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

Phase 1

• Conditions: SOLID TUMORS WITH SOMATIC ACTIVATING HER MUTATIONS; MedDRA version: 21.1Level: LLTClassification code 10065143Term: Malignant solid tumourSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

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

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-09-19
• Last Update Posted: 22 March 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 650

Inclusion Criteria

1. Men and women who are =18 years old at signing of informed consent.
2. At time of screening, histologically confirmed cancers in patients with previously documented activating EGFR (exon 18) or qualifying HER2 mutation and who are refractory to standard therapy or for which standard or curative therapy does not exist or is not considered sufficient or appropriate
3. At least one measurable lesion, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; Eisenhauer et al, 2009).
4. Left ventricular ejection fraction (LVEF) =50% measured by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
5. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2.
6. Female patients with cancers known to secrete ß-human chorionic gonadotropin (hCG), ie germinomas, are eligible if the pattern of serum ß-hCG is suggestive of the malignancy and the pelvic ultrasound is negative for pregnancy.
7. Male patients must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of trastuzumab, fulvestrant, or neratinib monotherapy. Patients of childbearing
potential must agree and commit to the use of a highly effective double-barrier method of contraception or a non-hormonal method, from the signing of the informed consent until:
i. 28 days after the last dose of neratinib monotherapy, or
ii. 7 months after last dose of trastuzumab or
iii. 1 year after the last dose of fulvestrant.
8. Written, informed consent to participate in the study and follow the study procedures.
9. Recent metastatic tumor sample or fresh tumor biopsy, and plasma/blood specimens for gene sequencing and other biomarker analysis.

Additional Inclusion Criteria for all Breast Cancer Patients with Tumors that Harbor HER2 Mutations and NSCLC patients that harbor EGFR exon 18 mutations
10. Pretreatment fresh biopsy within 28 days prior to starting treatment unless the biopsy procedure presents a safety concern.

Additional Inclusion Criteria for HR+ Breast Cancer Patients with Tumors that Harbor HER2 Mutations
11. HR+ disease defined as =1% estrogen receptor (ER) positive and/or progesterone receptor (PR) positive cells:
12. Biopsy from a non-bony metastatic site.
13. Postmenopausal.
14. Medically confirmed ovarian failure
OR
15. Pre/perimenopausal if amenable to be treated with a luteinizing hormone receptor hormone (LHRH) agonist.
16. Prior treatment with chemotherapy or hormonal therapy (including fulvestrant).

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 325
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 325

Exclusion Criteria

1. Patients harboring ineligible somatic HER2 mutations.
2. Prior treatment with pan HER, HER2 or EGFR-directed tyrosine kinase inhibitor (TKI) (eg, lapatinib, afatinib, dacomitinib, neratinib, tucatinib, gefitinib, erlotinib, osimertinib) is excluded with the following exception:
patients with EGFR exon 18 mutated non-small cell lung cancer (NSCLC) who may have received afatinib, osimertinib, or other pan-HER or EGFR TKIs remain eligible.
3. Not recovered to at least Grade 1 at screening (Common Terminology Criteria for Adverse Events v4.0 [CTCAE v4.0]) from all clinically significant adverse events related to prior therapies (excluding alopecia).
4. Received chemotherapy or biologic therapy =2 weeks or 5 half-lives (t½) of the agent used, whichever is shorter, prior to the initiation of investigational product.
5. Received radiation therapy =14 days prior to initiation of investigational product.
6. Patients who are receiving any other anticancer agents with the
exception of patients on 1) a stable dose of bisphosphonates or denosumab or 2) sex hormone therapy in the case of breast, or gynecological cancers.
7. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 mg/m2 doxorubicin.
8. Symptomatic or unstable brain metastases.
9. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of =2), unstable angina (symptomatic angina pectoris within the past 180 days that required the initiation of or increase in anti-anginal medication or other intervention), myocardial infarction within 12 months of enrollment, or ventricular arrhythmia (except for benign premature ventricular contractions).
10. Demonstrates a QTc interval >450 ms for men or >470 ms for women or known history of congenital QT prolongation or Torsade de pointes (TdP).
11. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory assessments outside the following limits:
Laboratory endpoint: Required limit for exclusion
Absolute neutrophil count (ANC): <1,000/µL (1.0 x 109 /L)
Platelet count: <100,000/µL (<100 x 109/L)
Hemoglobin: <8 g/dL (transfusion allowed to treat low hemoglobin)
Transfusion must be at least 7 days prior to C1D1.
Total bilirubin: >1.5 x institutional upper limit of normal (ULN) (in case
of known Gilbert's syndrome, >2x ULN)
Aspartate aminotransferase (AST) and/or alanine aminotransferase
(ALT): >3 x institutional ULN
OR >5 x ULN if liver metastases are present
Creatinine: >1.5 x institutional ULN OR Calculated Creatinine Clearance
<30 mL/min (as measured directly with a 24-hour urine or calculated by
Cockcroft-Gault or Modification of Diet in Renal Disease [MDRD])
12. Active infection or unexplained fever >38.5°C (101.3°F).
13. Women who are pregnant, are planning on becoming pregnant, or are breast-feeding.
14. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade =2 [CTCAE version 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 patien

Study & Design

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