CRD3874-SI for Sarcoma
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: Immunosuppressants, Steroids, Antibiotics, others
Disqualifiers: Autoimmune disease, Organ transplant, CNS metastases, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This study will test the safety of a study drug called CRD3874-SI. The researchers will test different doses of CRD3874-SI to find the highest dose that causes few or mild side effects in participants. After the researchers find the highest safe dose of CRD3874-SI, they will test that dose in new groups of participants to help them learn more about the side effects of the study drug and find out whether CRD3874-SI is an effective treatment for for patients with advanced or metastatic malignant solid tumors including sarcoma and Merkel Cell Carcinoma.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or certain other treatments, you may need to adjust or stop them. It's best to discuss your specific medications with the trial team.
What makes the drug CRD3874-SI unique for treating sarcoma?
CRD3874-SI is unique because it may target specific molecular pathways or genetic mutations in sarcoma subtypes, which are not effectively addressed by standard cytotoxic chemotherapy. This approach aligns with the growing trend of developing targeted therapies based on the molecular characteristics of different sarcoma subtypes.
12345Eligibility Criteria
This trial is for adults with advanced or metastatic sarcoma, Merkel cell carcinoma, or neuroendocrine carcinoma that's worsened after treatment. They must be in good health otherwise, have a life expectancy of at least three months, and not be pregnant. Participants need to agree to biopsies and have measurable disease. Those with certain heart conditions, active infections, other cancers, severe allergies to study drug components or recent treatments are excluded.Inclusion Criteria
I am 18 years old or older.
I weigh ≤90kg for dose level 5 or ≤70kg for dose level 6.
I am willing to follow the trial's rules and undergo tumor biopsies if needed.
+11 more
Exclusion Criteria
You have had a very bad allergic reaction to the study drug or any of its ingredients.
Patients expecting to conceive or father children within the projected duration of the trial
My heart condition has been stable for the last 6 months.
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive CRD3874-SI with dose escalation to determine the maximum tolerated dose, followed by dose expansion to assess safety and efficacy
48 weeks
Weekly infusions during 28-day cycles
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
CRD3874-SI is being tested in this study. Researchers will first find the highest dose with acceptable side effects before testing its effectiveness against specific cancers like Sarcoma and Merkel Cell Cancer. The trial involves gradually increasing doses for early participants then using the safest high dose on later groups.
1Treatment groups
Experimental Treatment
Group I: CRD3874-SIExperimental Treatment1 Intervention
Phase 1a: starting dose of 0.1 mg/kg, Phase 1b: RP2D determined during Phase 1a. Cycle 1 \& 2: once weekly infusion x 4 (Days 1, 8, 15, 22) over 28-day cycle. Cycle 3 onwards: weekly infusion x 3 (Days 1, 8, 15) over 28-day cycle From cycle 3 onwards if a patient is tolerating treatment well and agreeable to continue continuous weekly treatment this will be permitted.
CRD3874-SI is already approved in United States for the following indications:
🇺🇸 Approved in United States as CRD3874-SI for:
- Advanced solid tumors
- Sarcoma
- Merkel Cell Carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering at Basking Ridge (Limited Protocol Activities)Basking Ridge, NJ
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)Middletown, NJ
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
Memorial Sloan Kettering Suffolk - Commack (Limited Protocol Activities)Commack, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
Curadev PharmaCollaborator
References
Novel pathways and molecular targets for the treatment of sarcoma. [2021]Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed.
Novel Aspects of Genetics, Molecular Biology and Clinical Oncology of Sarcomas. [2020]The Connective Tissue Oncology Group Annual Meeting 2018 (CTOS 2018) took place in Rome from 4 to 17 November 2018, and the 39th Plenary Meeting of the Scandinavian Sarcoma Group (SSGM 2019) was held in Bergen from 8 to 10 May 2019. These two large international conferences brought together an overwhelming majority of molecular and clinical specialists in the sarcoma field, especially those working on soft tissue sarcoma. Topics discussed on the conferences included, among others, sarcoma genetics, clinical and molecular subclassification, targeted therapy, clinical prognostication, and new experimental sarcoma models. A large ongoing international study on germinal sarcoma genetics was presented, the interim results of which revealed the extremely complex nature of genetic disposition to sarcoma, and, surprisingly, a rather prominent place among predisposing genes for those coding for structural telomere constituents. Fusion oncogenes dominate somatic sarcoma genetics, especially because of their origin and impact on sarcoma clinical behaviour, and are especially relevant for karyotypically simple paediatric sarcomas. A crucial issue in karyotypically complex sarcomas are the efforts being made to obtain a subclassification of sarcoma, other than those based on pathology, using either the clinical characteristics of sarcomas (uterine leiomyosarcoma vs. soft tissue leiomyosarcoma) or specific gene expression profiles (molecular subtypes in undifferentiated pleiomorphic sarcoma), which showed that molecular characterization can open the way for subtype specific therapies. Other examples of where this type of strategy can be applied include gastrointestinal stromal tumours, infantile fibrosarcoma, and inflammatory myofibroblastic tumours, where targeted therapy could be conceived based on the actionable mutations identified. Attempts in this direction have been made also for clear cell sarcoma and dedifferentiated liposarcoma, albeit the effectiveness of molecular-targeted treatments for these sarcomas is still poor, and progress in the treatment of osteosarcoma is still rather slow. Actually, the platelet-derived growth factor signalling system holds a prominent position in searches for targeted therapies, not only against rare sarcoma types, where are activated by mutations (some gastrointestinal stromal tumours, infantile hereditary myofibromatosis, and dermatofibrosarcoma protuberans), but also against other more usual sarcoma types, where the blocking anti-PDGFRα-antibody olaratumab has been successfully integrated into combinatorial chemotherapeutic regimens. In the field of clinical prognostication, remarkable progress in sarcoma nomograms was reported. Interesting results were also presented in the area of new experimental sarcoma models. Participation on both scientifi c conferences and all the experimental work leading to the presented sarcoma models were supported by the Czech Science Foundation project No. 17-17636S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 20. 9. 2019 Accepted: 6. 11. 2019.
Emerging Targeted and Immune-Based Therapies in Sarcoma. [2019]Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials. Indeed, the spectrum of targeted drug development in sarcoma now spans many of the most active paradigms in cancer research and includes agents that target cancer-related vulnerabilities in receptor tyrosine kinases and intracellular signaling pathways, epigenetics, metabolism, nuclear-cytoplasmic transport, and many others. Our understanding of the sarcoma immune microenvironment and heterogeneous mechanisms of tumor immune evasion has also expanded. Although a subset of sarcomas appears inflamed and responsive to immune checkpoint blockade with programmed death 1 (PD-1) targeted agents, novel immunotherapies and combinations likely will be needed for most subtypes. A variety of approaches-including targeting immune checkpoints other than PD-1; modulating tumor-associated macrophage phenotype from tumor-promoting to tumor-suppressive status; using cellular-based therapies, such as chimeric antigen and high-affinity T-cell receptors to deepen the adaptive immune response; and reinvigorating older approaches, such as vaccines and oncolytic virus-based treatments-are being investigated. The goal of these new approaches is to harness subtype-specific insights into cancer and immune biology to bring more effective and less toxic treatments to the clinic for the benefit of patients with sarcoma.
Evaluation of PD-L1 Expression in Undifferentiated Pleomorphic Sarcomas, Liposarcomas and Chondrosarcomas. [2022]Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan-Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.
Targeted therapy in sarcoma: should we be lumpers or splitters? [2020]The identification of KIT as a critical driver in the pathogenesis of GI stromal tumor (GIST), and its subsequent inhibition with imatinib, have resulted in tremendous efforts to identify other potential therapeutic targets for the heterogeneous group of diseases known as sarcomas. Because of the rarity of sarcoma and the often limited number of patients per individual sarcoma subtype, clinical trials to date have often utilized unselected patient populations including multiple subtypes. Although this strategy increases the ease with which a particular trial may accrue patients, statistically significant therapeutic responses across an unselected patient population are often limited. Furthermore, in the absence of biologic correlatives, the identification of significant activity and subsequent interpretation of clinical trial results utilizing targeted therapies for this patient population have been challenging. However, hints have emerged, on the basis of preclinical and clinical observations, to suggest that certain targeted therapeutic approaches are appropriate in select histologic subtypes. This brief review will highlight data supporting the use of targeted therapy in both unselected and selected sarcoma patient populations.