IAM1363 for Breast Cancer

Recruiting at 12 trial locations

Overseen By Iambic Therapeutics, Inc., Senior Medical Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Iambic Therapeutics, Inc

Disqualifiers: Cardiac disease, HIV, Liver disease, Diabetes, others

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

Compensation: Varies

Number of Visits: 3

243 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/1b open-label, multi-center dose escalation and dose optimization study designed to evaluate the safety and preliminary efficacy of IAM1363 in participants with advanced cancers that harbor HER2 alterations.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug IAM1363 for breast cancer?

Research shows that entinostat, a component of IAM1363, can improve survival in women with advanced breast cancer when combined with another drug, exemestane. Additionally, entinostat has been shown to reduce tumor growth and resistance in certain breast cancer cells. ^{1 2 3 4 5}

Is IAM1363 (also known as Trastuzumab or Herceptin) safe for humans?

Research shows that Trastuzumab emtansine (T-DM1), a form of IAM1363, has been studied for safety in patients with breast cancer. While it is generally considered safe, some patients may experience severe side effects, so it's important to discuss potential risks with a healthcare provider. ^{6 7 8 9 10}

Research Team

Iambic Therapeutics, Inc., Senior Medical Director

Principal Investigator

Iambic Therapeutics, Inc

Eligibility Criteria

This trial is for adults with advanced cancers that have HER2 alterations. Participants must be able to receive treatment and provide a tumor sample. Specific details on who can or cannot participate are not provided.

Inclusion Criteria

My cancer has returned or didn't respond to treatment and involves a change in the HER2 gene.

Have radiographically measurable disease assessable by RECIST v1.1

I am 18 years old or older.

Exclusion Criteria

I have a serious heart condition.

I have HIV but it is well-controlled.

My diabetes is not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose Escalation

Participants with confirmed HER2 alterations receive IAM1363 to determine the maximum tolerated dose

21 days

3 visits (in-person)

Dose Optimization

Additional cohorts are enrolled to optimize dose selection and evaluate safety and preliminary efficacy

Estimated 3 months

Simon 2-Stage Evaluation

Tumor-specific cohorts are enrolled to evaluate IAM1363 at the selected dose(s) using a Simon 2-Stage Minimax Design

Estimated 46 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days after the last dose

Treatment Details

Interventions

• IAM1363
• Trastuzumab

Trial Overview The study is testing IAM1363, both alone and combined with Trastuzumab, to see how safe it is and if it works against advanced HER2-altered cancers. It's an early-stage trial where doses will be adjusted to find the right balance between safety and effectiveness.

Participant Groups

Group I: IAM1363 Monotherapy Experimental Treatment 1 Intervention

Treatment with IAM1363 capsules, dosed orally either once or twice daily in 21-day cycles.

Who Is Running the Clinical Trial?

Iambic Therapeutics, Inc

Lead Sponsor

Trials

1

Recruited

240+

Findings from Research

The combination of entinostat and exemestane has been shown to improve survival rates in women with estrogen receptor-positive (ER+) advanced breast cancer.

This finding suggests that entinostat may enhance the effectiveness of exemestane, a common treatment for this type of cancer, potentially offering a new therapeutic strategy for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entinostat plus exemestane has activity in ER+ advanced breast cancer. [2016]

The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor entinostat (ENT) significantly reduced HER2 expression and tumor viability in aromatase inhibitor (AI)-resistant breast cancer cells, indicating a potential mechanism to overcome resistance.

In animal models, the ATRA + ENT combination, especially when paired with letrozole, led to a notable decrease in tumor growth and tumor-initiating cell characteristics, suggesting that this treatment strategy could effectively reduce the risk of tumor recurrence in AI-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histone deacetylase inhibitor entinostat in combination with a retinoid downregulates HER2 and reduces the tumor initiating cell population in aromatase inhibitor-resistant breast cancer. Schech, AJ., Shah, P., Yu, S., et al.[2018]

The Breast Cancer Index (BCI) biomarker effectively predicts which early-stage hormone receptor-positive breast cancer patients will benefit from extended endocrine therapy (EET) with letrozole, showing a significant reduction in recurrence risk for those with high BCI scores.

Approximately 50% of patients identified as high-risk by clinical criteria did not benefit from extended therapy, while those with low-risk profiles showed significant improvement, highlighting the importance of personalized treatment plans based on BCI results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breast Cancer Index Predicts Extended Endocrine Benefit to Individualize Selection of Patients with HR+ Early-stage Breast Cancer for 10 Years of Endocrine Therapy. Noordhoek, I., Treuner, K., Putter, H., et al.[2022]

In a study of 94 estrogen receptor-positive breast tumors, higher levels of IFITM1 were linked to advanced clinical stages and poor responses to endocrine therapy, indicating its potential role in endocrine resistance.

Knocking down IFITM1 in AI-resistant breast cancer cells reduced tumor growth and invasion, while its overexpression in sensitive cells led to more aggressive growth, suggesting that targeting IFITM1 could be a promising strategy for treating endocrine-resistant breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Lui, AJ., Geanes, ES., Ogony, J., et al.[2021]

Lurbinectedin demonstrated a significant objective response rate of 41% in patients with BRCA1/2 mutations, indicating its efficacy in treating metastatic breast cancer, particularly in those with BRCA2 mutations who had an even higher response rate of 61%.

The safety profile of lurbinectedin improved with dose adjustments, although common side effects included nausea and fatigue, with neutropenia being the most severe hematologic adverse event, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy. Cruz, C., Llop-Guevara, A., Garber, JE., et al.[2019]

In the EMILIA phase 3 study, trastuzumab emtansine (T-DM1) significantly delayed the time to symptom worsening in patients with HER2-positive breast cancer, with a duration of 7.1 months compared to 4.6 months for capecitabine and lapatinib.

Patients treated with T-DM1 experienced a lower incidence of diarrhea symptoms during treatment, maintaining levels near baseline, while those on capecitabine and lapatinib saw a 1.5- to 2-fold increase, indicating better tolerability for T-DM1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Welslau, M., Diéras, V., Sohn, JH., et al.[2022]

In a study of 232 Japanese patients with HER2-positive advanced breast cancer, trastuzumab emtansine (T-DM1) was found to be well tolerated, with 98.3% of patients experiencing adverse events but only 2.2% discontinuing treatment due to these events.

The most common serious adverse effects included thrombocytopenia in 29.7% of patients and hepatotoxicity in 11.2%, but no new safety concerns were identified, indicating that T-DM1 is a viable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Evaluation of Trastuzumab Emtansine in Japanese Patients with HER2-Positive Advanced Breast Cancer. Watanabe, J., Ito, Y., Saeki, T., et al.[2022]

In a meta-analysis of 5,045 breast cancer patients, T-DM1 treatment was linked to a significantly increased risk of severe adverse events, including thrombocytopenia (10.66 times higher risk) and anemia (1.68 times higher risk).

While the overall incidence of severe adverse events is low, T-DM1 can lead to serious conditions such as elevated liver enzymes, hypertension, and peripheral sensory neuropathy, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and risk of severe adverse events associated with trastuzumab emtansine (T-DM1) in the treatment of breast cancer: an up-to-date systematic review and meta-analysis of randomized controlled clinical trials. Liu, K., Li, YH., Zhang, X., et al.[2022]

In the phase III MARIANNE trial involving patients with previously untreated HER2-positive metastatic breast cancer, trastuzumab emtansine (T-DM1) did not show predictive biomarker benefits for progression-free survival (PFS) compared to trastuzumab plus taxane, indicating that HER2-related biomarkers may not guide treatment decisions effectively.

However, higher HER2 mRNA levels and mutated PIK3CA status were found to be prognostic for PFS, suggesting that while they do not predict treatment response, they may provide insights into patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. Perez, EA., de Haas, SL., Eiermann, W., et al.[2020]

Trastuzumab emtansine (T-DM1) shows comparable pharmacokinetics across different ethnic groups, indicating that the recommended dosing is appropriate for all, based on data from 671 patients across multiple studies.

While ethnicity did not significantly affect the efficacy or safety of T-DM1, there was a noted trend of increased risk for thrombocytopenia in Asian patients, although most were able to continue treatment with dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer. Li, C., Wang, B., Lu, D., et al.[2022]

References

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

Entinostat plus exemestane has activity in ER+ advanced breast cancer. [2016]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Histone deacetylase inhibitor entinostat in combination with a retinoid downregulates HER2 and reduces the tumor initiating cell population in aromatase inhibitor-resistant breast cancer. [2018]

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

Breast Cancer Index Predicts Extended Endocrine Benefit to Individualize Selection of Patients with HR+ Early-stage Breast Cancer for 10 Years of Endocrine Therapy. [2022]

4. Ireland pubmed.ncbi.nlm.nih.gov

IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. [2021]

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

Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy. [2019]

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

Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. [2022]

7. Greece pubmed.ncbi.nlm.nih.gov

Safety Evaluation of Trastuzumab Emtansine in Japanese Patients with HER2-Positive Advanced Breast Cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Incidence and risk of severe adverse events associated with trastuzumab emtansine (T-DM1) in the treatment of breast cancer: an up-to-date systematic review and meta-analysis of randomized controlled clinical trials. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. [2020]

10. Germany pubmed.ncbi.nlm.nih.gov

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer. [2022]