ELVN-002 + Trastuzumab for HER2+ Colorectal and Breast Cancer

Recruiting at 30 trial locations

Overseen By Helen L Collins, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Enliven Therapeutics

Must be taking: Trastuzumab

Must not be taking: Corticosteroids, Chemotherapy

Disqualifiers: Brain lesions, Leptomeningeal disease, Seizures, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

275 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the safety, tolerability, and recommended dose of ELVN-002 in combination with trastuzumab in participants with advanced-stage HER2-positive tumors and in combination with trastuzumab, and chemotherapy in participants with advanced-stage HER2-positive colorectal cancer and breast cancer.

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, there are specific timeframes for stopping certain treatments before starting the trial, such as chemotherapy, immunotherapy, and hormonal therapy. It's best to discuss your current medications with the trial team to get personalized advice.

What data supports the effectiveness of this drug combination for HER2-positive colorectal and breast cancer?

Research shows that combining trastuzumab with other HER2-targeted drugs like lapatinib can be effective in treating HER2-positive cancers. In a study, 30% of patients with HER2-positive colorectal cancer responded to a similar dual HER2 blockade, suggesting potential benefits for this drug combination. ^{1 2 3 4 5}

Is the combination of ELVN-002 and Trastuzumab safe for humans?

Trastuzumab, used in combination with other treatments, has been shown to have a generally favorable safety profile, though it can increase the risk of cardiac issues like heart failure in some patients. The safety of ELVN-002 specifically is not detailed in the provided research, but trastuzumab's safety in breast cancer treatment is well-documented. ^{6 7 8 9 10}

How is the drug ELVN-002 + Trastuzumab different from other treatments for HER2-positive colorectal and breast cancer?

ELVN-002 combined with Trastuzumab is unique because it targets HER2-positive cancers, which are often resistant to standard treatments. This combination may offer a new option for patients who do not respond to existing therapies like EGFR inhibitors. ^{1 3 11 12 13}

Eligibility Criteria

This trial is for people with advanced-stage tumors that are HER2-positive, including those with breast or colorectal cancer. Participants should be able to receive the drug ELVN-002 along with trastuzumab and possibly chemotherapy.

Inclusion Criteria

My cancer is HER2-positive according to tests.

My previous cancer treatments vary based on the trial phase and my cancer type.

I am fully active or can carry out light work.

Exclusion Criteria

My cancer has spread to the lining of my brain and spinal cord.

I haven't had cancer treatment within the specified time before starting this trial.

I am taking more than 2 mg of dexamethasone daily for brain-related symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ELVN-002 in combination with trastuzumab, with or without chemotherapy, in 21-day cycles

24 months

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety, tolerability, and efficacy after treatment

24 months

Treatment Details

Interventions

• 5-Fluorouracil
• ELVN-002
• Eribulin
• Oxaliplatin
• Trastuzumab

Trial Overview The study is testing the safety and proper dosage of a new treatment, ELVN-002, when used with trastuzumab alone or in combination with various chemotherapies (like 5-Fluorouracil, Oxaliplatin) in patients with HER2-positive cancers.

Participant Groups

Group I: Part 4B: ELVN-002 + trastuzumab + mFOLFOX6 dose expansion in colorectal cancer Experimental Treatment 5 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered intravenously at 6 mg/kg IV cycle 1, day 2 followed by 4 mg/kg IV cycle 1, day 15, and then one dose at 4mg/kg IV every 14 days. Fluorouracil (5-FU) will be administered intravenously as a 400 mg/m2 IV bolus on days 1 and 15 followed by 2400 mg/m2 over 46-48 hours of continuous infusion on days 1-3 and days 15-17 of a 28-day cycle. Leucovorin will be administered intravenously at 400 mg/m2 concurrently with oxaliplatin on days 1 and 15 of a 28-day cycle. Oxaliplatin will be administered intravenously at 85 mg/m2 IV on days 1 and 15 of a 28-day cycle.

Group II: Part 4A: ELVN-002 + trastuzumab + CAPEOX dose expansion in colorectal cancer Experimental Treatment 4 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Capecitabine will be administered orally twice daily at 1000 mg/m2 on Days 1 - 14 of a 21-day cycle. Oxaliplatin: will be administered intravenously at 130 mg/m2 on Day 1 of a 21-day cycle.

Group III: Part 3E: ELVN-002 + trastuzumab dose expansion in other solid tumor type 3 Experimental Treatment 2 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+.

Group IV: Part 3D: ELVN-002 + trastuzumab dose expansion in other solid tumor type 2 Experimental Treatment 2 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+.

Group V: Part 3C: ELVN-002 + trastuzumab dose expansion in other solid tumor type 1 Experimental Treatment 2 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+.

Group VI: Part 3B: ELVN-002 + trastuzumab dose expansion in breast cancer Experimental Treatment 2 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+.

Group VII: Part 3A: ELVN-002 + trastuzumab dose expansion in colorectal cancer Experimental Treatment 2 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+

Group VIII: Part 2E: ELVN-002 + trastuzumab + eribulin dose escalation in breast cancer Experimental Treatment 3 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Eribulin will be administered intravenously at 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.

Group IX: Part 2D: ELVN-002 + trastuzumab + paclitaxel dose escalation in solid tumors Experimental Treatment 3 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Paclitaxel will be administered intravenously at 80 mg/m2 on days 1, 8, and 15 of a 21-day cycle.

Group X: Part 2C: ELVN-002 + trastuzumab + capecitabine dose escalation in breast cancer Experimental Treatment 3 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Capecitabine will be administered orally twice daily at 1000 mg/m2 on days 1 - 14 of a 21-day cycle.

Group XI: Part 2B: ELVN-002 + trastuzumab + mFOLFOX6 dose escalation in colorectal cancer Experimental Treatment 5 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered intravenously at 6 mg/kg IV cycle 1, day 2 followed by 4 mg/kg IV cycle 1, day 15, and then one dose at 4mg/kg IV every 14 days. Fluorouracil (5-FU) will be administered intravenously as a 400 mg/m2 IV bolus on days 1 and 15 followed by 2400 mg/m2 over 46-48 hours of continuous infusion on days 1-3 and days 15-17 of a 28-day cycle. Leucovorin will be administered intravenously at 400 mg/m2 concurrently with oxaliplatin on days 1 and 15 of a 28-day cycle. Oxaliplatin will be administered intravenously at 85 mg/m2 IV on day 1 and 15 of a 28-day cycle.

Group XII: Part 2A: ELVN-002 + trastuzumab + CAPEOX dose escalation in colorectal cancer Experimental Treatment 4 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+. Capecitabine will be administered orally twice daily at 1000 mg/m2 on days 1 - 14 of a 21-day cycle. Oxaliplatin will be administered intravenously at 130 mg/m2 on day 1 of a 21-day cycle.

Group XIII: Part 1: ELVN-002 + trastuzumab dose escalation Experimental Treatment 2 Interventions

ELVN-002 will be administered by mouth (orally) once or twice a day from cycle 1 day 1 onwards. Trastuzumab will be administered IV (intravenously) in 21-day cycles, at 8mg/kg on cycle 1 day 2 followed by a dose of 6mg/kg on day 1 of cycles 2+.

Who Is Running the Clinical Trial?

Enliven Therapeutics

Lead Sponsor

Trials

4

Recruited

670+

Findings from Research

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]

Recent trials show that new HER2-targeted agents like pertuzumab and trastuzumab emtansine (T-DM1) are effective in treating HER2-positive breast cancer, with T-DM1 being a powerful combination of trastuzumab and a cytotoxic agent.

Combining trastuzumab with lapatinib or pertuzumab has led to significantly better outcomes, nearly doubling the rates of complete response in patients, indicating a shift towards dual anti-HER2 therapies to overcome resistance in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging strategies for the dual inhibition of HER2-positive breast cancer. Konecny, GE.[2019]

In a study of 23 patients with HER2-positive metastatic breast cancer, the combination of Lapatinib and Trastuzumab resulted in a median progression-free survival of 7 months, indicating effective treatment outcomes.

The treatment was generally well-tolerated, although 7 patients experienced adverse events, and 4 had to stop treatment due to toxicity, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lapatinib plus transtuzumab for HER-2 positiva metastatic breast cancer: experience of use]. García-Muñoz, C., Cortijo-Cascajares, S., Cañamares-Orbis, I., et al.[2018]

Trastuzumab significantly improves disease-free survival (DFS) and overall survival (OS) in women with HER-2/neu-positive breast cancer when used as adjuvant therapy, based on a systematic review of eight randomized trials.

The evidence supports administering trastuzumab for 1 year to patients with HER-2-positive breast cancer who are also receiving chemotherapy, although the optimal timing and duration of treatment still need further clarification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Madarnas, Y., Trudeau, M., Franek, JA., et al.[2018]

In a randomized phase II trial involving 103 patients with HER2-positive non-small-cell lung cancer (NSCLC), adding trastuzumab to the standard chemotherapy (gemcitabine-cisplatin) was well tolerated, with side effects consistent with known profiles and no significant increase in toxicity.

Despite the good tolerability, the addition of trastuzumab did not show a significant clinical benefit compared to chemotherapy alone, although a small subgroup of patients with HER2 3+ or FISH-positive NSCLC showed promising results, indicating potential for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Gatzemeier, U., Groth, G., Butts, C., et al.[2022]

A meta-analysis of six randomized trials found that dual HER2 blockade (combination therapy) has a comparable risk of cardiac adverse events, such as congestive heart failure (CHF) and left ventricular ejection fraction (LVEF) decline, when compared to anti-HER2 monotherapy.

The incidence of CHF was slightly lower in the combination therapy group (0.88%) compared to monotherapy (1.49%), suggesting that dual HER2 blockade does not significantly increase cardiac risks, which is important for treatment decisions in HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Valachis, A., Nearchou, A., Polyzos, NP., et al.[2018]

In a meta-analysis of 11,941 breast cancer patients from 9 trials, dual HER-2 blockade treatment significantly increased the risk of severe diarrhea and treatment discontinuation compared to anti-HER2 monotherapy.

Despite the increased risk of diarrhea and discontinuation, there was no evidence of a higher risk of fatal adverse events or other severe toxicities like liver issues or heart failure with dual HER-2 blockade treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does dual HER-2 blockade treatment increase the risk of severe toxicities of special interests in breast cancer patients: A meta-analysis of randomized controlled trials. Hao, S., Tian, W., Gao, B., et al.[2018]

Adjuvant trastuzumab (Herceptin) significantly improves clinical outcomes, disease-free survival, and overall survival in patients with HER2-positive early breast cancer compared to chemotherapy alone, based on a review of clinical data from 1985 to 2009.

Trastuzumab has a favorable safety profile, with manageable levels of cardiac dysfunction reported in clinical trials, indicating it can be safely administered alongside treatment plans for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant trastuzumab for HER2-positive early breast cancer. Palmieri, FM., Myatt, CV., Perez, EA.[2015]

Ado-trastuzumab emtansine (KADCYLA) received FDA approval for treating HER2-positive early breast cancer patients with residual disease after chemotherapy, showing an impressive 88.3% event-free survival rate at 3 years compared to 77.0% for trastuzumab.

The treatment was associated with common side effects such as fatigue and nausea, but it represents a significant advancement as the first approved therapy for patients with residual disease post-neoadjuvant treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ado-Trastuzumab Emtansine for the Adjuvant Treatment of HER2-positive Early Breast Cancer. Wedam, S., Fashoyin-Aje, L., Gao, X., et al.[2021]

Trastuzumab, an anti-HER2 monoclonal antibody, significantly improves disease-free survival (DFS) by 33%-52% and overall survival by 34%-41% when added to standard adjuvant chemotherapy in early breast cancer, based on data from four large phase III trials involving HER2-positive patients.

The treatment has an acceptable safety profile, with low rates of congestive heart failure or cardiac death (0-3.8% in trastuzumab groups), indicating a positive benefit/risk ratio, although certain risk factors like older age and hypertension may increase the likelihood of cardiac issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant trastuzumab therapy for HER2-positive breast cancer. Jahanzeb, M.[2022]

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 combination of trastuzumab and vinorelbine has shown high objective response rates of 44%-86% in treating HER2-positive metastatic breast cancer, with first-line treatment rates reaching 51%-86%.

This treatment is well tolerated, with manageable side effects, including short-duration grade 3/4 neutropenia in about 50% of patients and infrequent serious cardiac events, making it suitable for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of the use of trastuzumab (Herceptin) plus vinorelbine in metastatic breast cancer. Chan, A.[2020]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Colorectal Cancer Yields to Dual HER2 Blockade. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Emerging strategies for the dual inhibition of HER2-positive breast cancer. [2019]

3. Spain pubmed.ncbi.nlm.nih.gov

[Lapatinib plus transtuzumab for HER-2 positiva metastatic breast cancer: experience of use]. [2018]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Does dual HER-2 blockade treatment increase the risk of severe toxicities of special interests in breast cancer patients: A meta-analysis of randomized controlled trials. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Adjuvant trastuzumab for HER2-positive early breast cancer. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ado-Trastuzumab Emtansine for the Adjuvant Treatment of HER2-positive Early Breast Cancer. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Adjuvant trastuzumab therapy for HER2-positive breast cancer. [2022]

11. Korea (South) 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. [2023]

12. England pubmed.ncbi.nlm.nih.gov

A review of the use of trastuzumab (Herceptin) plus vinorelbine in metastatic breast cancer. [2020]

13. England 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. [2022]