GRC 54276 + Immunotherapy for Advanced Cancers

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called GRC 54276, both alone and in combination with existing immunotherapy drugs, for individuals with advanced cancers. The main aim is to determine the treatment's safety and identify the optimal dose. It is open to those who have tried other treatments for their solid tumors or lymphomas without success and have not used therapies targeting HPK1. Individuals with advanced cancer that hasn't responded to standard treatments might find this trial suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that GRC 54276 is generally well tolerated at various dose levels, meaning most participants did not experience severe side effects. In these studies, the treatment also demonstrated some effectiveness against tumors in patients with Hodgkin's lymphoma.

When combined with atezolizumab, a drug approved for certain cancers, it is important to note that atezolizumab has its own side effects, such as fatigue, reduced appetite, and nausea.

Similarly, when GRC 54276 is used with pembrolizumab, another approved cancer treatment, pembrolizumab may cause side effects like tiredness, diarrhea, and skin rash.

This clinical trial marks the first time GRC 54276 is being tested in humans. This information helps researchers determine its safety and optimal dosing. Participants will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about GRC 54276 for advanced cancers because it offers a new approach by being combined with immunotherapies like atezolizumab and pembrolizumab. While standard cancer treatments often involve chemotherapy or radiation that target rapidly dividing cells, GRC 54276 works differently by enhancing the body's immune response. This combination aims to improve how the immune system detects and attacks cancer cells, potentially leading to better outcomes for patients. Additionally, the unique pairing of GRC 54276 with these established immunotherapies could provide a more comprehensive attack on the cancer, potentially overcoming resistance issues seen with current treatments.

What evidence suggests that this trial's treatments could be effective for advanced cancers?

Research has shown that GRC 54276, one of the treatments in this trial, has promising effects against tumors in early studies, particularly in Hodgkin's lymphoma. It enhances the immune system's ability to combat cancer cells. In this trial, some participants will receive GRC 54276 with atezolizumab, a well-known cancer treatment that may further boost the immune system's fight against cancer. Atezolizumab has already been shown to extend the lives of people with some advanced cancers. Another group in this trial will receive GRC 54276 with pembrolizumab, another potent cancer treatment proven to improve survival rates in various cancers when combined with other treatments. Overall, GRC 54276, especially when paired with these treatments, could offer new hope for fighting advanced cancers. ^{1 2 4 5 6}

Who Is on the Research Team?

Veena Gupta

Principal Investigator

Glenmark Pharmaceuticals Ltd.

Are You a Good Fit for This Trial?

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

Pregnant/planning to be pregnant or breast-feeding women

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05878691

A Study of GRC 54276 in Participants With Advanced Solid ... 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 ...

2. targetedonc.com targetedonc.com/view/fda-accepts-ind-for-grc-54276-in-advanced-solid-tumors-and-lymphomas

FDA Accepts IND for GRC 54276 in Advanced Solid ... Through the inhibition of HPK1, investigators are hopeful that treatment with GRC 54276 can potentially enhance the patient's own immune system ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10429257/

PB2258: PHASE 1 FIRST IN HUMAN STUDY ... GRC54276 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to Hodgkin's lymphoma.

4. cancernetwork.com cancernetwork.com/view/fda-accepts-ind-for-hpk1-inhibitor-in-advanced-solid-tumors-and-lymphomas

FDA Accepts IND for HPK1 Inhibitor in Advanced Solid ... According to its manufacturers, GRC 54276 has previously demonstrated stand-alone efficacy and the ability to enhance current immunotherapy ...

5. journals.lww.com journals.lww.com/hemasphere/fulltext/2023/08003/pb2258__phase_1_first_in_human_study_evaluating.2115.aspx

Phase 1 first in human study evaluating the safety, ... GRC54276 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to Hodgkin's lymphoma.

6. ctv.veeva.com ctv.veeva.com/study/a-study-of-grc-54276-in-participants-with-advanced-solid-tumors-and-lymphomas

A Study of GRC 54276 in Participants With Advanced Solid ... This is first in human (FIH) study to a) evaluate the safety and tolerability profile of GRC54276, b) determine the maximum tolerated dose ...