Tucatinib + Trastuzumab + Chemotherapy for Colorectal Cancer

(MOUNTAINEER-03 Trial)

Recruiting at 614 trial locations

Overseen By Pfizer CT.gov Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Seagen, a wholly owned subsidiary of Pfizer

Must not be taking: Anti-HER2 therapy

Disqualifiers: Prior systemic therapy, Radiation, Neuropathy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 1 year

400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new combination of drugs, including tucatinib, outperforms standard treatments for HER2-positive colorectal cancer that has spread or cannot be surgically removed. The trial aims to determine if this drug combination can control the cancer more effectively and to identify any side effects. Participants will receive either tucatinib with other cancer drugs or standard treatments for comparison. Suitable candidates have HER2-positive colorectal cancer that has spread and have not received previous anti-HER2 therapy. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not have had prior systemic anticancer therapy for colorectal cancer in the advanced setting, except for a limited amount of mFOLFOX6. It's best to discuss your current medications with the trial team.

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

Research has shown that using tucatinib and trastuzumab with chemotherapy is generally safe. In one study, diarrhea was the most common side effect. Serious side effects, such as intestinal blockage and urinary tract infections, occurred in about 22% of patients but were rare and affected only a small number of people.

Importantly, no deaths were linked to side effects from the treatment, and no new safety issues emerged. This suggests that the combination is generally well-tolerated by patients with HER2-positive colorectal cancer.

Tucatinib is already approved for other conditions, providing additional safety information. This can reassure those considering joining a trial with this treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for colorectal cancer?

Researchers are excited about the combination of tucatinib and trastuzumab for colorectal cancer because it introduces a unique approach by specifically targeting HER2, a protein that can promote cancer growth when overexpressed. Unlike standard treatments like mFOLFOX6 or combinations with bevacizumab or cetuximab, this combo aims to directly inhibit the HER2 pathway, potentially offering a more targeted and effective strategy. Tucatinib is a newer agent that enhances the ability of trastuzumab to block HER2, which might improve outcomes for patients whose cancers are driven by this protein.

What evidence suggests that this trial's treatments could be effective for colorectal cancer?

Research has shown that using tucatinib and trastuzumab together appears promising for treating HER2-positive metastatic colorectal cancer. In this trial, one group will receive a combination of tucatinib, trastuzumab, and mFOLFOX6. Studies indicate that this combination can be effective for patients who have already tried other treatments. Participants in these studies have generally tolerated the drugs well and experienced lasting benefits, suggesting the treatment might help slow the cancer's growth. While more research continues, early results offer encouragement for those with this type of cancer. ^{2 5 6 7 8}

Who Is on the Research Team?

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Are You a Good Fit for This Trial?

This trial is for adults with HER2 positive, RAS WT metastatic or unresectable colorectal cancer who haven't had systemic anticancer therapy in the metastatic setting. They should have measurable disease and be in good physical condition (ECOG 0-1). Prior adjuvant chemotherapy is allowed if completed over 6 months ago. Excluded are those with recent radiation, ongoing severe neuropathy, GI perforation within a year, or past anti-HER2 treatment.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My colon or rectum cancer is advanced and cannot be removed by surgery.

My cancer is RAS wild-type.

Exclusion Criteria

I've had treatment for colorectal cancer, but no more than 2 doses of mFOLFOX6 if it was in advanced stages.

I have not had a GI perforation in the last year.

I have been treated with anti-HER2 therapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either tucatinib with trastuzumab and mFOLFOX6 or standard of care treatment with mFOLFOX6, with or without bevacizumab or cetuximab

Approximately 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Cetuximab
• Fluorouracil
• Leucovorin
• Levoleucovorin
• Oxaliplatin
• Trastuzumab
• Tucatinib

Trial Overview The study compares tucatinib combined with trastuzumab and mFOLFOX6 against standard treatments for advanced colorectal cancer. Participants will randomly receive either this new combination or one of the standard options: mFOLFOX6 alone, with bevacizumab, or cetuximab. The goal is to see if tucatinib improves outcomes.

How Is the Trial Designed?

Group I: Tucatinib Arm Experimental Treatment 6 Interventions

Tucatinib + trastuzumab + mFOLFOX6

Group II: Standard of Care Arm Active Control 6 Interventions

Either (1) mFOLFOX6, (2) mFOLFOX6 and bevacizumab, or (3) mFOLFOX6 and cetuximab

Fluorouracil is already approved in United States, European Union, Canada for the following indications:

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Seagen, a wholly owned subsidiary of Pfizer

Lead Sponsor

Trials

20

Recruited

4,900+

Seagen Inc.

Lead Sponsor

Trials

212

Recruited

73,800+

Founded

1997

Headquarters

Bothell, USA

Known For

Antibody-Drug Conjugates

Top Products

Adcetris (brentuximab vedotin), Tukysa (tucatinib), Padcev (enfortumab vedotin-ejfv), Tivdak (tisotumab vedotin-tftv)

Dr. Roger Dansey

Seagen Inc.

Chief Medical Officer since 2018

MD from University of Witwatersrand

David R. Epstein

Seagen Inc.

Chief Executive Officer since 2022

BSc in Pharmacy from Rutgers University, MBA from Columbia University

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

In a study of 62 advanced colorectal cancer patients resistant to fluorouracil, the oxaliplatin/irinotecan (OC) combination showed promising safety and efficacy, with median overall survival of 12.3 months.

The tritherapy regimen (5-FU/folinic acid combined with irinotecan and oxaliplatin) resulted in lower activity, possibly due to reduced dose intensities of the drugs, despite both regimens being generally safe with no treatment-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. Bécouarn, Y., Gamelin, E., Coudert, B., et al.[2018]

New agents like irinotecan (CPT-11) and oxaliplatin have shown promising efficacy in treating colorectal carcinoma (CRC), especially for patients resistant to standard therapies like 5-fluorouracil (5-FU) and leucovorin.

Combination therapies involving 5-FU with newer agents such as trimetrexate, capecitabine, and S-1 are showing encouraging response rates, suggesting potential changes in the standard treatment protocols for advanced CRC in the near future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New drugs in the treatment of colorectal carcinoma. Punt, CJ.[2019]

In a study of 34 patients with advanced colorectal cancer resistant to 5-fluorouracil, the combination of irinotecan and oxaliplatin showed modest efficacy, with 18% of patients achieving partial remission and 33% experiencing disease stabilization.

The treatment was associated with significant toxicities, including diarrhea (27%) and neutropenia (18%), but no treatment-related deaths occurred, indicating a need for further research to improve treatment effectiveness and reduce side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and oxaliplatin combination, as second-line treatment, in fluoropyrimidine-pretreated advanced colorectal cancer. A phase II study by the Hellenic Cooperative Oncology Group (HeCOG). Timotheadou, E., Papakostas, P., Tsavdaridis, D., et al.[2022]

In a study of 86 patients with locally advanced rectal cancer, both neoadjuvant chemotherapy regimens (mFOLFOXIRI and XELOX/SOX) showed similar pathological response rates, with 36.7% for mFOLFOXIRI and 40.5% for XELOX/SOX.

However, mFOLFOXIRI was associated with significantly higher toxicity, as 45% of patients experienced severe neutropenia compared to only 8% in the XELOX/SOX group, indicating that while both regimens are effective, XELOX/SOX may be a safer option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Comparison of mFOLFOXIRI With XELOX/SOX as Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer. Kodama, H., Terazawa, T., Ishizuka, Y., et al.[2021]

The combination of oxaliplatin with oral fluoropyrimidines like capecitabine (XELOX) has shown over 50% response rates in first-line treatment for advanced colorectal cancer, indicating its efficacy.

Ongoing studies are exploring various combinations of oxaliplatin with biological therapies, such as cetuximab and bevacizumab, which target different cancer pathways, potentially leading to improved treatment outcomes for patients with advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New oxaliplatin-based combinations in the treatment of colorectal cancer. Cassidy, J., Hochster, H.[2019]

Approximately 50% of colorectal cancer patients develop metastatic disease, but long-term disease-free survival can be achieved in 25% to 40% of selected patients who undergo resection of liver or lung metastases.

New treatments like irinotecan and oxaliplatin, along with novel therapies such as targeted inhibitors and local interventions, have improved survival and quality of life for colorectal cancer patients, moving beyond the traditional use of 5-fluorouracil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic colorectal cancer. Kindler, HL., Shulman, KL.[2022]

The combination of FOLFIRI and aflibercept was found to be active and tolerable in treating metastatic colorectal cancer (mCRC), with an objective response rate of 46.6% among 73 patients, indicating potential effectiveness in this patient population.

Despite its activity, the regimen did not surpass historical benchmarks for efficacy in chemotherapy-naive patients, with a 12-month progression-free survival rate of only 21.9% and a median overall survival of 20.9 months, suggesting that while it may help some patients, it may not be a significant improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMALTHEA: Prospective, Single-Arm Study of the Hellenic Cooperative Oncology Group (HeCOG) Evaluating Efficacy and Safety of First-Line FOLFIRI + Aflibercept for 6 Months Followed by Aflibercept Maintenance in Patients With Metastatic Colorectal Cancer. Pentheroudakis, G., Kotoula, V., Koliou, GA., et al.[2019]

In a randomized phase II trial involving 159 patients with high-risk stage II/III colorectal cancer, the combination of tegafur-uracil/leucovorin and oxaliplatin (TEGAFOX) significantly improved the 3-year disease-free survival rate to 84.2% compared to 62.1% for the standard UFT/LV treatment.

While TEGAFOX showed better efficacy in preventing cancer recurrence, it also resulted in a higher incidence of any-grade adverse events (96.1% vs. 76.6% for UFT/LV), indicating that while it is a promising treatment option, it may come with increased side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of tegafur-uracil/leucovorin versus tegafur-uracil/leucovorin plus oxaliplatin after curative resection of high-risk stage II/III colorectal cancer (SOAC-1101 trial). Kosugi, C., Koda, K., Takiguchi, N., et al.[2021]

In a phase II trial involving 82 patients with advanced colorectal cancer, the combination of cetuximab and FOLFOX6 showed an overall response rate of 44.8%, indicating its efficacy as a first-line treatment.

Patients who developed skin toxicity while on the treatment had significantly longer median survival times (21.7 months) compared to those who did not experience this side effect, suggesting a potential correlation between skin reactions and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of FOLFOX6 and cetuximab in the first-line treatment of patients with metastatic colorectal cancer. Boccia, RV., Cosgriff, TM., Headley, DL., et al.[2016]

In a study of 285 patients with wild-type KRAS exon 2 metastatic colorectal cancer, the combination of panitumumab with mFOLFOX6 showed a significant improvement in overall survival (OS) compared to bevacizumab with mFOLFOX6, with median OS of 34.2 months versus 24.3 months, respectively.

While progression-free survival (PFS) was similar between the two treatment arms, patients with wild-type RAS tumors (including KRAS and NRAS) experienced greater clinical benefits from panitumumab, suggesting its efficacy in this specific genetic context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. Schwartzberg, LS., Rivera, F., Karthaus, M., et al.[2022]

Oxaliplatin combined with fluoropyrimidines is highly effective for treating advanced colorectal cancer and is also beneficial in the adjuvant treatment of stage III colon cancer.

The addition of targeted therapies, such as anti-VEGF and anti-EGFR agents, can enhance the efficacy of oxaliplatin-based regimens, although the presence of KRAS mutations has been identified as a negative predictor for the effectiveness of anti-EGFR treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer. Bonetti, A., Giuliani, J., Muggia, F.[2022]

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

In a study of 21 patients with advanced or recurrent colorectal cancer, a treatment regimen combining Irinotecan, 5FU, and Leucovorin resulted in a good response rate of 43% and a mean survival time of 15.7 months, indicating its potential efficacy.

The study identified predictive factors related to chemotherapy response, such as low levels of DPD mRNA in tumors being associated with longer survival, which could help tailor individualized treatment plans for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified Irinotecan/5FU/Leucovorin therapy in advanced colorectal cancer and predicting therapeutic efficacy by expression of tumor-related enzymes. Yanagisawa, Y., Maruta, F., Iinuma, N., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39723627/

first-line mFOLFOX6 + tucatinib + trastuzumab for HER2+ ... Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2-3 years.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3509

Final results of a phase 2 study of tucatinib and ... Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03043313

NCT03043313 | Tucatinib Plus Trastuzumab in Patients ... This trial studies how well the drug tucatinib works when given with trastuzumab and when given by itself. The participants in this trial have HER2-positive ...

4. ncoda.org ncoda.org/wp-content/uploads/2025/03/Tucatinib-TUKYSA-and-trastuzumab-in-HER2-positive-mCRC_PQI_NCODA.pdf

Tucatinib (TUKYSA®) and trastuzumab in HER2-positive ... Pertuzumab plus trastuzumab in patients with colorectal cancer with ERBB2 amplification or ERBB2/3 mutations: results from the TAPUR Study.

5. asco.org asco.org/abstracts-presentations/ABSTRACT183810

A phase II, open label study of tucatinib (ONT-380) ... A phase II, open label study of tucatinib (ONT-380) combined with trastuzumab in patients with HER2+ metastatic colorectal cancer (mCRC)(MOUNTAINEER).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05253651

NCT05253651 | A Study of Tucatinib With Trastuzumab ... Participants in this study have colorectal cancer that has spread through the body (metastatic) and/or cannot be removed with surgery (unresectable).

7. tukysa.com tukysa.com/mcrc/what-is-tukysa

About TUKYSA® (tucatinib), HER2+ mCRC - Safety Info The most common side effects of TUKYSA in combination with trastuzumab in adults with RAS wild-type HER2-positive colorectal cancer include: diarrhea ...

8. tukysahcp.com tukysahcp.com/mcrc/efficacy-and-safety

TUKYSA® (tucatinib) Efficacy - Safety Info Serious adverse reactions occurred in 22% of patients; the most common (in ≥2% of patients) were intestinal obstruction (7%), urinary tract infection (3.5%), ...