Neratinib + Ruxolitinib for Breast Cancer

Overseen By Page E Blas, MA

Age: 18+

Sex: Female

Trial Phase: Phase < 1

Sponsor: Baylor Research Institute

Must not be taking: Steroids, Anti-epileptics

Disqualifiers: Active infection, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 18 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The goal of this clinical trial is to assess the safety and efficacy of combined ruxolitinib and neratinib in patients with chemotherapy-pretreated metastatic triple negative breast cancer. This trial will evaluate one dosing schedule of neratinib in ruxolitinib in patients with metTNBC with locoregional recurrence.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not be on steroids or anti-epileptic drugs for brain metastases. Also, you should not have received any systemic anti-cancer therapy within 2 weeks or investigational agents within 4 weeks before starting the trial.

Is the combination of Neratinib and Ruxolitinib safe for humans?

Neratinib has been shown to be generally safe for humans, with diarrhea being the most common side effect, which can be managed with medication or dose adjustments. Other side effects include nausea, abdominal pain, fatigue, and rash, but these are usually manageable and reversible. ^{1 2 3 4 5}

What makes the drug combination of Neratinib and Ruxolitinib unique for breast cancer treatment?

The combination of Neratinib and Ruxolitinib is unique because it targets both the HER2 protein and the JAK-STAT signaling pathway, which are involved in breast cancer growth. This dual approach may offer a new strategy for treating breast cancer, especially in cases where other treatments have not been effective. ^{1 2 6 7 8}

What data supports the effectiveness of the drug combination Neratinib and Ruxolitinib for breast cancer?

Neratinib has been shown to significantly reduce the risk of breast cancer recurrence in patients with early-stage HER2-positive breast cancer, especially when started within a year of completing trastuzumab treatment. It is approved for use in this setting and has been effective in combination with other cancer drugs in clinical studies. ^{1 2 6 9 10}

Who Is on the Research Team?

Joyce A O'Shaughnessy, MD

Principal Investigator

Baylor Scott and White Research Institute

Are You a Good Fit for This Trial?

This trial is for women over 18 with metastatic triple-negative breast cancer (mTNBC) previously treated with specific chemotherapies. Participants must have adequate organ function and cannot be pregnant or breastfeeding. They should not have had more than four prior chemotherapy regimens, though exceptions may apply based on physician discretion.

Inclusion Criteria

My breast cancer is triple-negative or has very low estrogen receptors.

I have TNBC and was treated with specific chemotherapies, except doxorubicin if I was allergic.

I have had 4 or fewer chemotherapy treatments for my advanced cancer, but prior treatments with platinum or taxane are okay.

Exclusion Criteria

I have no other active cancer.

Any other investigational or anti-cancer treatments while participating in this study

Severe and/or uncontrolled medical conditions or other conditions that could affect participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neratinib in combination with ruxolitinib to assess safety and efficacy in metTNBC with chest wall recurrence

18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Neratinib
• Ruxolitinib

Trial Overview The trial tests the combination of two oral medications, ruxolitinib and neratinib, in patients with mTNBC who've had previous chemotherapy. It aims to determine the safety and effectiveness of this treatment regimen for those experiencing a recurrence of their cancer.

How Is the Trial Designed?

Group I: neratinib + ruxolitinib Experimental Treatment 2 Interventions

There is only one arm

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

Approved in United States as Nerlynx for:

• Extended adjuvant treatment of women with early-stage HER2-positive breast cancer

Approved in European Union as Nerlynx for:

• Extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer

Who Is Running the Clinical Trial?

Baylor Research Institute

Lead Sponsor

Trials

210

Recruited

205,000+

Published Research Related to This Trial

Neratinib is an oral, irreversible inhibitor targeting HER1, HER2, and HER4, specifically developed for treating HER2-positive breast cancer, and is approved in the USA for patients who have previously received trastuzumab-based therapy.

The drug is currently in various stages of clinical development for other cancers, including metastatic breast cancer and solid tumors like non-small cell lung cancer and glioblastoma, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib: First Global Approval. Deeks, ED.[2019]

Neratinib, a pan-HER tyrosine kinase inhibitor, shows promising efficacy when combined with other targeted therapies like mTOR inhibitors and CDK4/6 inhibitors in HER2+ cancers, leading to significant increases in event-free survival in patient-derived xenograft models.

The study found that combining neratinib with palbociclib increased event-free survival in all tested models, suggesting a strong potential for this combination in treating HER2+ breast cancer and possibly other HER2+ tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer. Zhao, M., Scott, S., Evans, KW., et al.[2022]

In a phase I study involving 21 women with HER2-positive metastatic breast cancer, the combination of neratinib, trastuzumab, and paclitaxel showed significant clinical benefits, with 38% of patients achieving objective responses and 52% experiencing clinical benefit lasting at least 24 weeks.

The recommended dose of neratinib was found to be 200 mg/day, and while common side effects included diarrhea and fatigue, the implementation of prophylactic measures effectively managed severe diarrhea, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study. Jankowitz, RC., Abraham, J., Tan, AR., et al.[2019]

Neratinib significantly reduces the risk of invasive disease recurrence or death in women with early-stage HER2-positive breast cancer who have completed trastuzumab therapy, as shown in the ExteNET trial over 12 months, with benefits observed at both 2 and 5 years post-treatment.

Patients with hormone receptor-positive disease and those who start neratinib within 1 year of completing trastuzumab experience greater benefits, leading to its approval in the EU as an extended adjuvant therapy for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU. Dhillon, S.[2021]

Neratinib is a promising oral medication that irreversibly inhibits HER kinases, showing potential in treating HER-2-positive breast cancer through targeted therapy.

The review highlights the development of neratinib from preclinical studies to Phase III clinical trials, suggesting its effectiveness when combined with chemotherapy in various treatment settings, including metastatic and adjuvant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib (HKI-272) in the treatment of breast cancer. López-Tarruella, S., Jerez, Y., Márquez-Rodas, I., et al.[2019]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

Neratinib was approved by the FDA for the extended treatment of early-stage HER2-positive breast cancer, showing a significant improvement in invasive disease-free survival (iDFS) with a 2-year rate of 94.2% compared to 91.9% for placebo in a study of 2,840 women.

While neratinib is effective, it is associated with a high incidence of diarrhea (40% grade 3 or 4), which is the most common reason for treatment discontinuation, though most adverse effects are manageable and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. Singh, H., Walker, AJ., Amiri-Kordestani, L., et al.[2019]

Neratinib, an irreversible HER kinase inhibitor, shows promise as an extended adjuvant therapy for patients with early-stage HER2+ breast cancer who have already received trastuzumab, potentially improving outcomes for those at risk of relapse.

In Phase II trials, neratinib demonstrated effectiveness in treating trastuzumab-resistant metastatic HER2+ breast cancer and HER2-mutated breast cancers, suggesting it could be a valuable treatment option for patients with limited current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of neratinib in HER2-driven breast cancer. Cherian, MA., Ma, CX.[2020]

In a phase II study of 23 patients with refractory metastatic triple-negative breast cancer, ruxolitinib was well-tolerated with minimal severe side effects, primarily causing fatigue.

Despite showing on-target activity by reducing pSTAT3+ cells in some patients, ruxolitinib did not achieve any objective responses, indicating it may not be effective as a single-agent treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. Stover, DG., Gil Del Alcazar, CR., Brock, J., et al.[2020]

In a phase III trial involving 202 Asian patients with HER2+ metastatic breast cancer, the combination of neratinib and capecitabine (N+C) showed a significantly longer median progression-free survival (7.0 months) compared to lapatinib and capecitabine (L+C) (5.4 months).

N+C also demonstrated a lower incidence of interventions for central nervous system disease (27.9% vs. 33.8%) and a longer duration of response (11.1 months vs. 4.2 months) compared to L+C, with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens. Dai, MS., Feng, YH., Chen, SW., et al.[2023]

Citations

1. New Zealand pubmed.ncbi.nlm.nih.gov

Neratinib: First Global Approval. [2019]

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

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study. [2019]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU. [2021]

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

Neratinib (HKI-272) in the treatment of breast cancer. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. [2023]

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

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. [2019]

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

The role of neratinib in HER2-driven breast cancer. [2020]

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

Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. [2020]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens. [2023]