CDR404 for Cancer
Recruiting in Palo Alto (17 mi)
+16 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: CDR-Life AG
Must not be taking: Systemic steroids, Immunosuppressives
Disqualifiers: CNS metastasis, Cardiac disease, Autoimmune, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
CDR404 is a highly potent and specific T-cell engaging bispecific and bivalent antibody designed for the treatment of cancers positive for the tumor-associated antigen melanoma-associated antigen 4 (MAGE-A4). This is a first-in-human study designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of CDR404 in adult patients who have the appropriate germline human leukocyte antigen HLA-A\*02:01 tissue marker and whose cancer is positive for MAGE-A4.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it mentions that you cannot have inadequate washout from prior anticancer therapy and cannot be on ongoing treatment with systemic steroids or other immunosuppressive therapies. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug CDR404 for cancer?
Research suggests that targeting the CXCR4 receptor, which is involved in cancer cell movement and spread, can be promising in cancer treatment. Anti-CXCR4 therapies have shown potential in improving outcomes when combined with chemotherapy, as seen in studies on pancreatic cancer and breast cancer.12345
Is CDR404 safe for humans?
Eligibility Criteria
This trial is for adults with certain advanced solid tumors that show the MAGE-A4 marker and have the HLA-A*02:01 tissue type. Participants must be in good physical condition, have relapsed or not responded to standard treatments, and have measurable disease. They should also have proper organ function and agree to use effective contraception if applicable.Inclusion Criteria
Provision of written informed consent
My organs are working well.
I am fully active or have some restrictions but can still care for myself.
See 6 more
Exclusion Criteria
I am currently taking steroids or other drugs that weaken my immune system.
I have brain metastases that are causing symptoms or have not been treated.
I have had surgery recently.
See 10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Participants receive escalating doses of CDR404 to identify the maximum tolerated dose and pharmacologically effective dose range
6 weeks
Multiple visits (in-person) during each 21-day cycle
Treatment
Participants continue receiving CDR404 to assess anti-tumor activity, pharmacokinetics, and immunogenicity
Up to 100 months
Regular visits (in-person) every 21 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
90 days after the last dose
Treatment Details
Interventions
- CDR404 (CAR T-cell Therapy)
Trial OverviewCDR404, a new antibody designed to target cancers expressing the MAGE-A4 antigen, is being tested for safety and effectiveness. This first-in-human study will assess how well CDR404 works against these specific tumors in participants with the right genetic markers.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: CDR404Experimental Treatment1 Intervention
Dose escalation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Providence Cancer InstitutePortland, OR
University of MichiganAnn Arbor, MI
Pennsylvania HospitalPhiladelphia, PA
University of MiamiMiami, FL
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Who Is Running the Clinical Trial?
CDR-Life AGLead Sponsor
References
Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC). [2014]Purpose Patients with locally advanced breast cancer (LABC) have a poor outcome. A molecular predictor to identify at-risk patients is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that in patients with LABC, CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome. Experimental design 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy and definitive surgical therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm(3) cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots, and results were quantified against 1 mug of protein from HeLa cells. CXCR4 expression was defined as low ( or =6.6-fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included independent samples t-test, chi-square test, Spearman Rank analysis, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results With a median follow-up of 30 months, patients with high CXCR4 overexpression (> or =6.6-fold) had a significantly higher incidence of recurrence (P = 0.0006) and cancer death (P = 0.0128) than those with low CXCR4 overexpression (
Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis. [2021]CC chemokine receptor 4 (CCR4) represents a potentially important target for cancer immunotherapy due to its expression on tumor infiltrating immune cells including regulatory T cells (Tregs) and on tumor cells in several cancer types and its role in metastasis.
The CXCR4 Antagonist, AMD3100, Reverses Mesenchymal Stem Cell-Mediated Drug Resistance in Relapsed/Refractory Acute Lymphoblastic Leukemia. [2022]To investigate the role of the CXCR4/CXCL12 axis in chemotherapy resistance in refractory/relapsed (R/R) ALL patients.
Towards a tailored therapy in pancreatic cancer. [2022]Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. As conventional treatments have shown only a modest impact on disease course, development of new therapeutic strategies based on the molecular biology of PDAC must be a high priority. The identification of relevant predictive and prognostic biomarkers which can be used to select patient subgroups that may benefit from conventional treatments and new targeted agents will be of considerable interest. We have demonstrated the ability of the metabolizing gemcitabine protein (the human Equilibrative nucleoside transporter 1 and the deoxycytidine kinase) in predicting the benefit of adjuvant gemcitabine-based therapy in resected PDAC patients. Beside these predictive biomarkers, we have evaluated different molecular factors that may impact on the likely course of this cancer. The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse). Our findings were validated in an independent cohort of patients. Overall our results suggested that (i) the benefit of an adjuvant gemcitabine-based therapy can be predicted based on the tumour expression of hENT1 and dCK, (ii) CXCR4 is an independent negative prognostic factor and an independent predictor of distant relapse suggesting that anti-CXCR4 targeting therapies can be a promising treatment in combination with cytotoxic chemotherapy in the adjuvant setting. These data open new perspectives for designing trials based on a molecular driven strategy.
Using breast cancer cell CXCR4 surface expression to predict liposome binding and cytotoxicity. [2021]The primary cause of mortality in breast cancer is tumor aggressiveness, characterized by metastases to regional lymph nodes, bone marrow, lung, and liver. C-X-C chemokine receptor type 4 (CXCR4) has been shown to mobilize breast cancer cells along chemokine gradients. Quantification of CXCR4 surface expression may predict the efficacy of anti-CXCR4 labeled liposomal therapeutics to target and kill breast cancer cells. We evaluated gene and surface receptor expression of CXCR4 on breast cancer cell lines distinguished as having low and high invasiveness, MDA-MB-175VII and HCC1500, respectively. CXCR4 surface expression did not correlate with invasiveness. MDA-MB-175VII exhibited more binding to anti-CXCR4 labeled liposomes relative to HCC1500. Increased binding correlated with greater cell death relative to IgG labeled liposomes. Quantitative cell characterization may be used to select targeted therapeutics with enhanced efficacy and minimal side effects.
New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5). [2021]Cluster of differentiation 40 (CD40) is a member of the tumour necrosis factor family and a new immune-modulating target in cancer treatment. B cells, myeloid cells and dendritic cells can express CD40 and mediate via the ligand cluster of differentiation 40 ligand (CD40L) cytotoxic T cell priming under physiological conditions. Therapeutically, recombinant CD40L molecules, intratumour application of adenoviral vectors leading to CD40L expression and agonistic monoclonal CD40 antibodies are currently tested in various cancer entities for their immune-modulating potential. Early clinical trials suggest safety for agonistic CD40 antibodies with encouraging antitumour effects. Adverse events encompass cytokine release storm, hepatoxicity, thromboembolic events and were so far reported to be clinically manageable and transient. Ongoing studies investigate CD40 activation in combination with chemotherapy, radiation, targeted therapies and immunomodulatory agents. Further studies are awaited to specifically identify patients with the greatest clinical benefit based on predictive biomarkers.
Prospect of targeting the CD40 pathway for cancer therapy. [2021]The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune, hematopoietic, vascular, epithelial, and other cells, including a wide range of tumor cells. CD40 itself lacks intrinsic kinase or other signal transduction activity but rather mediates its diverse effects via an intricate series of downstream adapter molecules that differentially alter gene expression depending on cell type and microenvironment. As a potential target for novel cancer therapy, CD40 may mediate tumor regression through both an indirect effect of immune activation and a direct cytotoxic effect on the tumor, resulting in a "two-for-one" mechanism of action of CD40 agonists. Several drug formulations that target the CD40 pathway have undergone phase 1 clinical evaluation in advanced-stage cancer patients, and initial findings show objective clinical responses and immune modulation in the absence of major toxicity.
Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies. [2020]Cluster of differentiation 40 (CD40) mediates many immune activities. Preclinical studies have shown that activation of CD40 can evoke massive antineoplastic effects in several tumour models in vivo, providing a rationale for using CD40 agonists in cancer immunotherapy. To date, several potential agonistic antibodies that target CD40 have been investigated in clinical trials. Early clinical trials have shown that the adverse events associated with agonists of CD40 thus far have been largely transient and clinically controllable, including storms of cytokine release, hepatotoxicity and thromboembolic events. An antitumour effect of targeting CD40 for monotherapy or combination therapy has been observed in some tumours. However, these antitumour effects have been moderate. The present review aimed to provide updated details of the clinical results of these agonists, and offer information to further investigate the strategies of combining CD40 activation with chemotherapy, radiotherapy, targeted therapy and immunomodulators. Furthermore, biomarkers should be identified for monitoring and predicting responses and informing resistance mechanisms.
CD40 activation as potential tool in malignant neoplasms. [2022]CD40, a cell surface molecule, is expressed on B-cell malignancies and many different solid tumors. It is capable of mediating diverse biological phenomena such as the induction of apoptosis in tumors and stimulation of the immune response. It has thus been studied as a possible target for antitumor therapy. The general aim of this review is to focus the attention of clinical oncologists on the involvement of CD40 in tumors and the rationale of CD40-activation-based therapies in new, biologically oriented antitumor protocols.
Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors. [2023]CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.
Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells. [2022]CD40 ligand (CD40L, CD154) plays a central role in immunoregulation and also directly modulates epithelial cell growth and differentiation. We previously showed that the CD40 receptor is commonly expressed in primary breast cancer tissues. In this proof-of-principle study, we examined the breast cancer growth-regulatory activities of an oncolytic adenoviral construct carrying the CD40L transgene (AdEHCD40L).
Biology and clinical applications of CD40 in cancer treatment. [2017]CD40 is a costimulatory molecule widely expressed by immune cells and by neoplastic cells of different histotypes. Engagement of surface CD40 mediates different effects depending on cell type and microenvironment. In particular, CD40 expression on immune cells regulates humoral and cellular immunity, while it has apoptotic and antiproliferative activity on selected neoplastic cells. Thus, CD40 targeting may indirectly affect tumor growth through the activation of immune cells and/or directly by mediating cytotoxic effects on neoplastic cells. Preliminary findings emerging from clinical trials indicate that antibodies to CD40 can induce immune modulation and clinical responses in cancer patients.