| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SOLID TUMORS WITH SOMATIC ACTIVATING HER MUTATIONS. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid cancer tumours with specific genetic mutations |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast cancer:
To determine the confirmed objective response rate (ORR) by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
For the metastatic cervical cancer cohort:
To determine the confirmed ORR by independent central review
according to RECIST v1.1
For all other cohorts:
To determine the first objective response rate (ORRfirst) by investigator at the first post-baseline tumor assessment
|
|
| E.2.2 | Secondary objectives of the trial |
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast cancer:
•To determine the confirmed objective response rate (ORR) by investigator
•To determine the duration of response (DOR), clinical benefit rate(CBR) and progression free survival (PFS) by both independent central review and investigator
•To assess the safety profile and tolerability of study treatments
•To assess Patient Reported Outcomes (PRO)
For metastatic cervical cancer:
- To determine the confirmed ORR by investigator
-To determine the DOR by both independent central review and investigator
- To determine the CBR by both independent central review and investigator
- To determine the PFS by both independent central review and investigator
-To determine overall survival (OS)
For all other cohorts:
• To determine the confirmed ORR, DOR, CBR and PFS by investigator
• To determine OS
• To assess the safety profile and tolerability of study treatments
• To assess PRO
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 β-human chorionic gonadotropin (hCG), ie germinomas, are eligible if the pattern of serum β-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).
|
|
| E.4 | Principal 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 patient inappropriate for this study.
17. Known hypersensitivity to any component of the investigational product, required combination therapy, or loperamide.
18. Unable or unwilling to swallow tablets.
19. Patients with known activating KRAS mutations.
Additional Exclusion Criteria for Patients with Breast Cancer With HER2 Mutations
20. Patients with known HER2+ tumors (protein overexpression or gene amplification as defined by ASCO/CAP guidelines or HER2 amplifications as determined by copy number alterations by NGS) are excluded.
Additional Exclusion Criteria for Patients With HER2 Mutations Treated With Trastuzumab Combination Therapy or Being Randomized into HR+ Breast Cancer Cohorts
21. Hypersensitivity to trastuzumab, murine proteins or any of the excipients listed in the Herceptin label.
22. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast cancer :
To determine the confirmed objective response rate (ORR) by independent central review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
For the metastatic cervical cancer cohort:
To determine the confirmed ORR by independent central review according to RECIST v1.1
For all other cohorts:
To determine the first objective response rate (ORRfirst) by investigator at the first post-baseline tumor assessment
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For cohorts receiving combination treatment that includes trastuzumab, post-treatment disease assessment by CT or magnetic resonance imaging (MRI) will be conducted at the beginning of Week 10 (ORRfirst), and every 3 cycles (± 7 days) thereafter.
For all other cohorts not receiving trastuzumab, post-treatment disease assessment will be conducted at the beginning of Week 9 (ORRfirst), and every 2 cycles (± 7 days) thereafter.
Complete or partial response (CR or PR) must be confirmed with a repeat scan performed no sooner than 4 weeks after the criteria for response are first met.
|
|
| E.5.2 | Secondary end point(s) |
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast cancer:
To determine the confirmed objective response rate (ORR) by investigator
To determine the duration of response (DOR), clinical benefit rate (CBR) and progression free survival (PFS) by both independent central review and investigator
To assess the safety profile and tolerability of study treatments
To assess Patient Reported Outcomes (PRO)
For metastatic cervical cancer:
- To determine the confirmed ORR by investigator
-To determine the DOR by both independent central review and investigator
- To determine the CBR by both independent central review and investigator
- To determine the PFS by both independent central review and investigator
- To determine overall survival (OS)
For all other cohorts:
To determine the confirmed ORR, DOR, CBR and PFS by investigator
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For cohorts receiving combination treatment that includes trastuzumab, post-treatment disease assessment will be conducted at the beginning of Week 10 (ORRfirst), and every 3 cycles (± 7 days) thereafter.
For all other cohorts not receiving trastuzumab, post-treatment disease assessment will be conducted at the beginning of Week 9 (ORRfirst), and every 2 cycles (± 7 days) thereafter.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| Serbia |
| United States |
| Belgium |
| Denmark |
| Finland |
| France |
| Ireland |
| Italy |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
