Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Trastuzumab

Fulvestrant

Neratinib

Antineoplastic Agents, Immunological

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.

-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.

-Optional at baseline and disease progression

Tumor biopsy

-Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)

Research blood sample

Cynthia Ma, M.D., Ph.D

This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.

Overexpression of HER2 due to gene amplification is an established therapeutic target in breast cancer for which multiple HER2 targeted drugs are now available. However, the majority of breast cancers are without HER2 overexpression/non-amplified and not currently eligible to receive HER2 targeted drugs. Advances in tumor genome sequencing technology led to the identification of recurrent HER2 mutations (HER2mut) in approximately 2% of HER2 non-amplified primary breast cancers, and 3-5% of metastatic tumors. Importantly, tumor cells harboring HER2mut are sensitive to the anti-tumor effects of HER2-targeted agents in preclinical models, especially neratinib, a potent irreversible pan-HER inhibitor. However, neratinib monotherapy has demonstrated only modest single agent activity in HER2mut,, non-amplified metastatic breast cancer (MBC). Based on the hypothesis that the combination of neratinib and fulvestrant will be more effective than neratinib alone in ER+/HER2mut, non-amplified MBC the investigators conducted a single arm phase II study of neratinib plus fulvestrant with 2 cohorts, fulvestrant (FUL)-treated and FUL-naïve, for patients with ER+/HER2mut, non-amplified MBC to assess the anti-tumor effects of this combination. An exploratory ER-negative (ER-) HER2mut cohort was also included for the efficacy of neratinib monotherapy.

Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer

* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
* Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
* Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
* Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

* Participants were followed for progressive disease from start of treatment until completion of follow-up.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

-Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.

* A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.
* An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.
* A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.

* Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.
* Stage I has a better outcome than Stage IV.

* Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
* Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

-CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.

* RR is defined as number of participants with complete response or partial response as best response.
* Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
* Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Puma Biotechnology, Inc.

United States Department of Defense

Washington University School of Medicine

Part I: Neratinib Only

Part II: Neratinib Only (ER-)

Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)

Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)

Crossover: Neratinib + Trastuzumab

Crossover: Neratinib + Fulvestrant + Trastuzumab

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Activating

Novel

HER2 Status

Ductal

Lobular

Other

Unknown

Histology Subtype

I/II

* Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.
* A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.
* An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.
* A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.

Tumor Grade

IIIA

IIIC

Tumor Stage at Initial Diagnosis

Cynthia Ma, M.D., Ph.D.

Only Part I participants were evaluable for this outcome measure.

Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone

Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.

Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation

Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.

Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation

Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.

Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation

Activating mutation - L7L755S

Activating mutation - S310F

Activating mutation - A775_G776insYVMA

Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1. The data represents exact number of weeks that each participant had progression-free survival. 2 participants with Activating mutation - S310F both had 8 weeks of PFS.

Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)

ECD mutation : Ductal histology

ECD mutation : Other histology

Exon 20 ins mutation : Ductal histology

Exon 20 ins mutation : Other histology

KD mutation : Ductal histology

KD mutation : Other histology

Number of Participants With HER2 Mutation Subtype and Histology Subtype

ECD mutation : Tumor grade I/II

ECD mutation : Tumor grade III

ECD mutation : Unknown

Exon 20 ins mutation : Tumor grade I/II

Exon 20 ins mutation : Tumor grade III

Exon 20 ins mutation : Unknown

KD mutation : Tumor grade I/II

KD mutation : Tumor grade III

KD mutation : Unknown

Number of Participants With HER2 Mutation Subtype and Tumor Grade

ECD mutation : Stage I

ECD mutation : Stage II

ECD mutation : Stage III

ECD mutation : Stage IV

Exon 20 ins mutation : Stage I

Exon 20 ins mutation : Stage II

Exon 20 ins mutation : Stage III

Exon 20 ins mutation : Stage IV

KD mutation : Stage I

KD mutation : Stage II

KD mutation : Stage III

KD mutation : Stage IV

Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis

ECD mutation

Exon 20 ins mutation

KD mutation

The number analyzed for each row adds up to overall total number analyzed.

Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival

Part II ER-cohort Only: Progression-free Survival (PFS)

Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)

Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)

Anemia

LVEF Decrease

Heart failure with preserved ejection fraction

Tinnitus

Dry eye

Abdominal cramping

Abdominal pain

Bloating

Constipation

Diarrhea

Dry mouth

Dyspepsia

Flatulence

Mucositis oral

Nausea

Stomach pain

Stomatitis

Vomiting

Fatigue

Fever

Generalized weakness

Pain

Rhinitis infective

Upper respiratory infection

Urinary tract infection

Alaline aminotransferase increased

Alkaline phosphatase increased

Alkaline phosphatase decreased

Aspartate aminotransferase increased

CD4 lymphocytes decreased

Creatinine increased

Ejection fraction decreased

INR increased

Lymphocyte count decreased

Neutrophil count decreased

Platelet count decreased

Weight loss

White blood cell decreased

Anorexia

Dehydration

Hypercalcemia

Hyperglycemia

Hyperkalemia

Hypoalbuminemia

Hypocalcemia

Hypokalemia

Hyponatremia

Hypophosphatemia

Arthralgia

Back pain

Bone pain

Flank pain

Generalized muscle weakness

Joint range of motion decreased

Leg cramp

Muscle weakness left sided

Muscle weakness lower limb

Myalgia

Pain at injection site

Pain in extremity

Dizziness

Dysgeusia

Headache

Peripheral sensory neuropathy

Syncope

Depression

Insomnia

Acute kidney injury

Urinary tract obstruction

Urine discoloration

Urine odor

Cough

Dyspnea

Epistaxis

Hoarseness

Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer	NCT01670877	Breast Neoplasm...	Neratinib Fulvestrant Trastuzumab Tumor biopsy Research blood ...	18 Years -	Washington University School of Medicine
Neoadjuvant Study of Palbociclib in Combination With Letrozole and Trastuzumab in Stage II-III ER+ HER2+ Breast Cancer	NCT02907918	Breast Cancer Cancer of Breas... Breast Carcinom...	Palbociclib Letrozole Trastuzumab Goserelin Breast surgery Research tumor ... Research bone m... Research blood ... Research blood ... Blood for detec...	18 Years -	Washington University School of Medicine

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