Neratinib + Targeted Therapy for Advanced Cancer

Overseen By Sarina Piha-Paul, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 28 days per cycle

93 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of neratinib in combination with everolimus, palbociclib, or trametinib in participants with solid tumors with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation, or KRAS mutation that do not respond to treatment (refractory) and have spread to other parts of the body (advanced or metastatic). Neratinib, palbociclib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving neratinib with everolimus, palbociclib, or trametinib may work better than neratinib alone in treating participants with solid tumors.

Will I have to stop taking my current medications?

The trial requires that participants stop taking medications that are potent inhibitors or inducers of CYP450 3A4 for 5 half-lives before starting treatment with everolimus or palbociclib. If you are on such medications, you will need to stop them before joining the trial.

What data supports the effectiveness of the drug combination Neratinib, Everolimus, and Trametinib for advanced cancer?

The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has shown effectiveness in treating BRAF-mutated non-small cell lung cancer, with a response rate of 64% and a median survival of 24.6 months, suggesting potential benefits of similar targeted therapies in advanced cancers. ^{1 2 3 4 5}

Is the combination of Neratinib and Everolimus safe for humans?

Neratinib has shown an acceptable safety profile in patients with HER2-positive breast cancer and other solid tumors. Everolimus is generally well tolerated, but common side effects include mouth sores, rash, infections, lung inflammation, and high blood sugar. Both drugs have been tested in various cancers, and while they are generally safe, side effects can occur, so monitoring by healthcare professionals is important. ^{6 7 8 9 10}

What makes the drug combination of Neratinib, Everolimus, Palbociclib, and Trametinib unique for advanced cancer?

This drug combination is unique because it targets multiple pathways involved in cancer growth, using Neratinib to inhibit HER2, Everolimus to block mTOR, and Trametinib to inhibit MEK, which together enhance the anti-tumor effects compared to using these drugs individually. ^{7 11 12 13 14}

Research Team

Sarina Piha-Paul, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with advanced or metastatic solid tumors that are unresponsive to standard treatments and have specific genetic mutations (EGFR, HER2, HER3/4, KRAS) may join. They should be in good physical condition (ECOG 0-1), have adequate organ function, not be pregnant or breastfeeding, agree to use contraception, and not have certain health conditions like active infections or recent major surgery.

Inclusion Criteria

My cancer has a KRAS mutation.

My previous nerve pain or damage has improved to mild or gone.

My skin rash is mild before starting trametinib.

Exclusion Criteria

I am not currently hospitalized for an infection or serious illness.

I do not have any uncontrolled illnesses like heart failure or untreated diabetes.

Subjects who are pregnant or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neratinib in combination with either everolimus, palbociclib, or trametinib. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

Long-term follow-up

Participants are monitored for objective response and adverse events

Up to 5 years

Treatment Details

Interventions

• Everolimus
• Neratinib
• Palbociclib
• Trametinib

Trial Overview The trial is testing the effectiveness of neratinib combined with everolimus, palbociclib, or trametinib on patients whose tumors carry certain mutations. It aims to find the safest doses and observe how well these drug combinations can control tumor growth compared to neratinib alone.

Participant Groups

Group I: Arm III (neratinib, trametinib) Experimental Treatment 2 Interventions

Participants receive neratinib PO daily and trametinib PO daily as directed. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (neratinib, palbociclib) Experimental Treatment 2 Interventions

Participants receive Neratinib PO daily for 28 days and Palbociclib PO daily for 21 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm I (neratinib, everolimus) Experimental Treatment 2 Interventions

Participants receive neratinib PO daily and everolimus PO daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Erlotinib and gefitinib are effective targeted therapies for advanced non-small cell lung cancer (NSCLC), specifically inhibiting the epidermal growth factor receptor (EGFR) to improve treatment outcomes.

Recent clinical trials have shown that using these tyrosine kinase inhibitors as first-line treatments can enhance personalized medicine approaches, potentially leading to better clinical outcomes for patients with advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians. Wang, Y., Schmid-Bindert, G., Zhou, C.[2022]

Recent advancements in targeted therapies for advanced non-small-cell lung cancer (NSCLC) have shown significant clinical benefits, even in patients who have previously failed one or two lines of chemotherapy.

Erlotinib and bevacizumab are highlighted as effective agents in this new class of treatments, demonstrating improved tumor control and patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies in the treatment of advanced non-small-cell lung cancer: update. Mendoza, L.[2022]

In a clinical trial involving 57 pretreated NSCLC patients, the combination of dabrafenib and trametinib showed a high overall response rate (ORR) of 68.4% and a median overall survival (OS) of 18.2 months, indicating its efficacy in treating BRAF V600E mutant non-small cell lung cancer.

The treatment was well tolerated, with manageable side effects such as pyrexia and nausea, leading to its approval for BRAF V600E metastatic NSCLC patients, regardless of prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. Sforza, V., Palumbo, G., Cascetta, P., et al.[2022]

Precision oncology is now the standard care for advanced non-small cell lung cancers (NSCLCs), with targeted therapies like tyrosine kinase inhibitors (TKIs) showing better outcomes than traditional treatments for tumors with EGFR mutations and ALK rearrangements.

Emerging therapies are being developed for additional genomic alterations, such as ROS1 and BRAF mutations, but KRAS mutations, which are common in NSCLC, currently lack effective targeted treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Shea, M., Costa, DB., Rangachari, D.[2022]

The combination of everolimus and vatalanib (PTK/ZK) showed at least additive and potentially synergistic anti-tumor effects in a mouse model of melanoma, enhancing efficacy without increasing toxicity compared to either drug alone.

Pharmacokinetic studies revealed that vatalanib increased the plasma concentration of everolimus, but this interaction did not fully explain the enhanced anti-tumor activity, suggesting that the two drugs may work together through distinct mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. O'Reilly, T., Lane, HA., Wood, JM., et al.[2021]

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]

In a phase I study involving 94 patients with advanced non-small-cell lung cancer (NSCLC), the combination of the mTOR inhibitor everolimus and the EGFR inhibitor erlotinib showed acceptable tolerability, with maximum tolerated doses established at 5 mg of everolimus daily or 50 mg weekly alongside 150 mg of erlotinib daily.

The combination therapy resulted in disease control for a median duration of 9.3 months in patients receiving daily everolimus, with some achieving complete or partial responses, indicating potential efficacy in treating chemotherapy-refractory NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. Papadimitrakopoulou, VA., Soria, JC., Jappe, A., et al.[2015]

Neratinib is an oral pan HER inhibitor that irreversibly blocks the activity of HER2 and other related receptors, showing promise in improving outcomes for patients with HER2-amplified breast cancer, which affects 20% to 25% of cases.

Current clinical trials are evaluating neratinib's safety and efficacy across various cancer types, including breast cancer, with a focus on its use in different treatment settings such as metastatic and adjuvant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Tiwari, SR., Mishra, P., Abraham, J.[2019]

In a phase I/II trial involving 105 patients, the combination of neratinib and capecitabine was found to have a manageable safety profile, with diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%) being the most common side effects.

The treatment demonstrated promising efficacy, achieving an objective response rate of 64% in patients without prior lapatinib exposure and 57% in those previously treated with lapatinib, indicating its potential as an effective option for HER2-positive metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. Saura, C., Garcia-Saenz, JA., Xu, B., et al.[2022]

Neratinib, a tyrosine kinase inhibitor, shows promising efficacy in treating HER2-positive breast cancer, with a higher response rate when used in combination with other therapies compared to monotherapy.

While neratinib is associated with a high incidence of adverse events, particularly diarrhea (83.9% of patients), these side effects are generally manageable, and the drug has been linked to improved survival outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials. Tao, Z., Li, SX., Shen, K., et al.[2021]

In a study investigating treatments for HER2+ breast cancer and triple-negative breast cancer (TNBC), combining neratinib with everolimus (an mTOR inhibitor) or trametinib (a MEK inhibitor) significantly enhanced tumor growth inhibition compared to using neratinib alone, achieving up to 81% inhibition in xenograft models.

The combination therapies not only improved anti-tumor effects but also activated apoptosis pathways, indicating a potential mechanism for their enhanced efficacy, making these combinations promising options for treating these aggressive breast cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening. Lee, J., Liu, H., Pearson, T., et al.[2021]

The combination of neratinib, a pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, was found to be tolerable in a phase I study involving 60 patients with advanced solid tumors, with diarrhea being the most common side effect (93%).

This treatment showed promising antitumor activity in patients with HER2-amplified breast cancer resistant to trastuzumab and other tumor types, suggesting potential for further evaluation in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. Gandhi, L., Bahleda, R., Tolaney, SM., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians. [2022]

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

Ongoing progress in BRAF-mutated non-small cell lung cancer. [2022]

3. Czech Republic pubmed.ncbi.nlm.nih.gov

Targeted therapies in the treatment of advanced non-small-cell lung cancer: update. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

BRAF Inhibitors in Non-Small Cell Lung Cancer. [2022]

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

Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. [2015]

9. Germany pubmed.ncbi.nlm.nih.gov

Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial. [2021]

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

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. [2019]

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

Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. [2022]

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

Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials. [2021]

13. Switzerland pubmed.ncbi.nlm.nih.gov

PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening. [2021]

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

Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. [2022]