GIGA-564 for Advanced Cancer

Overseen By James Gulley

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: GigaGen, Inc.

Must not be taking: Systemic steroids

Disqualifiers: Hepatitis B, Hepatitis C, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess the safety and tolerability of GIGA-564 and identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) level(s) of GIGA-564 in participants with metastatic or locally advanced solid tumor malignancies.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does allow certain FDA-approved hormonal therapies. If you are on systemic steroids, you need to stop them at least 10 days before enrolling, unless they are for specific conditions like hormone replacement or local treatments.

What data supports the effectiveness of the drug GIGA-564 for advanced cancer?

Research shows that drugs similar to GIGA-564, which block CTLA-4 (a protein that slows down the immune system), can help the body's immune system fight cancer. These drugs have shown some success in treating advanced cancers like melanoma by enhancing the body's immune response to tumors. ^{1 2 3 4 5}

What safety information is available for GIGA-564 (Anti-CTLA-4 monoclonal antibody)?

Anti-CTLA-4 antibodies, like GIGA-564, have been tested in cancer patients and can cause immune-related side effects, such as inflammation in the gut and skin rashes. These side effects are generally manageable, but in some cases, they may require treatment with immune-suppressing drugs and can lead to lasting damage. ^{1 5 6 7 8}

What makes the drug GIGA-564 unique for treating advanced cancer?

GIGA-564 is unique because it is an anti-CTLA-4 monoclonal antibody that works by blocking a protein (CTLA-4) on T-cells, which normally helps keep the immune system in check. By blocking this protein, GIGA-564 enhances the immune system's ability to attack cancer cells, offering a novel approach compared to traditional cancer treatments. ^{1 5 9 10 11}

Eligibility Criteria

This trial is for people with advanced or widespread solid tumors. Participants must have a tumor that's grown despite treatment, or they can't receive other standard treatments. The exact eligibility criteria are not provided, but typically include factors like age, health status, and previous treatments.

Inclusion Criteria

Life expectancy greater than three months

Willing and able to provide informed consent

Measurable disease on imaging as based on Response Evaluation Criteria in RECIST 1.1

Exclusion Criteria

History of hepatitis B (HBV) infection unless viral load is undetectable

Pregnant or breastfeeding

I have not been treated with therapies targeting CCR8, CD25, or TIGIT.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase 1A)

Participants receive GIGA-564 intravenously over at least 60 minutes on Day 1 of every 3 weeks for up to 4 cycles to evaluate up to 5 dose levels

12 weeks

Dose Expansion (Phase 1B)

Participants receive up to 4 cycles of one of up to three tolerable dose levels of GIGA-564 intravenously over at least 60 minutes on Day 1 of every 3 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GIGA-564

Trial Overview The study is testing GIGA-564 to find the highest dose patients can take without serious side effects (MTD) and to decide on the best dose for future studies (RP2D). It's an early-phase trial focusing on safety and dosage levels.

Participant Groups

Group I: GIGA-564: Dose Expansion (Phase 1B) Experimental Treatment 1 Intervention

Dose expansion (Phase 1B) of selected dose levels may be initiated following the preliminary clearance of those specified dose levels from the dose escalation (Phase 1A) as determined by the Sponsor and SRC. Participants will receive up to 4 cycles of one of up to three tolerable dose levels of GIGA-564. GIGA-564 will be given intravenously over at least 60 minutes on Day 1 of every 3 weeks (3 weeks = 1 cycle) for up to 4 cycles until time of confirmed disease progression, unacceptable toxicity, or other reason for treatment discontinuation.

Group II: GIGA-564: Dose Escalation (Phase 1A) Experimental Treatment 1 Intervention

Up to 5 dose levels \[0.3, 1.0, 3.0, 10.0, and 20.0 milligrams per kilogram (mg/kg)\] will be evaluated sequentially. Participants will receive GIGA-564 intravenously over at least 60 minutes on Day 1 of every 3 weeks (3 weeks = 1 cycle) for up to 4 cycles until time of confirmed disease progression, unacceptable toxicity, or other reason for treatment discontinuation.

Who Is Running the Clinical Trial?

GigaGen, Inc.

Lead Sponsor

Trials

2

Recruited

60+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Monoclonal antibodies targeting CTLA4 enhance T-cell activation, which may lead to a stronger immune response against advanced cancers, showing promise as a novel immunotherapy.

While these anti-CTLA4 mAbs have demonstrated antitumor activity in some patients with manageable side effects, further research is needed to fully understand their mechanisms and validate findings through randomized clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current experience with CTLA4-blocking monoclonal antibodies for the treatment of solid tumors. Agarwala, SS., Ribas, A.[2011]

In a study of 19 patients with metastatic melanoma treated with the anti-CTLA4 antibody tremelimumab, there was a significant increase in intratumoral infiltration (ITI) by CD8(+) T cells after treatment, with changes ranging from 1-fold to 100-fold in most cases.

Despite the increase in T cell infiltration, there was no significant difference in the characteristics or activation levels of T cells between patients who responded to treatment and those who did not, suggesting that increased T cell presence alone does not guarantee a positive tumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Huang, RR., Jalil, J., Economou, JS., et al.[2022]

CTLA-4 blockade, either alone or in combination with PD-1 blockade, effectively activates T cells and shows clinical benefits in melanoma patients, highlighting its role in cancer immunotherapy.

While CTLA-4 blockade has been established as a treatment for melanoma, further research is needed to explore its efficacy in other types of cancer, necessitating well-designed clinical trials that consider immune biology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTIA-4 blockade therapy; biology and clinical activity. Tada, K., Heike, Y.[2019]

Blocking CTLA-4 with anti-CTLA-4 monoclonal antibodies enhances T-cell activation, leading to a stronger immune response against tumors, particularly in metastatic melanoma.

Preliminary studies show that anti-CTLA-4 mAbs are effective and well-tolerated in cancer treatment, with ongoing trials exploring their use in various cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4: negative regulator of the immune response and a target for cancer therapy. Keilholz, U.[2022]

In a phase II trial involving 47 patients with treatment-refractory colorectal cancer, tremelimumab showed limited efficacy as a single agent, with only one patient (2%) achieving a partial response and 21 patients (45%) surviving for at least 180 days after treatment.

The treatment was associated with some grade 3/4 adverse events, including diarrhea and ulcerative colitis, but these were generally manageable, suggesting that while tremelimumab may not be effective alone, it could be safe for further exploration in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. Chung, KY., Gore, I., Fong, L., et al.[2022]

CTLA4 blocking monoclonal antibodies, specifically ipilimumab and tremelimumab, have shown the ability to induce long-lasting tumor responses in patients with metastatic melanoma, with objective responses observed in 5 to 20% of cases during early clinical trials.

While these treatments can lead to significant and sometimes severe immune-related toxicities, such as colitis and skin rashes, they also demonstrate the potential to break immune tolerance and achieve durable cancer regressions, warranting further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CTLA4 Antibody Clinical Trials in Melanoma. Ribas, A.[2022]

PF-06801591, a monoclonal antibody targeting the PD-1 receptor, was found to be safe and tolerable in a phase 1 trial with 40 patients, showing no dose-limiting toxic effects and manageable adverse events for both intravenous and subcutaneous administration.

The study demonstrated that monthly subcutaneous administration of PF-06801591 is a convenient and effective alternative to intravenous delivery, with an overall objective response rate of 18.4% and full PD-1 receptor occupancy achieved across all dose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Subcutaneous vs Intravenous Administration of Anti-PD-1 Antibody PF-06801591 in Patients With Advanced Solid Tumors: A Phase 1 Dose-Escalation Trial. Johnson, ML., Braiteh, F., Grilley-Olson, JE., et al.[2022]

The dual variable domain immunoglobulin (anti-CTLA4 DVD) effectively targets tumors while minimizing immune-related adverse events by preserving beneficial tissue-resident Tregs, as shown in experiments with Rag 1-/- mice.

This innovative approach enhances antitumor efficacy by reducing tumor-infiltrating Tregs and increasing CD8+ T lymphocyte infiltration, demonstrating a mechanism that separates effective cancer treatment from harmful side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. Pai, CS., Simons, DM., Lu, X., et al.[2020]

The study identified two specific single-chain variable fragment (scFv) antibodies that effectively bind to the CTLA-4 receptor, which is crucial for inhibiting T-cell function in cancer, suggesting their potential use in targeted cancer therapy.

These scFvs were shown to selectively react with the CTLA-4 epitope in laboratory tests, indicating their specificity and potential effectiveness in activating the immune response against tumors by blocking CTLA-4.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Production and Evaluation of Specific Single-Chain Antibodies against CTLA-4 for Cancer-Targeted Therapy. Hosseinzadeh, F., Mohammadi, S., Nejatollahi, F.[2022]

Zimberelimab (GLS-010) is a highly effective human monoclonal antibody that binds strongly to the PD-1 receptor, blocking its interaction with PD-L1/2, which is crucial for T cell activation.

In preclinical studies, GLS-010 demonstrated significant anti-tumor effects in mice, indicating its potential as a promising treatment for cancer, warranting further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. Lou, B., Wei, H., Yang, F., et al.[2022]

In a phase I trial involving 39 patients with solid tumors, CP-675,206, an anti-CTLA4 monoclonal antibody, was found to be safe at doses up to 15 mg/kg, with dose-limiting toxicities including autoimmune reactions like diarrhea and dermatitis.

The treatment showed promising antitumor activity, particularly in melanoma, with two patients achieving complete responses lasting over 25 months and several others experiencing stable disease or prolonged periods without disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. Ribas, A., Camacho, LH., Lopez-Berestein, G., et al.[2022]

References

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

Current experience with CTLA4-blocking monoclonal antibodies for the treatment of solid tumors. [2011]

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

CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. [2022]

3. Japan pubmed.ncbi.nlm.nih.gov

CTIA-4 blockade therapy; biology and clinical activity. [2019]

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

CTLA-4: negative regulator of the immune response and a target for cancer therapy. [2022]

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

Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. [2022]

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

Anti-CTLA4 Antibody Clinical Trials in Melanoma. [2022]

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

Assessment of Subcutaneous vs Intravenous Administration of Anti-PD-1 Antibody PF-06801591 in Patients With Advanced Solid Tumors: A Phase 1 Dose-Escalation Trial. [2022]

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

Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity. [2020]

9. Iran pubmed.ncbi.nlm.nih.gov

Production and Evaluation of Specific Single-Chain Antibodies against CTLA-4 for Cancer-Targeted Therapy. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. [2022]

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

Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. [2022]