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

Must not be taking: CYP450 3A4 inhibitors

Disqualifiers: Pregnancy, Hepatitis, HIV, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the drug neratinib works with other treatments for people with advanced cancers that have certain genetic changes and haven't responded to other treatments. The researchers aim to find the best dose and check for side effects when neratinib (also known as Nerlynx) is combined with one of three other drugs: everolimus (known as Afinitor, Votubia, or Zortress), palbociclib (known as Ibrance), or trametinib (known as Mekinist). The goal is to determine if these combinations can stop cancer growth more effectively than neratinib alone. People with solid tumors that have spread and specific genetic changes, like EGFR or KRAS mutations, may be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

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.

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

Research shows that patients generally tolerate the combination of neratinib and everolimus well. Studies have found that this pair has a promising safety record in patients with certain cancer mutations. Participants reported manageable side effects, indicating relative safety.

For the combination of neratinib and palbociclib, specific safety information is less available. However, palbociclib is generally safe when used with other cancer treatments, and the FDA has approved neratinib for certain cancer types, providing some assurance of safety.

In contrast, the combination of neratinib and trametinib has shown more difficulties. Some studies found this mix can be harmful, with patients experiencing significant side effects, suggesting higher risks compared to the others.

Overall, while each combination offers potential benefits, their safety varies. These factors are important to consider when thinking about joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine neratinib with other targeted therapies like everolimus, palbociclib, and trametinib, which each have unique mechanisms of action. Unlike traditional chemotherapy that attacks rapidly dividing cells indiscriminately, these treatments target specific components of cancer cell growth and survival pathways. For example, neratinib is an irreversible tyrosine kinase inhibitor that targets HER2 and EGFR, which are often overexpressed in certain cancers. Meanwhile, palbociclib works by inhibiting cyclin-dependent kinases, trametinib targets MEK enzymes involved in cell division, and everolimus inhibits mTOR, a key protein in regulating cell growth. This combination approach aims to more effectively halt cancer progression with potentially fewer side effects compared to conventional therapies.

What evidence suggests that this trial's treatments could be effective for advanced cancer?

This trial will evaluate different combinations of neratinib with other targeted therapies. Studies have shown that combining neratinib with everolimus, which participants in Arm I may receive, is generally safe and somewhat effective for patients with certain gene mutations. In an earlier trial, 19% of patients experienced a partial response, meaning their tumors became smaller. Participants in Arm II will receive neratinib with palbociclib. Research suggests that this combination can help control and prevent cancer spread to the brain in some breast cancer cases and shows promise in slowing other types of cancer. For participants in Arm III, who will receive neratinib with trametinib, early studies found limited benefits and some side effects, indicating challenges with this combination. Overall, while there is potential, the effectiveness of these combinations can depend on the type of cancer and specific genetic factors. ^{1 2 4 6 7}

Who Is on the Research Team?

Sarina Piha-Paul, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

Citations

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Phase I trial of the combination of the pan-ErbB inhibitor ... The objective response rate was 19% with partial response in four patients. Stable disease ≥16 weeks was seen in two patients (9.5%), resulting ...

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Phase I trial of the combination of the pan-ErbB inhibitor ... In this article, we present the safety and efficacy results of a single-center study of neratinib and everolimus in patients with EGFR mutations ...

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Neratinib Alone or in Combination with Immune ... Results. Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) ...

4. mdanderson.elsevierpure.com mdanderson.elsevierpure.com/en/publications/phase-i-trial-of-the-combination-of-the-pan-erbb-inhibitor-nerati

Phase I trial of the combination of the pan-ErbB inhibitor ... Combination therapy with neratinib and everolimus has a tolerable safety profile and clinical activity in ErbB-altered patients.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03065387

Study Details | NCT03065387 | Neratinib and Everolimus ... This phase I trial studies the side effects and best dose of neratinib in combination with everolimus, palbociclib, or trametinib in participants with solid ...

6. karger.com karger.com/lic/article/14/1/58/911518/Neratinib-Alone-or-in-Combination-with-Immune

Neratinib Alone or in Combination with Immune ... Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03065387?cond=(LUNG%20CANCER)%20OR%20(BRAF%20OR%20ERBB2%20OR%20PPP2R1B%20OR%20PIK3CA%20OR%20ERCC6%20OR%20CYP2A6%20OR%20SLC22A1L%20OR%20PRKN%20OR%20FASLG%20OR%20KRAS%20OR%20CASP8%20OR%20EGFR%20OR%20IRF1%20OR%20MAP3K8)&rank=1

Neratinib and Everolimus, Palbociclib, or Trametinib in Treating ... A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.