GRC 54276 + Immunotherapy for Advanced Cancers

Recruiting at 17 trial locations

Overseen By Jatin Kadam

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Glenmark Specialty S.A.

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Brain metastasis, Active malignancy, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 18 weeks

320 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive medications, you may need to stop them at least 14 days before starting the study drugs, unless they fall under specific exceptions.

What data supports the effectiveness of the drug combination GRC 54276 + Immunotherapy for Advanced Cancers?

The research suggests that combining different treatments, like immunotherapy and other drugs, can enhance effectiveness in treating advanced cancers, as seen in studies with other cancer types. ^{1 2 3 4 5}

What is the safety profile of immunotherapy treatments like GRC 54276 and immune checkpoint inhibitors?

Immunotherapy treatments, including immune checkpoint inhibitors like Atezolizumab (Tecentriq) and Pembrolizumab (KEYTRUDA), can cause a range of immune-related side effects affecting various body systems, such as the endocrine, nervous, and gastrointestinal systems. These side effects can be uncommon but significant, and patients receiving these treatments are at a higher risk of developing them compared to those on other cancer therapies. ^{6 7 8 9 10}

What makes the treatment GRC 54276 unique for advanced cancers?

GRC 54276 combined with immunotherapy is unique because it potentially offers a novel approach by enhancing the immune system's ability to fight cancer, which may differ from traditional treatments that primarily focus on directly targeting cancer cells. This combination could provide a new option for patients with advanced cancers who have limited treatment choices. ^{11 12 13 14 15}

What is the purpose of this trial?

This is first in human (FIH) study to a) evaluate the safety and tolerability profile of GRC54276, b) determine the maximum tolerated dose (MTD) and recommended Phase 2 doses (RP2D), and c) pharmacokinetic profile of GRC54276 alone and in combination with pembrolizumab or atezolizumab in participants with advanced solid tumors and lymphomas.

Research Team

Veena Gupta

Principal Investigator

Glenmark Pharmaceuticals Ltd.

Eligibility Criteria

Adults with advanced solid tumors or lymphomas that have progressed after standard treatments, who haven't tried HPK1-targeting therapy. They should be in relatively good health (ECOG ≤1), have a life expectancy of at least 3 months, measurable disease per RECIST 1.1 criteria, and proper organ function including heart and kidneys. Pregnant women, those with severe allergies to trial drugs or their components, uncontrolled brain metastases, recent other cancers or immunosuppressive treatment are excluded.

Inclusion Criteria

My kidneys work well, with a creatinine clearance rate of 60 mL/min or more.

My heart pumps well, with an ejection fraction of 50% or higher.

I am 18 or older with advanced cancer or lymphoma that can't be surgically removed, have tried or can't undergo standard treatment, and haven't had HPK1-targeted therapy.

Exclusion Criteria

I haven't taken strong immune system medications in the last 2 weeks, except for low-dose or topical steroids.

Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of subject safety or study results

I have stable brain metastases and haven't needed steroids for them in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GRC54276 alone or in combination with pembrolizumab or atezolizumab to evaluate safety, tolerability, and pharmacokinetics

18 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 120 days

Long-term follow-up

Participants are evaluated for overall response rate and disease control rate

up to 9 months

Treatment Details

Interventions

• Atezolizumab
• GRC 54276
• Pembrolizumab

Trial Overview This first-in-human study tests GRC54276 alone and combined with pembrolizumab or atezolizumab in patients with advanced cancer. It aims to find the safest dose for future studies (MTD), decide on Phase 2 doses (RP2D), and understand how the body processes these drugs (pharmacokinetics).

Participant Groups

Group I: GRC 54276 with pembrolizumab Experimental Treatment 1 Intervention

Group II: GRC 54276 with atezolizumab Experimental Treatment 1 Intervention

Group III: GRC 54276 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Glenmark Specialty S.A.

Lead Sponsor

Trials

6

Recruited

3,900+

Findings from Research

The combination of regorafenib, ipilimumab, and nivolumab (RIN) was found to be safe and effective for treating patients with microsatellite stable (MSS) metastatic colorectal cancer, with a recommended phase 2 dose (RP2D) established at 80 mg of regorafenib daily, showing an overall response rate of 27.6%.

In patients without liver metastases, the treatment showed even better outcomes, with a response rate of 36.4% and a median overall survival of over 22 months, indicating that this combination therapy could be a promising option for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. Fakih, M., Sandhu, J., Lim, D., et al.[2023]

In a large registry study involving 1976 patients with metastatic castration-resistant prostate cancer, sipuleucel-T immunotherapy demonstrated a median overall survival of 30.7 months, indicating its potential effectiveness in prolonging life for this patient group.

The treatment was associated with a low incidence of serious adverse events (3.9%) and cerebrovascular events (2.8%), suggesting that sipuleucel-T is a relatively safe option for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer. Higano, CS., Armstrong, AJ., Sartor, AO., et al.[2021]

In a phase II clinical trial involving 60 patients with advanced solid tumors, the combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenic therapy resulted in an objective response rate (ORR) of 34.6% and a disease control rate (DCR) of 82.7%, indicating promising anti-tumor activity.

The treatment was generally well tolerated, with 91.7% of patients experiencing treatment-related adverse events, the most common being lymphopenia, anemia, and leukopenia, suggesting that while side effects were prevalent, the combination therapy was manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter, single-arm, phase II study (CAP) of radiotherapy plus liposomal irinotecan followed by camrelizumab and anti-angiogenic treatment in advanced solid tumors. Shen, J., Yan, J., Du, J., et al.[2023]

The OTSGC-A24 cancer vaccine was well tolerated in a phase I/Ib trial with 24 patients suffering from advanced gastric cancer, showing no dose-limiting toxicities and manageable side effects like decreased appetite and injection site reactions.

Significant immune responses were observed, with 90% of patients showing positive cytotoxic T lymphocyte (CTL) responses at 12 weeks, leading to a recommended dosing schedule of 1 mg every 2 weeks for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer. Sundar, R., Rha, SY., Yamaue, H., et al.[2022]

Immunotherapy has revolutionized cancer treatment, becoming a standard approach for various cancer types, but it also introduces a wide range of adverse events affecting multiple organ systems.

The review highlights the increasing occurrence of uncommon immune-related adverse events (affecting less than 1% of patients) as immunotherapy use expands, emphasizing the need for better awareness and diagnostic strategies among healthcare professionals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Uncommon Adverse Events in Patients with Cancer Treated with Immunotherapy. Albarrán-Artahona, V., Laguna, JC., Gorría, T., et al.[2022]

A review of 2217 adverse drug reaction reports related to immune checkpoint inhibitors (ICIs) from 2011 to 2018 revealed that these drugs, particularly nivolumab, are associated with a higher frequency of serious immune-related adverse events, including gastrointestinal and respiratory disorders.

Emerging safety signals, such as ischaemic heart disease and cardiac failure, were identified, indicating the need for further investigation into the long-term safety profile of ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. Cutroneo, PM., Isgrò, V., Ientile, V., et al.[2021]

In a study analyzing nationwide insurance claims data from 92,858 patients over 8 years, it was found that patients receiving immune checkpoint inhibitors had a 1.50-4.00 times higher risk of developing immune-related adverse events (irAEs) compared to those receiving chemotherapy or targeted therapy.

Among the immunotherapy agents, nivolumab was associated with a higher risk of irAEs than pembrolizumab, highlighting the importance of monitoring these adverse effects in cancer patients undergoing immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types. Wang, F., Yang, S., Palmer, N., et al.[2023]

Immunotherapy, particularly immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1, has shown high efficacy in treating various cancers, with approvals for at least 16 tumor types, including those with specific genetic markers like MSI-H.

Despite their effectiveness, immunotherapies can lead to significant adverse events, including immune-related adverse events (irAEs) and other toxicities, highlighting the need for careful monitoring and management in patients undergoing these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The dark side of immunotherapy. Okwundu, N., Grossman, D., Hu-Lieskovan, S., et al.[2022]

The phase I clinical trial involving 18 patients with advanced colorectal cancer demonstrated that a combination vaccine using multiple peptides was well tolerated, with no severe systemic adverse events reported.

The treatment induced a dose-dependent immune response, with patients showing better outcomes (median overall survival of 27.8 months) when specific cytotoxic T lymphocytes were activated, highlighting the potential efficacy of this peptide-based vaccine approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome. Hazama, S., Nakamura, Y., Takenouchi, H., et al.[2021]

References

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

Regorafenib, Ipilimumab, and Nivolumab for Patients With Microsatellite Stable Colorectal Cancer and Disease Progression With Prior Chemotherapy: A Phase 1 Nonrandomized Clinical Trial. [2023]

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

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Multicenter, single-arm, phase II study (CAP) of radiotherapy plus liposomal irinotecan followed by camrelizumab and anti-angiogenic treatment in advanced solid tumors. [2023]

4. England pubmed.ncbi.nlm.nih.gov

A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer. [2022]

5. Pakistan pubmed.ncbi.nlm.nih.gov

Clinical effect and safety of targeted therapy combined with chemotherapy in the treatment of patients with advanced colon cancer. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Immune-Related Uncommon Adverse Events in Patients with Cancer Treated with Immunotherapy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types. [2023]

9. China pubmed.ncbi.nlm.nih.gov

The dark side of immunotherapy. [2022]

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

Evaluating Survival After Hospitalization Due to Immune-Related Adverse Events From Checkpoint Inhibitors. [2023]

11. England pubmed.ncbi.nlm.nih.gov

The evolving landscape of immunotherapy in advanced prostate cancer. [2020]

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

Treatment of biochemical recurrence of prostate cancer with granulocyte-macrophage colony-stimulating factor secreting, allogeneic, cellular immunotherapy. [2008]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Trial on the Safety and Tolerability of Personalized Cancer Vaccines Using Human Platelet Lysate-Induced Antigen-Presenting Cells. [2023]

14. England pubmed.ncbi.nlm.nih.gov

A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome. [2021]

15. Greece pubmed.ncbi.nlm.nih.gov

Quantitative analysis and clonal characterization of T-cell receptor β repertoires in patients with advanced non-small cell lung cancer treated with cancer vaccine. [2020]