Neratinib or Neratinib + Palbociclib for Cancer

Recruiting at 149 trial locations

Overseen by Haider Mahdi, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Tyrosine kinase inhibitors, CDK4/6 inhibitors

Disqualifiers: Breast cancer, RB1 loss, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II ComboMATCH treatment trial compares the effect of neratinib to the combination of neratinib and palbociclib in treating patients with HER2 positive solid tumors. Neratinib and palbociclib are in a class of medications called kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of tumor cells. Giving neratinib and palbociclib in combination may shrink or stabilize cancers that over-express a specific biomarker called HER2.

Will I have to stop taking my current medications?

The trial requires that you stop any cancer-directed therapy at least 3 weeks before joining, and for oral therapies, you need to stop them for a period equal to or greater than 5 times the drug's half-life. You cannot have had prior therapy with certain drugs like neratinib or CDK4/6 inhibitors.

What data supports the effectiveness of the drug Neratinib for cancer?

Neratinib has been shown to significantly reduce the risk of cancer recurrence in patients with early-stage HER2-positive breast cancer, especially when started within a year of completing previous treatment. It has demonstrated antitumor activity and is approved for use in certain breast cancer patients in the USA and EU. ^{1 2 3 4 5}

Is Neratinib safe for human use?

Neratinib has been shown to have an acceptable safety profile in patients with HER2-positive breast cancer and other solid tumors, but it commonly causes diarrhea, which can be severe. Other side effects include nausea, abdominal pain, fatigue, vomiting, rash, and muscle spasms, but these are generally manageable with standard medical care. ^{1 2 3 6 7}

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

The combination of Neratinib and Palbociclib is unique because Neratinib is an oral drug that irreversibly inhibits multiple human epidermal growth factor receptors (HER1, HER2, and HER4), which are often overactive in certain cancers, while Palbociclib is a CDK4/6 inhibitor that helps control cell division. This combination targets different pathways in cancer cells, potentially enhancing treatment effectiveness compared to using each drug alone. ^{1 2 3 5 8}

Research Team

Haider Mahdi, MD

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for patients with HER2 positive solid tumors, excluding breast cancer. Participants can have up to five prior treatments and treated brain metastases if stable for 3+ months without steroids. They must not have leptomeningeal disease or RB1 loss/mutation, agree to a biopsy (or provide recent tissue), and show measurable disease.

Inclusion Criteria

Not pregnant and not nursing

No history of allergic reaction to study agents or similar compounds

Total bilirubin level ≤ 1.5 x institutional ULN

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive neratinib alone or in combination with palbociclib in 28-day cycles

Up to 2 years

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months (in-person)

Treatment Details

Interventions

• Neratinib (Kinase Inhibitor)
• Palbociclib (Kinase Inhibitor)

Trial Overview The study compares the effectiveness of neratinib alone versus its combination with palbociclib in treating HER2 positive solid tumors. These kinase inhibitors block proteins that cause cancer cells to multiply, potentially shrinking or stabilizing the tumor.

Participant Groups

Group I: Arm II (neratinib maleate, palbociclib) Experimental Treatment 8 Interventions

Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 and palbociclib PO QD on days 1-21 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

Group II: Arm I (neratinib maleate) Active Control 7 Interventions

Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may crossover to Arm II. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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 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 has been shown to improve 2-year invasive disease-free survival in early-stage HER2-positive breast cancer patients after trastuzumab treatment, particularly in HER2+/HR+ tumors, according to the phase III ExteNET trial.

In phase II trials, neratinib demonstrated efficacy as both a standalone treatment and in combination with other therapies for HER2-positive metastatic breast cancer, with manageable side effects like diarrhea through early prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Kourie, HR., Chaix, M., Gombos, A., et al.[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 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 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 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]

References

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

Neratinib: First Global Approval. [2019]

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

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

3. England pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. [2019]

5. 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]

6. 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]

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

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

8. 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]