A study of Neratinib in patients with solid tumours that have specific genetic mutations

Phase 1

Active, not recruiting

• Conditions: Cancer tumor with somatic human epidermal growth factor receptor mutation (EGFR, ERBB2 (HER2), ERBB3 (HER3) or EGFR gene amplification; MedDRA version: 16.1Level: LLTClassification code 10065143Term: Malignant solid tumourSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2013-002872-42-ES
• Lead Sponsor: Puma Biotechnology, Inc

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2014-01-20
• Last Update Posted: 26 September 2023

Recruitment & Eligibility

• Status: Not Recruiting
• Sex: All
• Target Recruitment: 180

Inclusion Criteria

1. Men and women who are ?18 years old at signing of informed consent.
2. Histologically confirmed cancers for which no curative therapy exists.
3. Documented human epidermal growth factor receptor (EGFR, HER2, or HER3) mutation identified through mutation analysis assays as routinely performed at each participating site according to their local laboratory procedures:
i. HER2 mutation or
ii. EGFR mutation or EGFR amplification primary brain tumor (see additional criteria for this cohort only) or
iii. HER3 mutation
4. Patients must have at least one measurable or evaluable lesion, preferably as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Patients without RECIST-measurable disease will be eligible for enrollment to the EGFR-mutation primary brain tumor cohort or the solid tumor NOS cohorts, regardless of tumor type, provided their disease can be evaluated using another accepted response criteria (eg, Gynecologic Cancer InterGroup [GCIG] CA125 Response Criteria, Pediatric Cancer Working Group 2 (PCWG2) Criteria; PET Response Criteria in Solid Tumors PERCIST).
5. Left ventricular ejection fraction (LVEF) ?50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
6. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2.
7. Negative ?-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
8. Women of child-bearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the investigator, from the time of informed consent until 28 days after the last dose of the investigational product. Men must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of the investigational product.
9. Provide written, informed consent to participate in the study and follow the study procedures.

Additional inclusion criteria for patients with Primary Brain Tumors that harbor EGFR Mutations (Cohort 2a):
10. Glioblastoma multiforme (GBM), gliosarcoma, and/or Grade III glioma.
11. Has received prior treatment including radiation and/or chemotherapy.
12. Documentation of EGFR gene amplification or EGFR mutation from most recent tumor sample.
13. Able to undergo repeated magnetic resonance imaging (MRI) scans.
14. Subjects with recurrent disease (confirmed by MRI and evaluable by Macdonald criteria) at the time of first or second recurrence or progression following initial definitive therapy(s) such as surgery with or without adjuvant radiation therapy and/or chemotherapy.
15. Have ? 1 site of bi-dimensionally measurable disease:
i. The size of at least one of the measurable lesions should ? 1 cm in each dimension and noted on more than one imaging slice.
ii. Measured using contrast-enhanced MRI clearly limited residual lesion (re-growth within the surgical or irradiated field is acceptable).
iii. Imaging study performed within 28 days before enrollment while on stable dose steroid medication for at least 5 days immediately before and during the imaging study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 90

Exclusion Criteria

1. Prior treatment with any HER2 directed TKI (eg, lapatinib, afatinib, dacomitinib, neratinib).
2. Not recovered to at least Grade 1 or baseline (CTCAE v4.0) from all clinically significant AEs related to prior therapies (excluding alopecia).
3. Received chemotherapy or biologic therapy ? 2 weeks or 5 half-lives (t½) of the agent used, whichever is shorter, prior to the start of neratinib.
4. Received radiation therapy ?14 days prior to initiation of the investigational product, except primary brain tumor patients.
5. Patients who are receiving any other anticancer agents with the exception of patients on 1) a stable dose of bisphosphonates or denosumab or 2) a gonadotropin-releasing agonist/antagonist in the case of prostate cancer.
6. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose ?350 mg/m2 or equivalent dose of other anthracyclines.
7. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study.) Patients with primary central nervous system tumors are eligible.
8. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ?2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
9. QTc interval > 450 ms for men or > 470 ms for women, or known history of congenital QT prolongation or Torsade de pointes (TdP).
10. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory assessments outside the following limits:
- Absolute neutrophil count (ANC): <1,000/µL (1.0 x 10e9 /L);
- Platelet count <100,000/µL (<100 x 10e9/L);
- Hemoglobin: <8 g/dL (transfusion allowed to treat low hemoglobin-transfusion must be at least 7 days prior to baseline);
- Total bilirubin: >1.5 x institutional upper limit of normal (ULN) (in case of known Gilbert's syndrome, >2× ULN);
- Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT): >3 x institutional ULN (>5 × ULN if liver metastases are present);
- Creatinine: >1.5 × ULN or calculated Creatinine Clearance <50 mL/min (as calculated by Cockroft-Gault formula or Modification of Diet in Renal Disease [MDRD] formula).
11. Active infection or unexplained fever >38.5°C (101.3°F).
12. Uncontrolled concurrent malignancy (early stage or chronic disease is allowed if not requiring active therapy or intervention and is under control).
13. Women who are pregnant or breast-feeding.
14. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ?2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline).
15. Clinically active infection with a hepatitis virus.
16. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the patient inappropriate for this study.
17. Known hypersensitivity to any component of the investigational product.
18. Unable or unwilling to swallow tablets.

Additional exclusion criteria for patients with Primary Brain Tumors that harbor EGFR Mutations (Cohort 2a):
19. Prior or scheduled Gliadel® wafer implant unless area of asses

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified