Immunotherapy + Targeted Therapy for Metastatic Colorectal Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Waitlist Available
Sponsor: University of California, San Francisco
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 3 jurisdictions
Trial Summary
What is the purpose of this trial?This phase II trials studies how well pembrolizumab and vactosertib work after standard of care chemotherapy in patients with colorectal cancer that has spread to the liver that can be removed by surgery (resectable hepatic metastases). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vactosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and vactosertib after standard of care chemotherapy, but before liver metastases surgery, may help shrink the cancer prior to surgery. This study also investigates pembrolizumab and vactosertib after liver metastases surgery, decrease the risk of the cancer recurring (coming back).
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.
Is the drug Pembrolizumab a promising treatment for metastatic colorectal cancer?
Yes, Pembrolizumab is a promising treatment for metastatic colorectal cancer, especially for patients with a specific type of cancer called microsatellite instability-high (MSI-H). It has been approved by the FDA for this use and has shown to improve survival rates compared to standard chemotherapy.
13579What safety data is available for the treatment of metastatic colorectal cancer using Pembrolizumab and Vactosertib?
Pembrolizumab, also known as Keytruda or MK-3475, has been evaluated for safety in various studies. In the KEYNOTE-177 study for metastatic colorectal cancer, common adverse reactions in over 30% of patients included diarrhea, fatigue/asthenia, and nausea. In other studies, such as for metastatic melanoma, common adverse reactions included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions like pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders were also noted. Pembrolizumab has shown a manageable safety profile with durable clinical benefits in various cancers. However, specific safety data for the combination of Pembrolizumab and Vactosertib (also known as EW-7197, TEW-7197, NOV 1301) in metastatic colorectal cancer is not detailed in the provided research.
12789What data supports the idea that Immunotherapy + Targeted Therapy for Metastatic Colorectal Cancer is an effective drug?
The available research shows that pembrolizumab, a drug used in Immunotherapy + Targeted Therapy, is effective for treating metastatic colorectal cancer with specific genetic features. In the KEYNOTE-177 study, patients who received pembrolizumab had a longer time before their cancer got worse compared to those who received standard chemotherapy. Specifically, the median time was 16.5 months for pembrolizumab versus 8.2 months for standard care. This suggests that pembrolizumab can be more effective than traditional treatments for certain patients with this type of cancer.
34679Eligibility Criteria
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
My colorectal cancer has spread to my liver.
My colorectal cancer is not microsatellite instability-high (MSI-H).
I am 18 years old or older.
I have been treated with oxaliplatin-based chemotherapy before.
I have received oxaliplatin-based chemotherapy before.
I am fully active or restricted in physically strenuous activity but can do light work.
I am fully active or can carry out light work.
Exclusion Criteria
I have an immune system disorder or have been on steroids or immune-suppressing drugs recently.
I have not needed treatment for an autoimmune disease in the last 2 years.
I have had brain function issues in the last 6 months.
My cancer has spread to my brain or its coverings.
I have fluid buildup in my abdomen or around my lungs that causes symptoms.
I am currently on medication for an infection.
I have been diagnosed with HIV.
I have had pneumonitis treated with steroids or have it now.
I do not have any serious illnesses that are not under control.
I have had an organ or bone marrow transplant.
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Treatment (vactosertib, pembrolizumab, surgery)Experimental Treatment3 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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of California, San FranciscoSan Francisco, CA
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Who is running the clinical trial?
University of California, San FranciscoLead Sponsor
Chloe Atreya, MD, PhDLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
MedPacto, Inc.Industry Sponsor
References
Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.
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. [2022]- The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti-programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability-high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability-high CRC.
Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. [2021]KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC).
Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.
PD-1 Inhibitor Bests Chemo for Colorectal Cancer. [2021]Findings from the KEYNOTE-177 study indicate that pembrolizumab is superior to the current standard of care, significantly improving progression-free survival when deployed up front to treat patients with metastatic DNA mismatch repair/microsatellite instability-high colorectal cancer.
FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. [2022]The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4-32.4) versus 8.2 months (95% CI: 6.1-10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45-0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0-30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.
Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).
Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. [2023]Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented.