CX-904 for Advanced Solid Cancers

Recruiting at 4 trial locations

Overseen By Karen Deane

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: CytomX Therapeutics

Disqualifiers: Active malignancy, Autoimmune diseases, Myocarditis, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing CX-904, a new medicine that helps the immune system fight advanced cancers that can't be removed by surgery. It works by connecting immune cells to cancer cells, making it easier for the body to attack the cancer.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug CX-904 for advanced solid cancers?

Research on similar treatments, like the Probody-drug conjugate CX-2029, shows promising results in targeting cancer cells while minimizing harm to normal cells. This approach has demonstrated effective tumor growth inhibition in preclinical models, suggesting potential for CX-904. ^{1 2 3 4 5}

What safety data exists for CX-904 and related Probody therapeutics?

Probody therapeutics, like CX-904, are designed to be activated only in the tumor environment, which helps reduce side effects in normal tissues. Studies on similar Probody drugs have shown improved safety profiles compared to traditional treatments, with reduced off-target effects and better tolerability in preclinical models. ^{2 4 5 6 7}

What makes the drug CX-904 unique for treating advanced solid cancers?

CX-904 is a novel treatment that uses a Probody therapeutic approach, which means it remains inactive until it reaches the tumor environment, reducing side effects on healthy tissues. This drug specifically targets EGFR (a protein often overexpressed in cancer cells) and engages T-cells (a type of immune cell) to attack the cancer, offering a more targeted and potentially safer treatment option compared to traditional therapies. ^{2 4 8 9 10}

Research Team

Monika Vainorius, M.D.

Principal Investigator

CytomX Therapeutics, Inc

Eligibility Criteria

This trial is for adults with advanced solid tumors that can't be surgically removed and have spread. They should have tried standard treatments already, not have serious heart issues or autoimmune diseases, and agree to use effective birth control. Those with small, symptom-free brain metastases may join after special consideration.

Inclusion Criteria

Adequate baseline laboratory values

I have small brain tumors (≤1 cm) that need treatment.

Patients of childbearing potential or those with partners of childbearing potential must agree to use a highly effective method of birth control from signing the ICF, and for a period of 30 days after the last dose of CX-904.

Exclusion Criteria

I had cancer within the last 2 years, but it's considered cured and low risk of coming back.

Additional exclusion criteria may apply

Screening electrocardiogram demonstrating a mean QTcF value > 480 msec; a screening echocardiogram with left ventricular ejection fraction (LVEF) < 50%

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of CX-904 to determine safety and tolerability

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 months

Treatment Details

Interventions

• CX-904 (Other)

Trial Overview The study tests CX-904's safety and effectiveness in treating advanced solid tumors. It will assess how the body processes the drug (PK), its impact on the tumor (PD), tolerability at different doses, and any potential benefits in shrinking or controlling tumor growth.

Participant Groups

Group I: CX-904 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

CytomX Therapeutics

Lead Sponsor

Trials

9

Recruited

1,000+

Findings from Research

The novel nanobody-based trispecific T cell engager (Nb-TriTE) effectively targets tumor cells and enhances T cell activation, leading to significant tumor killing and improved survival in mouse models of solid tumors.

Unlike traditional therapies, Nb-TriTE demonstrated the ability to overcome tumor-mediated immunosuppression without causing toxicity, suggesting it could be a safer and more effective treatment option for patients with solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanobody-based trispecific T cell engager (Nb-TriTE) enhances therapeutic efficacy by overcoming tumor-mediated immunosuppression. Ding, Z., Sun, S., Wang, X., et al.[2023]

The probody therapeutic CX-2029, designed to target the CD71 antigen, showed potent tumor growth inhibition in over 80% of preclinical patient-derived xenograft models, indicating strong efficacy as a cancer treatment.

CX-2029 demonstrated a significantly improved safety profile, with over 80% of the drug remaining inactive in circulation, leading to a 10-fold increase in tolerability compared to traditional anti-CD71 antibody-drug conjugates, which were lethal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody-Drug Conjugate. Singh, S., Serwer, L., DuPage, A., et al.[2023]

The study of 89Zr-CX-072, a PD-L1-targeting Probody therapeutic, demonstrated significant tumor uptake in patients, even in tumors with low PD-L1 expression (≤1%), indicating its potential effectiveness in a broader range of tumors.

PET imaging showed that 89Zr-CX-072 had a favorable safety profile, with no unexpected uptake in healthy tissues and modest uptake in normal lymphoid organs, suggesting it could be a safe option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Study of the Biodistribution and Pharmacokinetics of 89Zr-CX-072, a Novel Immunopet Tracer Based on an Anti-PD-L1 Probody. Kist de Ruijter, L., Hooiveld-Noeken, JS., Giesen, D., et al.[2022]

CX-2029, a Probody-drug conjugate targeting CD71, was evaluated in a phase I study with 45 patients, showing that it can be administered safely at doses up to 4 mg/kg, with a recommended phase II dose of 3 mg/kg due to dose-limiting toxicities observed at higher levels.

The study demonstrated preliminary efficacy with confirmed partial responses in three patients with squamous cell tumors, highlighting the potential of CX-2029 to target a previously undruggable receptor while minimizing off-tumor toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies. Johnson, M., El-Khoueiry, A., Hafez, N., et al.[2023]

The study established the maximum tolerated dose (MTD) of the Probody immune checkpoint inhibitor CX-072 (pacmilimab) combined with ipilimumab as 10 mg/kg and 3 mg/kg respectively, administered every 3 weeks, showing a favorable safety profile with manageable adverse effects.

Among the 27 patients treated, the overall response rate was 19%, with notable long-lasting responses in some patients, indicating potential efficacy in advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study. Sanborn, RE., Hamid, O., de Vries, EG., et al.[2022]

Antibody-based immunotherapies, particularly immune checkpoint inhibitors (ICIs), have significantly improved cancer treatment outcomes but are associated with severe immune-related adverse events (irAEs) that can limit treatment duration and cause high morbidity.

Probody therapeutics, a new class of antibody prodrugs designed to activate specifically within the tumor microenvironment, show promise in maintaining anticancer efficacy while potentially reducing the incidence of irAEs compared to traditional antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology. Autio, KA., Boni, V., Humphrey, RW., et al.[2023]

Probody therapeutics (Pb-Tx) targeting PD-1 and PD-L1 showed similar antitumor effects as traditional antibodies while significantly reducing systemic activity and toxicity, particularly in preventing autoimmune diabetes in mice.

The localized action of Pb-Tx allows for effective tumor treatment with minimized side effects, supporting the ongoing clinical trials of the anti-PD-L1 Pb-Tx CX-072.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti-PD-1/PD-L1 Agents. Assi, HH., Wong, C., Tipton, KA., et al.[2023]

CX-072, an anti-PD-L1 Probody therapeutic, is designed to be activated specifically in the tumor microenvironment, which may enhance its efficacy while minimizing effects on healthy tissues.

Preliminary data from a study involving 130 subjects indicated that CX-072 maintains a stable pharmacokinetic profile, with simulations suggesting that a fixed dose of 800 mg would effectively achieve the desired therapeutic levels in most patients, without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Model-Informed Drug Development of the Masked Anti-PD-L1 Antibody CX-072. Stroh, M., Green, M., Millard, BL., et al.[2021]

CX-2009, a Probody drug conjugate targeting CD166, shows effective tumor targeting in a lung cancer mouse model, with comparable biodistribution to other constructs, indicating its potential for treating CD166-expressing tumors.

The study suggests that the enzymatic activation of CX-2009 within the tumor microenvironment does not hinder its ability to target tumors, but further clinical studies are needed to confirm its reduced binding to healthy tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The tumor targeting performance of anti-CD166 Probody drug conjugate CX-2009 and its parental derivatives as monitored by 89Zr-immuno-PET in xenograft bearing mice. Chomet, M., Schreurs, M., Nguyen, M., et al.[2021]

TNB-928B is a novel T-cell engager designed to selectively target tumor cells overexpressing folate receptor alpha (FRα), minimizing damage to healthy tissues with low FRα expression, which enhances its safety profile.

In preclinical mouse models of ovarian cancer, TNB-928B demonstrated effective tumor clearance and T-cell activation while inducing minimal cytokine release, suggesting a favorable therapeutic window for treating solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer. Avanzino, BC., Prabhakar, K., Dalvi, P., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Nanobody-based trispecific T cell engager (Nb-TriTE) enhances therapeutic efficacy by overcoming tumor-mediated immunosuppression. [2023]

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

Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody-Drug Conjugate. [2023]

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

First-in-Human Study of the Biodistribution and Pharmacokinetics of 89Zr-CX-072, a Novel Immunopet Tracer Based on an Anti-PD-L1 Probody. [2022]

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

Phase I, First-in-Human Study of the Probody Therapeutic CX-2029 in Adults with Advanced Solid Tumor Malignancies. [2023]

5. England pubmed.ncbi.nlm.nih.gov

CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study. [2022]

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

Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology. [2023]

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

Conditional PD-1/PD-L1 Probody Therapeutics Induce Comparable Antitumor Immunity but Reduced Systemic Toxicity Compared with Traditional Anti-PD-1/PD-L1 Agents. [2023]

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

Model-Informed Drug Development of the Masked Anti-PD-L1 Antibody CX-072. [2021]

9. Australia pubmed.ncbi.nlm.nih.gov

The tumor targeting performance of anti-CD166 Probody drug conjugate CX-2009 and its parental derivatives as monitored by 89Zr-immuno-PET in xenograft bearing mice. [2021]

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

A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer. [2022]