Immunotherapy + Targeted Therapy for Metastatic Colorectal Cancer

Overseen By UCSF HDFCCC Cancer Immunotherapy Program (CIP)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Francisco

Must not be taking: Immunosuppressants, Steroids, others

Disqualifiers: HIV, Autoimmune, Hepatitis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 98

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, pembrolizumab and vactosertib, for individuals with colorectal cancer that has spread to the liver. Pembrolizumab (also known as KEYTRUDA) is an immunotherapy that aids the immune system in fighting cancer, while vactosertib targets enzymes essential for cancer cell growth. The researchers aim to determine if these treatments, administered after standard chemotherapy and before liver surgery, can shrink the cancer and reduce the likelihood of recurrence. This trial may suit someone with colorectal cancer that has spread to the liver, who has already undergone chemotherapy, and whose cancer is surgically removable. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy, systemic steroids, or have recently received certain cancer treatments, you may need to stop or adjust those medications. It's best to discuss your specific situation with the trial team.

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 certain immunosuppressive therapies or have recently received certain cancer treatments, you may need to stop or adjust those before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research shows that the combination of pembrolizumab and vactosertib is generally safe. Studies have found that this treatment has a manageable safety profile, with side effects typically not severe and treatable with standard care. For patients with metastatic colorectal cancer (MSS mCRC), this combination has shown promising results in both effectiveness and safety. Most patients tolerated the treatment well, experiencing no serious problems. While all treatments can have side effects, the data suggest these are not overwhelming for this combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and vactosertib for metastatic colorectal cancer because it offers a new approach by integrating immunotherapy with targeted therapy. While standard treatments often involve chemotherapy and radiation, pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells more effectively. Vactosertib, on the other hand, targets specific proteins involved in cancer cell growth, potentially enhancing the effectiveness of pembrolizumab. By combining these mechanisms, this treatment could improve outcomes for patients with advanced colorectal cancer beyond what current options provide.

What evidence suggests that pembrolizumab and vactosertib might be effective for metastatic colorectal cancer?

In this trial, participants will receive a combination of pembrolizumab and vactosertib, which research has shown to be promising for treating microsatellite stable metastatic colorectal cancer (MSS mCRC), a type of advanced colon cancer. Studies have found that this treatment can shrink tumors and extend patient survival. Most side effects are manageable and not too severe for most people. Vactosertib blocks certain proteins that tumors need to grow, while pembrolizumab enhances the immune system's ability to fight cancer cells. Together, they may reduce tumor size before surgery and lower the risk of cancer returning afterward. ^{1 2 3 4 6}

Who Is on the Research Team?

Chloe E. Atreya, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for adults with colorectal cancer that has spread to the liver and can be surgically removed. Participants must have had oxaliplatin-based chemo, be able to undergo a liver biopsy and surgery, use contraception if of childbearing potential, and not have certain health conditions or recent treatments that could affect the trial.

Inclusion Criteria

Willing and able to provide written informed consent/assent for the trial

I agree to provide a recent biopsy sample for the study.

I am a man who can father a child and will use birth control.

Exclusion Criteria

I have another cancer that has gotten worse or needed treatment in the last 5 years.

I am still recovering from side effects or complications of a recent surgery or procedure.

I have had liver-targeted therapy like radiotherapy or yttrium-90 on the lesion to be biopsied in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive pembrolizumab intravenously and vactosertib orally before surgery to shrink the cancer

2 weeks

1 visit (in-person) for pembrolizumab administration, daily oral intake of vactosertib

Surgery

Standard of care surgical removal of liver metastases

1 week

1 visit (in-person) for surgery

Optional Adjuvant Treatment

Eligible patients may receive pembrolizumab and vactosertib every 6 weeks for up to 1 year

Up to 1 year

Every 6 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 90 days (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Vactosertib

Trial Overview

The study tests pembrolizumab (an immunotherapy drug) combined with vactosertib after standard chemotherapy but before liver surgery in patients with colorectal cancer. The goal is to shrink the cancer before removal and reduce recurrence risk after surgery.

How Is the Trial Designed?

Group I: Treatment (vactosertib, pembrolizumab, surgery) Experimental Treatment 3 Interventions

Neoadjuvant pembrolizumab will be administered at a fixed dose of 200 mg (IV) for 1 cycle plus 200 mg vactosertib (PO QD, 5 days per week x 2 weeks). Adjuvant pembrolizumab (400 mg IV) + vactosertib (200 mg PO QD Cycle 1, 5 days per week, Cycles 2 and beyond (200 mg BID, 5 days per week) will be administered for up to eight 6-week cycles

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Chloe Atreya, MD, PhD

Lead Sponsor

Trials

1

Recruited

6+

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

MedPacto, Inc.

Industry Sponsor

Trials

11

Recruited

370+

Published Research Related to This Trial

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]

In a phase II study involving 124 patients with metastatic MSI-H/dMMR colorectal cancer, pembrolizumab demonstrated an objective response rate of 33% in both treatment cohorts, indicating its efficacy in this difficult-to-treat population.

The treatment showed a manageable safety profile, with 16% of patients in cohort A and 13% in cohort B experiencing grade 3-4 adverse events, suggesting that pembrolizumab can be safely administered to patients with prior treatment failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. Le, DT., Kim, TW., Van Cutsem, E., et al.[2021]

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]

In the final analysis of the KEYNOTE-164 study, pembrolizumab demonstrated a 32.8% objective response rate in patients with advanced MSI-H/dMMR colorectal cancer who had received multiple prior treatments, indicating its efficacy in this difficult-to-treat population.

The treatment was associated with a median overall survival of 31.4 months for patients with more prior therapies and 47.0 months for those with fewer, while maintaining a manageable safety profile with no new safety concerns reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Le, DT., Diaz, LA., Kim, TW., et al.[2023]

Pembrolizumab (Keytruda) has been approved for treating metastatic microsatellite instability-high colorectal cancer (CRC), showing promising efficacy in a small phase 2 clinical trial, which highlights the potential of immunotherapy in this cancer type.

Microsatellite instability-high CRCs that express PD-L1 are more likely to respond to PD-1/PD-L1 checkpoint inhibitors, while microsatellite-stable tumors show much less response, indicating the importance of PD-1/PD-L1 testing in guiding treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II-The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer. Marginean, EC., Melosky, B.[2022]

Pembrolizumab significantly improved progression-free survival (PFS) in patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer, with a median PFS of 16.5 months compared to 8.2 months for standard chemotherapy, indicating its efficacy as a first-line treatment.

The FDA found no safety concerns during the approval process, and while both pembrolizumab and standard of care had similar adverse reactions, the duration of treatment with pembrolizumab was nearly double that of standard care, suggesting a potentially more favorable treatment profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. Casak, SJ., Marcus, L., Fashoyin-Aje, L., et al.[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 (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

The KEYNOTE-177 study demonstrated that pembrolizumab significantly improves progression-free survival compared to the current standard of care for patients with metastatic colorectal cancer that has DNA mismatch repair or microsatellite instability-high.

This finding suggests that pembrolizumab could be a more effective first-line treatment option for this specific type of colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Inhibitor Bests Chemo for Colorectal Cancer. [2021]

Citations

1.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(23)02646-7/fulltext

618P Efficacy and safety of vactosertib and pembrolizumab ...

Vactosertib combined with pembrolizumab showed anti-tumor activity, prolonged overall survival and manageable safety profiles in patients with MSS mCRC.

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.3573

Efficacy and safety of vactosertib and pembrolizumab ...

The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03724851

Study Details | NCT03724851 | Vactosertib in Combination ...

This is phase 1b/2a, open label, multi-center study to assess safety, tolerability, pharmacokinetics and anti-tumor activity of vactosertib in combination ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10624787/

Vactosertib potently improves anti-tumor properties of 5-FU ...

It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation ...

5.

medpacto.com

medpacto.com/uploadata/publication/20/20_2022-11-22

Efficacy and Safety of Vactosertib and Pembrolizumab ...

Efficacy and Safety of Vactosertib and Pembrolizumab Combination in Patients with Previously Treated. Microsatellite Stable Metastatic Colorectal Cancer.

6.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(23)02646-7/pdf

618P Efficacy and safety of vactosertib and pembrolizumab ...

Here we report the updated safety and efficacy data of this phase 1b/2a study ... (3L) metastatic colorectal cancer (mCRC) patients: Interim results from the ...