Grapiprant + Pembrolizumab for Colorectal Cancer

No longer recruiting at 3 trial locations

Overseen By Eliana Talcove-Berko

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Arrys Therapeutics

Must not be taking: NSAIDs, COX-2 inhibitors, Aspirin

Disqualifiers: Immunodeficiency, Active CNS metastases, Autoimmune, others

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

Compensation: Varies

Number of Visits: 8

Duration: 4 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a new combination treatment for individuals with advanced colorectal cancer unresponsive to standard therapies. The treatment involves two drugs, grapiprant and pembrolizumab (KEYTRUDA), studied to assess their combined effectiveness and determine the appropriate dose for future studies. Individuals with colorectal cancer that has spread or worsened, who have tried at least two other treatments including one with fluorouracil, and have tumors suitable for biopsy might be a good fit. 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 combination therapy.

Will I have to stop taking my current medications?

The trial requires you to stop using NSAIDs, COX-2 inhibitors, and aspirin products within 3 days (preferably 7 days) before starting the treatment and during the study, unless used for managing side effects. If you are on strong CYP3A4 or P glycoprotein inhibitors or inducers, you may also need to stop those medications.

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

Research has shown that pembrolizumab is usually well-tolerated. Most people report side effects such as tiredness, rash, or itching. Less information is available about the safety of grapiprant, but it is under investigation for its potential to work well with pembrolizumab. This study is in an early stage, focusing primarily on the safety and tolerability of the combination. Researchers closely monitor for any new side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Grapiprant and Pembrolizumab for advanced or progressive MSS colorectal cancer because they bring a fresh approach to treatment. Unlike traditional therapies like chemotherapy and targeted agents such as bevacizumab, this combination leverages Grapiprant's unique ability to block the EP4 receptor, which plays a role in tumor growth and immune evasion. Pembrolizumab, an immunotherapy, works by unleashing the immune system to attack cancer cells. This combination could offer a powerful one-two punch: Grapiprant potentially making tumors more vulnerable and Pembrolizumab enhancing the immune response, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for advanced or progressive MSS CRC?

Research shows that pembrolizumab, also known as Keytruda, treats several types of cancer, such as melanoma and non-small cell lung cancer, by boosting the immune system to fight cancer cells. In this trial, participants in Cohort 1 will initially receive grapiprant alone, followed by a combination of grapiprant and pembrolizumab. Participants in Cohort 2 will receive grapiprant with pembrolizumab from the start. Researchers are studying grapiprant to see if it can enhance pembrolizumab's effectiveness. Early results suggest that using these two drugs together might offer a new way to treat advanced or worsening colorectal cancer. Although this combination remains under study, the hope is to provide a new treatment option for those who haven't had success with other therapies. ^{1 2 3 5 6}

Who Is on the Research Team?

Sergio Santillana, MD

Principal Investigator

Ikena Oncology

Sergio Santillana, MD

Principal Investigator

Ikena Oncology

Are You a Good Fit for This Trial?

Inclusion Criteria

Patients must have a histologically confirmed advanced, metastatic, or progressive Microsatellite Stable (MSS) Colorectal Cancer (CRC) per institutional standards.

Patient has received at least two prior lines of therapy for advanced or metastatic CRC, at least one of which included fluorouracil.

Highly effective birth control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

Participants receive grapiprant alone to assess safety and tolerability

1 week

Daily visits for 7 days

Treatment

Participants receive grapiprant in combination with pembrolizumab to determine the recommended phase 2 dose and evaluate pharmacokinetics

4 months

Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 90 days after the end of treatment

What Are the Treatments Tested in This Trial?

Interventions

• Grapiprant
• Pembrolizumab

How Is the Trial Designed?

Group I: Cohort 2 Experimental Treatment 1 Intervention

Participants will be treated with grapiprant in combination with pembrolizumab.

Group II: Cohort 1 Experimental Treatment 2 Interventions

Single Agent run-in with grapiprant and then combination treatment of grapiprant and pembrolizumab.

Who Is Running the Clinical Trial?

Arrys Therapeutics

Lead Sponsor

Trials

2

Recruited

70+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03658772

NCT03658772 | Grapiprant and Pembrolizumab in Patients ... This is a phase 1b, multi-center, open label study designed to assess safety and tolerability of grapiprant in combination with pembrolizumab, to determine the ...

2. med.stanford.edu med.stanford.edu/mosslab/research/_jcr_content/main/clinicaltrials.html?start=2520

Grapiprant (ARY-007) and Pembrolizumab in Patients With ... This is a phase 1b/2, multi-center, open label study designed to assess safety and tolerability of grapiprant in combination with pembrolizumab, to determine ...

3. withpower.com withpower.com/trial/phase-1-colorectal-neoplasms-8-2018-83d7c

Grapiprant and Pembrolizumab in Patients With Advanced ... Pembrolizumab, also known as Keytruda, has shown effectiveness in treating various cancers, including melanoma and non-small cell lung cancer, by helping the ...

4. mayo.edu mayo.edu/research/clinical-trials/cls-20447145

A Study of Grapiprant and Pembrolizumab in Patients with ... The purpose of this study is to assess safety and tolerability of grapiprant in combination with pembrolizumab, to determine the recommended phase 2 dose (RP2D) ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-00036

Grapiprant and Pembrolizumab in Patients With Advanced ... This is a phase 1b, multi-center, open label study designed to assess safety and tolerability of grapiprant in combination with pembrolizumab.

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/01/NCT05041101/Prot_SAP_001.pdf

Proprietary Information of MD Anderson To determine the safety and efficacy of grapiprant and eribulin combination treatment for the patient with metastatic inflammatory breast cancer ...