CAR-GPC3 T Cell Therapy for Cancer

(DUET-1 Trial)

Recruiting at 5 trial locations

Overseen By Richard Kapsa

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sotio Biotech Inc.

Must not be taking: Antineoplastics, Corticosteroids

Disqualifiers: CNS tumors, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 23

Duration: 4 weeks

110 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in-human (FIH), Phase 1/2, open-label, multicenter study to assess safety and determine the recommended Phase 2 dose (RP2D) of BOXR1030 administration after lymphodepleting chemotherapy (LD chemotherapy) in subjects with glypican-3 positive (GPC3+) advanced solid tumors.

Do I need to stop my current medications to join the trial?

The trial requires a washout period for certain medications before starting treatment. You may need to stop some medications, especially antineoplastic treatments, for a specific time before the trial begins. It's best to discuss your current medications with the trial team to understand what changes might be necessary.

What data supports the effectiveness of the treatment BOXR1030 T Cells for cancer?

Research shows that T cells engineered to target glypican-3 (GPC3), a protein found on some cancer cells, can effectively attack and reduce tumors in models of lung and liver cancer. These studies suggest that similar GPC3-targeted treatments, like BOXR1030 T Cells, might also be effective against cancers expressing GPC3. ^{1 2 3 4 5}

Is CAR-GPC3 T Cell Therapy safe for humans?

CAR T cell therapies, including those targeting glypican-3 (GPC3), have shown potential in treating certain cancers, but they can also cause serious side effects like cytokine release syndrome (CRS) and neurological issues. Safety strategies are being developed to manage these risks, and some studies suggest that modifying the therapy can reduce side effects. However, it's important to monitor for severe reactions, especially shortly after treatment. ^{1 3 6 7 8}

What makes the CAR-GPC3 T Cell Therapy treatment unique compared to other cancer treatments?

CAR-GPC3 T Cell Therapy is unique because it uses specially engineered T cells to target glypican-3 (GPC3), a protein found on certain cancer cells, allowing for precise attack on tumors while sparing normal cells. This approach is particularly promising for solid tumors, which have been challenging to treat with traditional CAR-T therapies. ^{1 2 3 4 9}

Research Team

Pauline Duhard, Pharm.D.

Principal Investigator

SOTIO Biotech AG

Eligibility Criteria

Adults aged 18-80 with advanced solid tumors positive for GPC3, such as liver cancer or lung squamous cell carcinoma. They must have a life expectancy over 16 weeks, good organ function, and no severe complications like major untreated brain metastasis. Women of childbearing age and men with partners must agree to effective contraception.

Inclusion Criteria

My cancer is advanced, cannot be surgically removed, and tests show high levels of GPC3.

My liver cancer is not fibrolamellar or mixed hepatocellular cholangiocarcinoma.

I may have had radiation for symptom relief or hormone treatment, but it's been over a week since.

Exclusion Criteria

I have a heart condition that affects my daily life.

I do not have severe diseases like uncontrolled bleeding, serious infections, or active hepatitis.

I have untreated brain tumors or metastasis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis

Eligible subjects undergo leukapheresis to obtain T cells for BOXR1030 manufacturing

1 week

Lymphodepleting Chemotherapy

Subjects receive a 3-day LD chemotherapy regimen with fludarabine and cyclophosphamide

1 week

Treatment

Subjects receive BOXR1030 administration and remain hospitalized for 10 days post-infusion

4 weeks

Inpatient stay for 10 days post-infusion

Post-treatment Evaluation

Subjects are monitored for safety and effectiveness with regular visits and assessments

6 months

Daily visits for the first week, then weekly visits up to 6 months

Long-term Follow-up

Subjects are monitored for long-term safety and disease status for up to 15 years

15 years

Visits at Months 7, 9, 11, 13, 15, 18, 21, 24, every 6 months until Year 5, then annually

Treatment Details

Interventions

• BOXR1030

Trial Overview The trial is testing BOXR1030 T Cells after chemotherapy in patients with GPC3-positive tumors. It's the first time this treatment is being used on humans (Phase 1), aiming to find the safest dose for Phase 2 trials while monitoring its safety across multiple centers.

Participant Groups

Group I: GPC3+ solid tumors Experimental Treatment 1 Intervention

One time intravenous administration of BOXR1030 after completion of cyclophosphamide and fludarabine LD chemotherapy

Who Is Running the Clinical Trial?

Sotio Biotech Inc.

Lead Sponsor

Trials

2

Recruited

150+

SOTIO, LLC

Lead Sponsor

Trials

1

Recruited

110+

SOTIO Biotech a.s.

Industry Sponsor

Trials

3

Recruited

270+

SOTIO Biotech AG

Industry Sponsor

Trials

5

Recruited

450+

SOTIO Biotech

Industry Sponsor

Trials

2

Recruited

150+

Findings from Research

Glypican 3 (GPC3) is expressed in 66.3% of lung squamous cell carcinoma (LSCC) samples, making it a promising target for therapy, as it is rarely found in normal lung tissues.

CARgpc3 T cells, engineered to target GPC3, showed strong antitumor activity by effectively eliminating GPC3-positive LSCC cells in vitro and in two xenograft models, suggesting they could be a novel treatment option for LSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma. Li, K., Pan, X., Bi, Y., et al.[2020]

The fourth-generation GPC3-targeted CAR-T cells (GPC3-BBZ-7×19) demonstrated enhanced proliferation and chemotactic abilities compared to second-generation CAR-T cells, indicating a potentially more effective treatment for hepatocellular carcinoma (HCC).

In vivo studies showed that GPC3-BBZ-7×19 CAR-T cells significantly eliminated GPC3-positive HCC tumors in immunodeficient mice, suggesting they could provide a durable and effective therapeutic option for HCC in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. Huang, W., Liu, Y., Hu, Y., et al.[2020]

The study engineered CAR-T cells that can express IL-12, which significantly enhances their ability to target and destroy GPC3+ tumor cells, showing improved efficacy in both laboratory and animal models.

Inducible IL-12 expression not only boosts the antitumor response but also reduces regulatory T cell infiltration, suggesting a safer profile for CAR-T therapy, making it a promising option for patients who cannot undergo traditional lymphodepletion chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. Liu, Y., Di, S., Shi, B., et al.[2020]

T cells engineered with GPC3-targeted chimeric antigen receptors (CAR) effectively kill GPC3-positive hepatocellular carcinoma (HCC) cells in vitro, demonstrating a strong correlation between their cytotoxic activity and the level of GPC3 expression in target cells.

In vivo studies showed that third-generation GPC3-targeted CAR T cells could eradicate HCC xenografts with high GPC3 expression and significantly prolong the survival of mice with established tumors, indicating their potential as a promising treatment for GPC3-positive HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Gao, H., Li, K., Tu, H., et al.[2022]

CDR3δ-grafted γ9δ2T cells, developed from genetically modified peripheral blood lymphocytes, show strong antitumor activity against ovarian epithelial carcinoma and cervical adenocarcinoma in vitro and in vivo, indicating their potential as a promising immunotherapy.

These modified γ9δ2T cells can produce cytokines and effectively kill tumor cells, demonstrating significant antitumor effects in animal models, which supports their candidacy for clinical applications in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity. Zhao, H., Xi, X., Cui, L., et al.[2021]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

CAR-T cell therapy has shown remarkable success in treating B-cell malignancies, but researchers are focused on improving its safety and effectiveness due to risks like cytokine release syndrome and off-target effects.

Innovative safety strategies, such as ON- and OFF-switch CARs and multi-antigen-targeting CAR-T cells, are being developed to enhance the persistence and reduce adverse events associated with CAR-T therapy, paving the way for a new generation of treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Next-Generation CAR-T Cells for Better Toxicity Management. Andrea, AE., Chiron, A., Bessoles, S., et al.[2023]

Chimeric-antigen-receptor T cells (CAR-T) targeting CD19 are associated with several adverse drug reactions (ADRs), with the most common being cytokine release syndrome (CRS), neurological disorders, and hematological disorders, as identified in a study analyzing 1783 safety reports.

While CAR-T therapy can lead to severe ADRs, particularly in the week following administration, the overall fatality rate from these reactions is relatively low at 5.5%, though serious conditions like hemophagocytic-lymphohistiocytosis and infections require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. Dolladille, C., Ederhy, S., Ezine, E., et al.[2021]

T cells engineered with GPC3-specific CARs demonstrated strong cytotoxic effects against various solid tumors, including hepatocellular carcinoma and malignant rhabdoid tumors, indicating their potential as an effective treatment option.

Among the different CAR constructs tested, the GBBz CAR showed superior T cell expansion and a Th1-biased cytokine profile, suggesting it may be the most promising candidate for further clinical development in treating GPC3-positive solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. Li, W., Guo, L., Rathi, P., et al.[2022]

References

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

Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma. [2020]

2. China pubmed.ncbi.nlm.nih.gov

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. [2020]

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

Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. [2020]

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

Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. [2022]

5. China pubmed.ncbi.nlm.nih.gov

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity. [2021]

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

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Engineering Next-Generation CAR-T Cells for Better Toxicity Management. [2023]

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

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. [2021]

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

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. [2022]