Tucatinib + Trastuzumab for Rectal Cancer

Recruiting at 14 trial locations

Overseen By Rona Yaeger, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Experimental therapies

Disqualifiers: Recurrent cancer, Active infection, HIV, 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

Compensation: Varies

Number of Visits: Unknown

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether a combination of two drugs, trastuzumab (also known as Herceptin, Trazimera, Herzuma, or Ontruzant) and tucatinib (also known as Tukysa, ONT-380, or ARRY-380), along with standard chemotherapy, can help treat rectal cancer. It specifically targets rectal cancer that tests positive for a protein called HER2. Suitable candidates for this trial include those diagnosed with HER2-positive rectal cancer that hasn't spread and affects their daily life. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take other experimental therapies or certain medications that affect liver enzymes (CYP2C8 and CYP3A4) close to the start of the study.

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

Research has shown that the combination of tucatinib and trastuzumab is under study for potential benefits in treating HER2-positive colorectal cancer. In a previous study with patients who had advanced colorectal cancer, this combination showed promising results. Most patients tolerated the treatment well, with common side effects such as mild to moderate diarrhea and fatigue being manageable.

Reports of more serious side effects were less common. Tucatinib and trastuzumab have been used together in earlier studies, and their safety profile is well-understood. Researchers have a good understanding of how these drugs work together and their potential effects on patients.

Overall, safety information from previous studies suggests that the treatment could be well-tolerated by people with rectal cancer. However, individual experiences can vary, so discussing any concerns with the trial team is important. ^{1 2 3 4 5}

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

Researchers are excited about Tucatinib and Trastuzumab for rectal cancer because these treatments specifically target the HER2 protein, which is overexpressed in certain cancer cells. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells and can affect healthy tissues, Tucatinib and Trastuzumab aim directly at HER2-positive cancer cells, potentially reducing side effects. Tucatinib is a small molecule that can penetrate cells more effectively, while Trastuzumab is an antibody that marks cancer cells for the immune system to attack, offering a one-two punch against the disease. This targeted approach gives hope for more effective and less harmful treatment options for patients with HER2-positive rectal adenocarcinoma.

What evidence suggests that the combination of trastuzumab and tucatinib might be an effective treatment for rectal cancer?

Studies have shown that combining tucatinib and trastuzumab can help treat HER2-positive colorectal cancer, which is similar to rectal cancer. Tests using patient samples demonstrated that tucatinib alone effectively fights tumors, and adding trastuzumab enhances its effectiveness. This trial will evaluate the combination of tucatinib and trastuzumab for participants with HER2-positive locally advanced rectal adenocarcinoma. Research suggests this drug combination is a promising option for people with HER2-positive colorectal cancer that has spread, offering hope for effective treatment of rectal cancer as well. ^{1 2 3 4 6}

Who Is on the Research Team?

Andrea Cercek, MD

Principal Investigator

Memorial Sloan Kettering Cancer

Are You a Good Fit for This Trial?

Adults with HER2-positive rectal adenocarcinoma, without distant metastases and measurable disease. Participants must be over 18, have an ECOG performance status of 0 or 1 (fully active or restricted in physically strenuous activity but ambulatory), and adequate organ function. Women of childbearing potential must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

My cancer has not spread to distant parts of my body.

I am fully active or can carry out light work.

Radiologically measurable or clinically evaluable disease per Protocol Section 13.0

Exclusion Criteria

My tumor is causing blockage in my intestines.

I have a history of HIV or active Hepatitis B or C.

My rectal cancer has come back.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Participants receive neoadjuvant tucatinib and trastuzumab

Approximately 8 weeks

Chemotherapy

Participants receive standard of care induction chemotherapy (capecitabine and oxaliplatin/FOLFOX)

Approximately 13 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trastuzumab
• Tucatinib

Trial Overview The trial is testing the effectiveness of combining tucatinib and trastuzumab with standard chemotherapy (CAPOX) in treating rectal cancer. Researchers hope this combination will benefit participants by targeting specific aspects of cancer cells.

How Is the Trial Designed?

Group I: Participant with Rectal Adenocarcinoma Experimental Treatment 2 Interventions

Participants will have HER2-positive locally advanced rectal adenocarcinoma.

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

Approved in European Union as Herceptin for:

• Early breast cancer
• Metastatic breast cancer
• Advanced gastric cancer

Approved in United States as Herceptin for:

• Adjuvant treatment of HER2-positive breast cancer
• Metastatic breast cancer
• Advanced gastric cancer

Approved in Canada as Herceptin for:

• Early breast cancer
• Metastatic breast cancer
• Advanced gastric cancer

Approved in Japan as Herceptin for:

• Breast cancer
• Gastric cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

In a phase II trial involving 21 patients with HER2-positive metastatic colorectal cancer, trastuzumab combined with chemotherapy resulted in a 33.3% objective response rate and a median progression-free survival of 4.3 months, indicating its potential efficacy.

The treatment was generally well-tolerated, with only 19% of patients experiencing grade 3 adverse events, and no treatment-related deaths reported, suggesting a favorable safety profile for trastuzumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Combined with Irinotecan in Patients with HER2-Positive Metastatic Colorectal Cancer: A Phase II Single-Arm Study and Exploratory Biomarker Analysis. Xu, T., Wang, X., Xin, Y., et al.[2023]

The FDA granted accelerated approval for tucatinib in combination with trastuzumab for patients with HER2-positive colorectal cancer, showing a 38% overall response rate in a trial with 84 patients and a median follow-up of 16 months.

Patients experienced a median duration of response of 12.4 months, with 81% of responders maintaining their response for over 6 months, indicating significant efficacy in a patient population with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer. Casak, SJ., Horiba, MN., Yuan, M., et al.[2023]

In a study involving 117 patients with chemotherapy-refractory, HER2-positive metastatic colorectal cancer, the combination of tucatinib and trastuzumab showed a confirmed objective response rate of 38.1%, indicating significant anti-tumor activity.

The treatment was well-tolerated, with the most common side effect being diarrhea, and no deaths were attributed to adverse events, marking it as a promising new option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Strickler, JH., Cercek, A., Siena, S., et al.[2023]

In a phase 2 trial involving 27 patients with HER2-positive metastatic colorectal cancer, the combination of trastuzumab and lapatinib resulted in an objective response rate of 30%, indicating significant antitumor activity in treatment-refractory cases.

The treatment was well tolerated, with only 22% of patients experiencing grade 3 adverse events, and no serious drug-related adverse events reported, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Sartore-Bianchi, A., Trusolino, L., Martino, C., et al.[2022]

A new bispecific antibody targeting both EGFR and HER3, combined with trastuzumab (an HER2 blocker), effectively inhibited cancer cell growth and signaling in colorectal cancer cells, particularly in cases resistant to cetuximab treatment.

This triple-HER receptor blockade not only suppressed tumor growth in laboratory models but also showed promise in patient-derived organoid cultures, suggesting it could be a powerful strategy against resistance in KRAS WT colorectal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple Targeting of HER Receptors Overcomes Heregulin-mediated Resistance to EGFR Blockade in Colorectal Cancer. Rau, A., Janssen, N., Kühl, L., et al.[2022]

In a phase II study, the combination of trastuzumab and lapatinib showed effectiveness in treating patients with KRAS-wild-type, HER2-positive metastatic colorectal cancer, achieving a 30% objective response rate.

This treatment was particularly notable as none of the participants had responded to prior standard therapies with EGFR inhibitors like cetuximab or panitumumab, highlighting the potential of dual HER2 blockade in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colorectal Cancer Yields to Dual HER2 Blockade. [2018]

In a study involving 57 patients with HER2-amplified metastatic colorectal cancer, dual therapy with pertuzumab and trastuzumab resulted in an objective response rate of 32%, indicating potential efficacy for this treatment in a non-traditional cancer type.

The treatment was generally well tolerated, with the most common side effects being diarrhea, fatigue, and nausea, and no treatment-related deaths reported, suggesting a favorable safety profile for patients who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Meric-Bernstam, F., Hurwitz, H., Raghav, KPS., et al.[2023]

In a phase 2 study involving 78 patients with HER2-expressing metastatic colorectal cancer, trastuzumab deruxtecan demonstrated a confirmed objective response rate of 45.3% in patients with HER2-positive tumors, indicating significant antitumor activity in a population that had previously failed standard treatments.

The treatment was associated with a manageable safety profile, although there were notable risks of interstitial lung disease and pneumonitis, which necessitate careful monitoring, as these conditions led to treatment-related deaths in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Siena, S., Di Bartolomeo, M., Raghav, K., et al.[2021]

In a phase 2 trial involving 20 patients with HER2-positive recurrent/metastatic colorectal cancer, the combination of pyrotinib and trastuzumab demonstrated promising antitumor activity, achieving an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 61.1%.

The treatment was generally well-tolerated, with the most common severe side effect being diarrhea in 65% of patients, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: A phase 2 trial. Fu, X., Ying, J., Yang, L., et al.[2023]

In a study of 34 patients with HER2-positive advanced gastric cancer, the combination of trsatuzumab (Herceptin) with the FOLFIRI regimen resulted in a significantly higher overall response rate of 58.8% compared to 35.3% for the FOLFIRI regimen alone.

The combination treatment also demonstrated a high disease control rate of 88.2%, indicating its efficacy, while the most common side effects were manageable grade I/II adverse events like diarrhea and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of trsatuzumab (Herceptin) combined with FOLFIRI regimen in the treatment of HER2-positive advanced gastric cancer]. Sun, J., Pan, SY., Chen, QQ., et al.[2015]

In the HERACLES-A trial, 35 patients with HER2-positive metastatic colorectal cancer were treated with trastuzumab and lapatinib, showing a response rate of 28% and a median overall survival of 10 months over a follow-up period of 6.7 years.

Despite the treatment's effectiveness, 19% of patients experienced progression in the central nervous system, highlighting the need for ongoing monitoring and potential new strategies to address CNS recurrences in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Clinical Outcome of Trastuzumab and Lapatinib for HER2-positive Metastatic Colorectal Cancer. Tosi, F., Sartore-Bianchi, A., Lonardi, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05672524?term=AREA%5BInterventionSearch%5D(tucatinib)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=9

NCT05672524 | A Study of Tucatinib and Trastuzumab in ... The study researchers believe that a combination of the drugs trastuzumab and tucatinib, given with standard chemotherapy (capecitabine and oxaliplatin/FOLFOX), ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.TPS3624

A phase II, open label study of tucatinib (ONT-380) ... In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37941353

A study to learn how well tucatinib plus trastuzumab works ... Tucatinib with trastuzumab could be a good treatment option for people with HER2-positive colorectal cancer that has spread to other parts of the body.

4. 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). download.

5. withpower.com withpower.com/trial/phase-2-adenocarcinoma-11-2022-70fe1

Tucatinib + Trastuzumab for Rectal Cancer Research shows that the combination of Tucatinib and Trastuzumab has been effective in treating HER2-positive metastatic colorectal cancer, which is similar to ...

6. tukysahcp.com tukysahcp.com/mcrc/mountaineer-clinical-trial

MOUNTAINEER Trial, TUKYSA® (tucatinib) - Safety Info MOUNTAINEER was a multicenter, open-label, phase 2 clinical trial that enrolled adult patients with unresectable or metastatic RAS WT, HER2+ colorectal cancer.