CDR404 for Cancer

Recruiting at 16 trial locations

Overseen By Shet Biswas Chief Medical Officer, CDR-Life

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: CDR-Life AG

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: CNS metastasis, Cardiac disease, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 42

Duration: Up to 100 months

42 Participants Needed

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. ^{1 2 3 4 5}

Is CDR404 safe for humans?

Early clinical trials of treatments targeting CD40, like CDR404, suggest they are generally safe in humans, with side effects such as cytokine release storm, liver issues, and blood clots being manageable and temporary. ^{6 7 8 9 10}

How is the drug CDR404 different from other cancer treatments?

CDR404 targets the CD40 pathway, which can both activate the immune system and directly kill cancer cells, offering a unique 'two-for-one' mechanism compared to other treatments that typically focus on one approach. ^{6 7 9 11 12}

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.

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.

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

Trial Overview CDR404, 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

Group I: CDR404 Experimental Treatment 1 Intervention

Dose escalation

Who Is Running the Clinical Trial?

CDR-Life AG

Lead Sponsor

Trials

1

Recruited

40+

Findings from Research

In a study of 54 patients with locally advanced breast cancer (LABC) who underwent neoadjuvant chemotherapy, high levels of CXCR4 overexpression in cancer specimens were linked to significantly worse outcomes, including higher rates of recurrence and cancer death.

Patients with high CXCR4 levels had a 27.3-fold increased risk of recurrence and a 4.8-fold increased risk of death compared to those with low CXCR4 levels, indicating that CXCR4 could serve as a valuable molecular predictor for identifying at-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC). Holm, NT., Abreo, F., Johnson, LW., et al.[2014]

The study successfully developed anti-CCR4 antibodies that can block signaling and induce the killing of CCR4-positive tumor cells, showing promise for cancer immunotherapy.

In a mouse model of human T-cell lymphoma, treatment with these anti-CCR4 antibodies resulted in a significant survival benefit, indicating their potential effectiveness in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis. Hagemann, UB., Gunnarsson, L., Géraudie, S., et al.[2021]

In a study of 37 patients with refractory/relapsed acute lymphoblastic leukemia (R/R ALL), higher levels of CXCR4 expression were found in R/R patients compared to those newly diagnosed, indicating a potential role in chemotherapy resistance.

Blocking the CXCR4/CXCL12 signaling pathway with the antagonist AMD3100 significantly enhanced the effectiveness of the chemotherapy drug vincristine, leading to increased apoptosis in leukemic cells and suggesting a promising strategy to overcome drug resistance in R/R ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The CXCR4 Antagonist, AMD3100, Reverses Mesenchymal Stem Cell-Mediated Drug Resistance in Relapsed/Refractory Acute Lymphoblastic Leukemia. Wang, S., Wang, X., Liu, S., et al.[2022]

The expression of specific proteins, hENT1 and dCK, in pancreatic ductal adenocarcinoma (PDAC) tumors can predict the effectiveness of adjuvant gemcitabine therapy, helping to tailor treatment for patients after surgery.

The chemokine receptor CXCR4 is identified as a negative prognostic factor for survival and is linked to patterns of tumor recurrence, suggesting that therapies targeting CXCR4 could enhance treatment outcomes when combined with traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a tailored therapy in pancreatic cancer. Maréchal, R., Van Laethem, JL.[2022]

The study found that CXCR4 surface expression on breast cancer cells does not correlate with the cells' invasiveness, suggesting that other factors may influence tumor aggressiveness.

MDA-MB-175VII cells, which have lower invasiveness, showed greater binding to anti-CXCR4 labeled liposomes and experienced more cell death compared to HCC1500 cells, indicating that targeting CXCR4 could enhance the efficacy of liposomal therapeutics in treating breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using breast cancer cell CXCR4 surface expression to predict liposome binding and cytotoxicity. Guo, P., You, JO., Yang, J., et al.[2021]

CD40 is a promising new target for cancer treatment, as it plays a role in activating immune responses through its interaction with CD40L, and various therapeutic approaches are being tested, including agonistic monoclonal antibodies.

Early clinical trials of agonistic CD40 antibodies show they are generally safe with manageable side effects, such as cytokine release syndrome and hepatotoxicity, while also demonstrating encouraging anti-tumor effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5). Piechutta, M., Berghoff, AS.[2021]

CD40 is a promising target for cancer therapy because it can activate the immune system and directly kill tumor cells, providing a dual mechanism of action.

Initial phase 1 clinical trials of CD40-targeting drugs in advanced cancer patients have shown encouraging results, including objective clinical responses and immune system changes, without significant toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospect of targeting the CD40 pathway for cancer therapy. Vonderheide, RH.[2021]

CD40 agonists have shown potential in cancer immunotherapy, demonstrating moderate antitumor effects in some tumors, based on early clinical trials.

The adverse events associated with CD40 agonists, such as cytokine release and hepatotoxicity, have been mostly transient and manageable, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies. Li, DK., Wang, W.[2020]

CD40 activation has been shown to promote the death of tumor cells and stimulate immune responses, making it a promising target for cancer therapies, particularly in B-cell malignancies and solid tumors.

Preclinical studies and early clinical trials suggest that therapies targeting CD40, such as agonistic antibodies and recombinant CD40L, can inhibit tumor growth and enhance immune responses, although the exact role of CD40 in cancer progression remains complex and not fully understood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD40 activation as potential tool in malignant neoplasms. Ottaiano, A., Pisano, C., De Chiara, A., et al.[2022]

ABBV-428, a tumor-targeted bispecific antibody, demonstrated an acceptable safety profile in a phase I study with 59 patients, showing no maximum tolerated dose reached and only mild infusion-related reactions reported.

Despite its safety, ABBV-428 showed minimal clinical activity in treating advanced mesothelioma and ovarian cancer, with only 36% of patients achieving stable disease, indicating that while the drug is safe, its effectiveness may need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors. Luke, JJ., Barlesi, F., Chung, K., et al.[2023]

The oncolytic adenoviral construct AdEHCD40L significantly inhibited the growth of CD40+ human breast cancer cells by up to 80% in vitro, demonstrating its potential as an effective treatment option.

In vivo studies showed that intratumoral injections of AdEHCD40L reduced tumor growth by over 99% in mouse models, outperforming both the parental virus and recombinant CD40L protein, indicating strong antitumor activity and enhanced apoptosis in cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells. Gomes, EM., Rodrigues, MS., Phadke, AP., et al.[2022]

CD40 is a crucial molecule that can influence both immune responses and cancer cell behavior, acting differently depending on the type of cell and its environment.

Preliminary clinical trials suggest that targeting CD40 with antibodies can enhance immune modulation and potentially lead to positive clinical outcomes in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology and clinical applications of CD40 in cancer treatment. Fonsatti, E., Maio, M., Altomonte, M., et al.[2017]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC). [2014]

2. United States pubmed.ncbi.nlm.nih.gov

Fully human antagonistic antibodies against CCR4 potently inhibit cell signaling and chemotaxis. [2021]

3. New Zealand pubmed.ncbi.nlm.nih.gov

The CXCR4 Antagonist, AMD3100, Reverses Mesenchymal Stem Cell-Mediated Drug Resistance in Relapsed/Refractory Acute Lymphoblastic Leukemia. [2022]

4. Belgium pubmed.ncbi.nlm.nih.gov

Towards a tailored therapy in pancreatic cancer. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Using breast cancer cell CXCR4 surface expression to predict liposome binding and cytotoxicity. [2021]

6. England pubmed.ncbi.nlm.nih.gov

New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5). [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Prospect of targeting the CD40 pathway for cancer therapy. [2021]

8. Greece pubmed.ncbi.nlm.nih.gov

Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

CD40 activation as potential tool in malignant neoplasms. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Antitumor activity of an oncolytic adenoviral-CD40 ligand (CD154) transgene construct in human breast cancer cells. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Biology and clinical applications of CD40 in cancer treatment. [2017]