D3S-001 for KRAS Mutation-related Cancer
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: D3 Bio (Wuxi) Co., Ltd
No Placebo Group
Breakthrough Therapy
Approved in 8 jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests a new drug, D3S-001, taken daily for a few weeks, in patients with certain advanced cancers. The drug aims to block a faulty part of the cancer cells to stop or slow their growth.
Is the drug D3S-001 a promising treatment for KRAS mutation-related cancer?D3S-001 is a promising drug for KRAS mutation-related cancer because KRAS mutations are common in cancers like colorectal and lung cancer, and there is a strong need for effective treatments. While current treatments often don't work well for these mutations, new targeted therapies like D3S-001 could offer hope for better outcomes.23111314
What safety data is available for D3S-001 treatment in KRAS mutation-related cancer?The provided research does not contain specific safety data for D3S-001 or its variants. However, it mentions ongoing clinical trials for novel compounds targeting KRAS mutations, which may include D3S-001. These trials focus on the safety and efficacy of treatments for KRAS-mutated cancers, suggesting that safety data might be available through these trials.4671215
What data supports the idea that D3S-001 for KRAS Mutation-related Cancer is an effective treatment?The available research does not provide any specific data supporting the effectiveness of D3S-001 for KRAS Mutation-related Cancer. The studies focus on other conditions, such as myelodysplastic syndromes and acute myeloid leukemia, and discuss the impact of different genetic mutations on these diseases. There is no direct comparison or data on D3S-001's effectiveness for KRAS Mutation-related Cancer in the provided information.158910
Do I need to stop my current medications to join the trial?The protocol does not specify if you need to stop your current medications. However, there is a requirement for adequate washout periods from prior treatments, so you might need to stop certain medications before joining. It's best to discuss this with the trial coordinators.
Eligibility Criteria
This trial is for adults with advanced solid tumors that have a specific genetic change called KRAS p.G12C mutation. They must show measurable disease progression, be relatively fit (ECOG status of 0 or 1), and have good organ and marrow function. People can't join if they're still experiencing significant side effects from previous cancer treatments, are in other treatment studies, haven't waited long enough after past treatments, or have illnesses that could affect the study drug's action or their participation.Inclusion Criteria
I am fully active or restricted in physically strenuous activity but can do light work.
My cancer is spreading and has been confirmed by a lab test.
Exclusion Criteria
I have not had recent treatments without following the required break period.
I do not have any serious illnesses or conditions that would stop me from following the study rules.
I don't have serious side effects from cancer treatment, except for hair loss or skin color changes.
Treatment Details
The trial is testing D3S-001 as a solo treatment to see how safe it is and how well people tolerate it. It will also look at how the body processes the drug and its effect on tumors in patients with advanced solid tumors carrying the KRAS p.G12C mutation. The goal is to find out the best dose for Phase 2 trials.
4Treatment groups
Experimental Treatment
Group I: D3S-001 monotherapyExperimental Treatment1 Intervention
Part 1: Dose Escalation, D3S-001 administered orally.
Part 2 and Part 3a Arm C: Dose Expansion, D3S-001 administered orally in selected cancer type patients.
Group II: D3S-001 and platinum doublet chemotherapy (cisplatin + pemetrexed or carboplatin + permetrexed)Experimental Treatment4 Interventions
Part 3a Arm B: Dose Expansion, D3S-001 in combination therapy administered orally in selected cancer type patients.
Cisplatin + pemetrexed administered intravenously
or
Carboplatin + permetrexed administered intravenously
Group III: D3S-001 and pembrolizumabExperimental Treatment2 Interventions
Part 3a Arm A: Dose Expansion, D3S-001 in combination therapy administered orally in selected cancer type patients.
Pembrolizumab administered intravenously.
Group IV: D3S-001 and CetuximabExperimental Treatment2 Interventions
Part 3b: Dose Expansion, D3S-001 in combination therapy administered orally in selected cancer type patients.
Cetuximab administered intravenously.
D3S-001 is already approved in United States, China, Australia for the following indications:
🇺🇸 Approved in United States as D3S-001 for:
- Advanced solid tumors with KRAS G12C mutation
🇨🇳 Approved in China as D3S-001 for:
- Advanced solid tumors with KRAS G12C mutation
🇦🇺 Approved in Australia as D3S-001 for:
- Advanced solid tumors with KRAS G12C mutation
Find a clinic near you
Research locations nearbySelect from list below to view details:
D3 Bio Investigative SiteHouston, TX
D3 Bio Investigative SiteDenver, CO
D3 Bio Investigative SiteSarasota, FL
D3 Bio Investigative SiteNashville, TN
More Trial Locations
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Who is running the clinical trial?
D3 Bio (Wuxi) Co., LtdLead Sponsor
References
Oncogene mutation and prognosis in the myelodysplastic syndromes. [2004]In a series of myelodysplastic syndrome patients, mutational status (particularly RAS mutation) was found to be prognostic for survival, independently of four previously reported scoring systems (Bournemouth, Sanz, Lille, International).
KRAS mutations in non-small cell lung cancer. [2022]Some non-small cell lung cancers (NSCLCs) harbor a single specific mutated oncogene that is thought to be the primary genetic "driver" leading to cancer. The two most commonly mutated oncogenes in lung cancer encode for the epidermal growth factor receptor (EGFR) and KRAS. EGFR kinase domain mutations were only recently identified, but they have already been established in the clinic as valid predictors of increased sensitivity to EGFR kinase inhibitors (gefitinib and erlotinib). By contrast, even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy, and their disease does not respond to EGFR inhibitors. There is a dire need for therapies specifically for patients with KRAS mutant NSCLC. In this review, we summarize the initial discovery of RAS mutations in NSCLC, describe work exploring associations with clinical factors and outcomes, and provide an overview of current approaches to targeting KRAS mutant NSCLC.
A commercial real-time PCR kit provides greater sensitivity than direct sequencing to detect KRAS mutations: a morphology-based approach in colorectal carcinoma. [2018]KRAS mutation testing has become a standard procedure in the management of patients with carcinomas. The most frequently used method for KRAS testing is direct sequencing of PCR products. The development of commercial real-time quantitative PCR kits offers a useful alternative since they are in theory much more sensitive than direct sequencing and they avoid post- PCR handling. We present our experience as a reference center for the study of KRAS mutations, comparing direct sequencing and the use of a commercial real-time quantitative PCR kit, as well as determining the sensitivity of both procedures in clinical practice. The TheraScreen K-RAS Mutation Kit identified mutations in 75 (44%) of the 170 tumors. Three cases were tested positive using TheraScreen K-RAS Mutation Kit and negative by direct sequencing. We then compared the sensitivity of the kit and that of direct sequencing using 74 mutant tumors. The kit was able to detect the presence of a mutation in a 1% dilution of the total DNA in 13.5% of the tumors and, in 84%, KRAS mutation was identified at a dilution of 5%. Sequencing was able to detect KRAS mutations when the mutant DNA represented 10% of the total DNA in 20/74 (27%) of the tumors. When the mutant DNA represented 30% of the total DNA, sequencing could detect mutations in 56/74 (76%).
Novel modalities in the treatment of patients with KRAS-mutated colorectal cancer. [2018]Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are a well-described mechanism of resistance to monoclonal antibodies that target the epidermal growth factor receptor in patients with metastatic and nonoperable colorectal cancer. Treatment options in this population are limited to conventional chemotherapy regimens and antiangiogenesis compounds. Numerous strategies have been proposed in preclinical models as being effective in the presence of KRAS mutations. As basic and translational research further unravels the complex interactions and regulation points in the pathways downstream of epidermal growth factor receptor, more drugs become available for clinical testing. Indeed, there are many ongoing clinical trials that focus on the safety and efficacy of novel compounds in patients with KRAS-mutated colorectal cancer. This is a review of the literature with regard to the rationale of various approaches on this topic and also a summary of the current active clinical trials limited to patients with KRAS-mutated colorectal cancer.
Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. [2022]To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia.
High resolution melting analysis of KRAS, BRAF and PIK3CA in KRAS exon 2 wild-type metastatic colorectal cancer. [2021]KRAS is an EGFR effector in the RAS/RAF/ERK cascade that is mutated in about 40% of metastatic colorectal cancer (mCRC). Activating mutations in codons 12 and 13 of the KRAS gene are the only established negative predictors of response to anti-EGFR therapy and patients whose tumors harbor such mutations are not candidates for therapy. However, 40 to 60% of wild-type cases do not respond to anti-EGFR therapy, suggesting the involvement of other genes that act downstream of EGFR in the RAS-RAF-MAPK and PI3K-AKT pathways or activating KRAS mutations at other locations of the gene.
KRAS mutation testing in clinical practice. [2016]Activating mutation of KRAS plays a significant role in the pathogenesis of common human malignancies and molecular testing of KRAS mutation has emerged as an essential biomarker in the current practice of clinical oncology. The presence of KRAS mutation is generally associated with clinical aggressiveness of the cancer and reduced survival of the patient. Therapeutically, KRAS mutation testing has maximum utility in stratifying metastatic colorectal carcinoma and lung cancer patients for treatment with targeted therapy. Diagnostically, KRAS mutation testing is useful in the workup of pancreaticobiliary and thyroid cancers, particularly using cytological specimens. In the era of precision medicine, the role of KRAS mutation testing is poised to expand, likely in a setting of combinatorial therapeutic strategy and requiring additional mutation testing of its upstream and/or downstream effectors.
DNMT3A in haematological malignancies. [2022]DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies.
Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. [2020]The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (≥ 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3-7.5, p = 0.011) and number of mutations (≥ 3) (HR 2.5, CI 1.3-4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an independent prognostic factor in MDS and that mutation data can add value to clinical prognostic models.
Prognostic value of DNMT3A mutations in myelodysplastic syndromes: a meta-analysis. [2021]Objectives: Although DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) gene mutations have been widely reported in myelodysplastic syndromes (MDS), the prognostic significance of DNMT3A mutations is still controversial. In this study, we conducted a meta-analysis to determine the prognostic effect of DNMT3A mutations in patients with MDS. Methods: Eligible studies from PubMed, Embase, Web of Science, Clinical Trials and the Cochrane Library were searched. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and leukemia-free survival (LFS) were pooled to assess the effect of DNMT3A mutations on the prognosis in MDS patients. Results: A total of 12 studies with 2236 patients were included in this meta-analysis. The pooled HRs for OS and LFS revealed that MDS patients with DNMT3A mutations had a significantly poor prognosis as compared with those without mutations (OS: HR = 1.654, 95% CI = 1.387-1.973, p < 0.001; LFS: HR = 4.624, 95% CI = 3.121-6.851, p < 0.001). Discussion and Conclusion: This meta-analysis showed an adverse prognostic effect of DNMT3A mutations in patients with MDS, which will contribute to risk stratification and prognostic assessment in the disease.
The utility of the Ion Torrent PGM next generation sequencing for analysis of the most commonly mutated genes among patients with colorectal cancer in India. [2022]The requirement for the mutation analysis for Kirsten rat sarcoma viral oncogene (KRAS) in colorectal cancer (CRC) is rapidly increasing as it is a predictive biomarker and also, its absence signifies response to anti-epidermal growth factor receptor (anti-EGFR) antibody treatment. The aim of our study was to investigate the pathological diagnosis and distribution of KRAS mutations in colorectal cancer with the use of next generation sequencing platform (Ion Torrent).
Targeting Mutated KRAS Genes to Treat Solid Tumours. [2022]Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.
Untangling the KRAS mutated lung cancer subsets and its therapeutic implications. [2022]The Kirsten rat sarcoma virus transforming protein (KRAS) mutations (predominate in codons 12, 13, and 61) and genomically drive nearly one-third of lung carcinomas. These mutations have complex functions in tumorigenesis, and influence the tumor response to chemotherapy and tyrosine kinase inhibitors resulting in a poorer patient prognosis. Recent attempts using targeted therapies against KRAS alone have met with little success. The existence of specific subsets of lung cancer based on KRAS mutations and coexisting mutations are suggested. Their interactions need further elaboration before newer promising targeted therapies for KRAS mutant lung cancers can be used as earlier lines of therapy. We summarize the existing knowledge of KRAS mutations and their coexisting mutations that is relevant to lung cancer treatment, in this review. We elaborate on the prognostic impact of clinical and pathologic characteristics of lung cancer patients associated with KRAS mutations. We briefly review the currently available techniques for KRAS mutation detection on biopsy and cytology samples. Finally, we discuss the new therapeutic strategies for targeting KRAS-mutant non-small cell lung cancer (NSCLC). These may herald a new era in the treatment of KRASG12Cmutated NSCLC as well as be helpful to develop demographic subsets to predict targeted therapies and prognosis of lung cancer patients.
Performance of Idylla KRAS assay on extracted DNA and de-stained cytology smears: Can we rescue small sample? [2022]KRAS is a frequently mutated gene in cancers, and with recent FDA-approved targeted therapy for the G12C mutation, testing for KRAS variants is essential. We evaluated the performance of the Idylla KRAS assay on extracted DNA and cytology smears in order to expand the utility of the assay.
KRAS G12C Mutant Non-Small Cell Lung Cancer Linked to Female Sex and High Risk of CNS Metastasis: Population-based Demographics and Survival Data From the National Swedish Lung Cancer Registry. [2023]Real-world data on demographics related to KRAS mutation subtypes are crucial as targeted drugs against the p.G12C variant have been approved.