this combination, associated in some cases with BRCA reversion mutations. Based on these results, the combination of sapacitabine and the PARP inhibitor olaparib is now being investigated in patients with PARP-naïve metastatic HER2-negative breast cancer and germline BRCA1/2 mutations."

BRCA Biomarker • Clinical • P1 data • PARP Biomarker

Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). (PubMed, Cancer) - P3 | "The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 10 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed."

Clinical • Journal • P3 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

[VIRTUAL] EHA GUIDELINE: ANTIFUNGAL PROPHYLAXIS IN ACUTE MYELOID LEUKEMIA TREATED WITH NOVEL AGENTS (EHA 2021) - "Results The following novel agents for treatment of AML were identified with not all of them being yet licensed for treatment: Hypomethylating agents (HMA; Azacytidine and decitabine), Midostaurin, Venetoclax (+HMA), Lestaurtinib, Gilteritinib, Sorafenib, Quizartinib, Ivosidenib, Enasidenib, Crenolanib, Glasdegib, Sapacitabine, Custatuzumab, Iomab B, Idanasutlin. Evidence-based recommendations were formulated for HMA, Midostaurin, and Venetoclax/HMA, for all other agents, consensus-based recommendations were given including the patient-specific setting of application of the novel agents (relapsed/refractory AML, single therapy or in combination with chemotherapy, induction treatment or maintenance etc.) into the decision process Antifungal prophylaxis is not recommended or moderately recommended in most settings, and strongly recommended if the novel AML agent is administered with intensive chemotherapy during induction treatment. Dose adaptations of some of the AML..."

Acute Myelogenous Leukemia • Critical care • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Oncology

Cyclacel Pharmaceuticals Reports First Quarter 2021 Financial Results (GlobeNewswire) - "1H 2021: First patient dosed with oral fadraciclib in Phase 1b/2 advanced solid tumor study...2H 2021: First patient dosed with oral fadraciclib in Phase 1b/2 leukemia study, First patient dosed with oral CYC140 in Phase 1/2 advanced solid tumor study...1H 2022: First patient dosed with oral CYC140 in Phase 1/2 leukemia study, Phase 1 data with oral fadraciclib in advanced solid tumor study, Update data from the Phase 1b/2 IST of sapacitabine-olaparib combination in patients with BRCA mutant metastatic breast cancer when reported by the investigators."

Enrollment status • P1 data • P1/2 data • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Cyclacel Pharmaceuticals Reports Fourth Quarter and Full Year 2020 Financial Results (GlobeNewswire) - "Key Business Objectives for 2021: First patient dosed with oral fadraciclib in Phase 1b/2 advanced solid tumor and leukemia studies; First patient dosed with oral CYC140 in Phase 1/2 advanced solid tumor and leukemia studies; Manufacture clinical supplies of oral fadraciclib and oral CYC140 for registration-enabling studies; Data on safety and antileukemic activity from the i.v. fadraciclib-venetoclax Phase 1 study in relapsed/refractory AML and CLL; Data from the sapacitabine-venetoclax Phase 1/2 study in relapsed/refractory AML or MDS; Initial data from the i.v. CYC140 Phase 1 First-in-Human study in patients with advanced leukemias; Data from the Phase 1b/2 IST of sapacitabine-olaparib combination in patients with BRCA mutant metastatic breast cancer when reported by the investigators."

Clinical • P1 data • P1/2 data • Trial status • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor