Recruiting Phase III Clinical Trials for Colorectal Cancer

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Clinical Trial Conversations
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Phase III clinical trials evaluate new treatments that have already worked well for patients in a phase II clinical trial. Physicians compare the experimental treatment with the conventional treatment, which is the most effective known treatment at this time, also called standard of care. Phase III clinical trials seek to answer the question, "Is the new treatment being studied in this phase III trial more effective than the current standard of care? These phase III clinical trials have the potential to change clinical practice guidelines.

So far in smaller early phase trials, this treatment has given very promising results, but unless tested in a large group of people, it cannot be confirmed that the benefits seen in the earlier phase trials will be seen in larger phase III trials. As a result, phase III trials are randomized, which means the patients are assigned to the arms by chance. Another usual characteristic of phase III clinical trials is that both participants and researchers don't know which arm the patient will be in (also known as a "double blind" study). Most phase III clinical trials involve a large number, at least several hundred, of participants. Phase III clinical trials usually take longer than phase I and phase II studies.

Often, phase III studies are conducted across and throughout the country – and even around the world – at the same time. So phase III clinical trials may be available at local healthcare centers in addition to large hospitals.

Patients in clinical trials are always receiving treatment. If a placebo is being used in a phase III clinical trial, it is often used in addition to a treatment that works for a patient. 

A phase III clinical trial grants the possibility of benefiting from a therapy that is not yet available to patients outside the clinical trial setting. Even those in the arm receiving standard of care will benefit from increased monitoring of their disease. Every participant in these research studies is helping to ensure that other patients can benefit in the future from the discoveries made.

Trials with targeted therapies against specific mutations:

Sotorasib and Panitumumab Versus Investigator's Choice for Participants with KRAS p.G12C Mutation (CodeBreak 300): https://clinicaltrials.gov/ct2/show/NCT05198934

This is a 153 participant trial in the second line setting open at 83 locations all over the world for metastatic colorectal cancer patients with a KRAS G12C mutation.

The trial has three arms: In Arm A patients will get 960 mg daily dose of of sotorasib + panitumumab (pmab), an anti-EGFR antibody, Arm B patients will get 240 mg of sotorasib + Pmab, and Arm C is the investigator choice control arm where patients get third-line SOC drugs, TAS 102 or regorafenib. Eligible participants have received at least one prior line of therapy and progressed on 5FU + oxaliplatin or irinotecan, or not a candidate for these drugs, but they are able to have TAS102 or regorafenib. Patients with brain mets are ineligible. Other inclusion/exclusion criteria are on the clinicaltrials.gov website.

The primary endpoint is progression-free survival. Overall survival, objective response rate, duration of response, time to response, and disease control rate are secondary endpoints.

MRTX849 with Cetuximab vs Chemotherapy in Patients with Advanced Colorectal Cancer with KRAS G12C Mutation (KRYSTAL-10): https://clinicaltrials.gov/ct2/show/NCT04793958

This 420 participant trial is open at 220 locations all over the world. 

This is a trial in the second-line setting (after progression on a 5FU + oxaliplatin or irinotecan containing regimen) where people are randomized into MRTX849 + cetuximab versus FOLFOX or FOLFIRI. Primary endpoints include progression-free survival and overall survival. Secondary endpoints include adverse events, objective response rate, duration of response, patient reported outcomes, and quality of life assessment. Patients must have KRAS G12C mutated colorectal cancer to participate. Prior treatment with drugs against KRAS G12C and anti-EGFR antibody is an exclusion, as is the presence of brain mets.

Tucatinib with Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer (MOUNTAINEER-03): https://clinicaltrials.gov/ct2/show/NCT05253651

This 400 participant study open at 21 locations in the U.S. is being done to find out if tucatinib with other cancer drugs works more effectively than standard of care to treat participants with HER2+ colorectal cancer. This study will also test the side effects that occur when participants take this combination of drugs. 

Participants will be assigned randomly to the tucatinib or standard of care group. The tucatinib group will get tucatinib, trastuzumab, and mFOLFOX6. The standard of care group will get either:

  • mFOLFOX6 alone,
  • mFOLFOX6 with bevacizumab, or
  • mFOLFOX6 with cetuximab 

Eligible patients have metastatic HER2+, RAS wild-type colorectal cancer that cannot be removed by surgery. Currently asymptomatic, previously treated brain mets is not an exclusion. The primary endpoint is progression-free survival. Secondary endpoints include overall survival, confirmed objective response rate, duration of response, side effects, and quality of life. Prior chemotherapy or anti-HER2 therapy is an exclusion, but adjuvant chemotherapy for early- stage colorectal cancer more than six months ago is not an exclusion. More inclusion/exclusion criteria are available on clinicaltrials.gov.

Immunotherapy-based clinical trials:

Nivolumab-relatlimab Fixed-dose Combination Versus Regorafenib or TAS-102 in Participants with Later-lines of Metastatic Colorectal Cancer (RELATIVITY-123): https://clinicaltrials.gov/ct2/show/NCT05328908

Taking place at many locations in the U.S. and worldwide, this study is for colon and rectal patients for whom at least one prior line of therapy for metastatic disease has failed. The goal of this phase III trial is to determine if a combination of immunotherapies works better than the standard of care, oral drugs regorafenib (Stivarga®) or TAS-102 (Lonsurf®).

To participate, the patients should not have received immunotherapy, regorafenib (Stivarga) or TAS-102 (Lonsurf) yet as treatment.

Some of the patients will take the standard of care pills, while the patients in the experimental arm will receive infusions of nivolumab + relatlimab FDC (Fixed-dose Combination).

Nivolumab (Opdivo®) is a PD-1 checkpoint inhibitor; relatlimab is a novel immune checkpoint inhibitor that targets LAG-3 (lymphocyte activation gene-3).

Relatlimab received FDA approval in March 2022, alongside the PD-1 inhibitor nivolumab in the combination product OpdualagTM, for the treatment of unresectable or metastatic melanoma that did not respond to anti-PD-1 alone. Relatlimab was the first anti-LAG-3 antibody to demonstrate benefit in a phase III study, as well as the first to receive FDA approval.

Preliminary results from prior/ongoing trials with this combination for colorectal cancer (like NCT01968109, NCT02966548, and NCT03642067) and the mentioned approval for immunotherapy-resistant melanoma have led to the design of this phase III trial, potentially practice-changing.

Study of XL092 + Atezolizumab vs Regorafenib in Subjects with Metastatic Colorectal Cancer (STELLAR-303): https://clinicaltrials.gov/ct2/show/NCT05425940

STELLAR-303 is a randomized, two-arm, U.S. multicenter trial of 600 participants to investigate if the combination of an oral targeted-therapy with an immunotherapy given as infusion works equally, is more effective, or is inferior than the standard of care treatment regorafenib (Stivarga®), for MSS metastatic colorectal cancer.

The trial is open to patients who have not received yet regorafenib (Stivarga), trifluridine/tipiracil (Lonsurf®), or PD-L1/PD-1 targeting immune checkpoint inhibitors (Tecentriq®, Opdivo®, Nivolumab, for example)

Patients assigned to the control arm will take Stivarga, while patients in the experimental arm will take XL092 (a novel, oral multitargeted inhibitor of receptor tyrosine kinases MET, VEGFR2, and TAM kinases (AXL, MER)) and receive atezolizumab (Tecentriq), a PD-L1 checkpoint inhibitor, intravenously, every three weeks.

Personalized Neoantigen Vaccine (GRT-C901/ GRT-R902) in Combination with Immune Checkpoint Blockade for mCRC Patients: https://clinicaltrials.gov/ct2/show/NCT05141721

Sometimes, the trial is a "phase II/III trial": In that case, the study tests the efficacy of a new cancer treatment (phase II), and then compares the new cancer treatment with the standard treatment (phase III).

This is a phase II/III clinical trial ongoing at several U.S. locations for colorectal cancer patients who are about to receive first-line therapy for metastatic disease. This study tests if the addition of immunotherapies to the usual treatment results in clinical activity and in longer progression-free survival.

The main, novel experimental agent in this trial is a personalized cancer vaccine that targets  neoantigens unique to each patient's tumor, to stimulate an immune response. 

All patients will receive the standard of care chemotherapy Folfox + bevacizumab (Avastin®) for 24 weeks and undergo vaccine-production screening.

After that, the patients in the control arm will continue receiving the standard of care therapy (Folfox + bevacizumab), while the patients in the experimental arm will receive immunotherapies along with that standard of care: a total of six doses of the vaccine (GRT-C901/ GRT-R902), one dose of the checkpoint inhibitor ipilimumab (Yervoy®) administered with the first dose of the vaccine, and the anti-PD-L1 checkpoint inhibitor atezolizumab (Tecentriq®) with the usual chemotherapy combination.

Stay Tuned for More Colorectal Cancer Clinical Trials Conversations!

Once a month, Maia and Manju will spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the colorectal cancer world!

You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov for more information on trials.

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Clinical trials are critical to finding a cure for colorectal cancer. As an advocacy organization dedicated to supporting and empowering a community of patients, caregivers and families, Fight CRC has partnered with COLONTOWN to deliver a monthly blog series highlighting everything patients need to know about clinical trials and the best treatment options available. 

In this series, we hope to cover promising trials that are enrolling, lessons learned from past research, logistics and resources to joining a clinical trial, and provide relevant and timely updates for our colon and rectal cancer community.

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