| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Malignant solid tumor with somatic human epidermal growth factor receptor (EGFR, ERBB2, ERBB3) mutations or EGFR amplification (primary brain tumors). |
|
| 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 | 20.0 |
| 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 |
| To determine the objective response rate at 8 weeks (ORR8) for all cohorts. |
|
| E.2.2 | Secondary objectives of the trial |
• Objective response rate (ORR) according to RECIST v1.1 or other defined response criteria with neratinib monotherapy and combination therapy.
• Clinical benefit rate (CBR) of neratinib monotherapy and combination therapy.
• Progression-free survival (PFS).
• Change in tumor growth rate for patients with primary brain tumors.
• Duration of response (DOR) of neratinib monotherapy and combination therapy, defined as the time from which measurement criteria are met for overall response of CR and PR until the first date of documented disease progression.
• Overall survival (OS) defined as the time from C1D1 to death due to any cause.
• The role of dual modality PET/CT scans in measuring metabolic response to neratinib monotherapy and combination therapy.
• Safety profile and tolerability of neratinib monotherapy and combination therapy.
• Patient Reported Outcomes using the EuroQol EQ-5D-5L instrument.
Exploratory objectives are detailed in the protocol |
|
| 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. Histologically confirmed cancers in patients with activating ERBB mutations and/or EGFR amplification and who are refractory to standard therapy or for which standard or curative therapy does not exist or is not considered sufficient or appropriate by the Investigator.
3. At the time of screening, a previously documented mutation:
i. ERBB2 mutation in breast, bladder/urinary tract, biliary tract, colorectal, endometrial, gastroesophageal, lung, ovarian, and any other cancers, or
ii. EGFR mutation/amplification in a primary brain tumor, or
iii. ERBB3 mutation in any cancer.
4. At least one measurable lesion, preferably as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; Eisenhauer et al, 2009). Patients without RECIST measurable disease may be eligible for enrollment provided their disease can be evaluated for response using another accepted criteria (eg, Gynecologic Cancer InterGroup [GCIG] CA125 Response Criteria [Rustin et al, 2011], Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria [Scher et al, 2008]; PET Response Criteria [PET Response Criteria]).
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 0-2.
7. 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.
8. 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 IP. Women of child-bearing potential must agree and commit to the use of a highly effective double-barrier method of contraception (eg, a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) 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. 6 months after the last dose of paclitaxel, or
iii. 1 year after the last dose of fulvestrant.
9. Provide written, informed consent to participate in the study and follow the study procedures.
10. A biomarker request form for the patient’s mutation has been signed and approved for eligibility by the Sponsor.
Details for additional Inclusion Criteria for Patients with Primary Breast Tumors that Harbor ERBB2 Mutations AND for Patients with Primary Brain Tumors that Harbor EGFR Mutations (closed to enrollment in Amendment 4) can be found in the protocol. |
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| E.4 | Principal exclusion criteria |
1. Prior treatment with any ERBB2-directed TKI (eg, lapatinib, afatinib, dacomitinib, neratinib) with the exception of NSCLC patients who may have received afatinib and remain eligible.
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 IP, 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) sex hormone therapy in the case of breast, prostate or gynecological cancers.
6. 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.
7. Symptomatic or unstable brain metastases. 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 (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). For patients with NSCLC, the following are additionally excluded: conduction abnormality requiring a pacemaker; supraventricular and/or nodal arrhythmias not controlled with medication; valvular disease with documented compromise in cardiac function; symptomatic pericarditis; any history of myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function; any history of documented congestive heart failure and/or cardiomyopathy.
9. 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).
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 haemoglobin) Transfusion must be at least 7 days prior to baseline;
- Total bilirubin: >1.5 x institutional ULN (in case of known Gilbert's syndrome, >2× ULN);
- Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT): >3 x institutional ULN OR >5 × ULN if liver metastases are present;
- Creatinine: >1.5 × institutional ULN or calculated Creatinine Clearance <30 mL/min (as calculated by Cockroft-Gault formula or MDRD formula).
11. Uncontrolled concurrent malignancy (early stage or chronic disease is allowed if not requiring active therapy or intervention and is under control).
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 National Cancer Institute 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 IP, required combination therapy, or loperamide.
18. Unable or unwilling to swallow tablets.
19. Patients bearing certain somatic ERBB mutations, such as those that are subclonal in nature, or resulting in the expression of truncated proteins including alterations that result in a premature stop codon or a change in reading frame (ie, frame shift mutations) may not be considered for eligibility.
20. Patients with known activating KRAS mutations.
Additional Exclusion Criteria for Patients with ERBB2 Mutant Bladder/Urinary Tract Tumors for Combination Therapy Cohort:
21. Prior progression after taxane therapy for metastatic bladder/urinary tract cancer.
22. Known hypersensitivity to paclitaxel (Taxol) or products containing Cremophor EL (polyoxyethylated castor oil).
23. Pre-existing Grade 2 or greater motor or sensory neuropathy.
Additional exclusion criteria for the following patients can be found in the protocol:
- Patients with Primary Brain Tumors that Harbor EGFR Mutations (closed to enrollment in Amendment 4)
- Patients with Colorectal Cancer (closed to enrollment in Amendment 4)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study for all cohorts is objective response rate following 2 cycles of treatment (8 weeks) (ORR8), who have solid tumors that have human somatic mutations in the ERBB gene family (EGFR, ERBB2, and/or ERBB3) or EGFR gene amplification per RECIST version 1.1 or other defined response criteria. The efficacy response is assumed binary, ie, a patient is a responder (achieving CR or PR) versus non-responder based upon criteria outlined in the protocol.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 8 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
• The confirmed ORR will be estimated and its associated 2-sided 80% and 95% Clopper-Pearson confidence intervals will be determined..
• The clinical benefit rate (CBR) is defined as CR+PR +SD ≥16 weeks (≥24 weeks for the breast cancer patients). The CBR will be estimated, and its associated 2-sided 80% and 95% Clopper-Pearson confidence intervals will be determined.
• The PFS is defined as the interval from C1D1 until the first date on which recurrence, progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy. Median PFS will be estimated via Kaplan-Meier with its associated 2-sided 80% and 95% confidence intervals.
• The DOR is defined as the time response criteria were met until progression or death. Median DOR will be estimated via Kaplan-Meier with its associated 2-sided 80% and 95% confidence intervals.
• OS for each cohort will be estimated using Kaplan-Meier method..
• The role of dual modality PET/CT scans will be evaluated in measuring response to neratinib monotherapy and combination therapy.
• The safety profile and tolerability of neratinib monotherapy and combination therapy will be assessed in patients treated in this study.
• Patient reported outcomes will be evaluated using the EuroQol EQ-5D-5L questionnaire. The assessments will be summarized and plotted over time. Changes from baseline will be provided with both point estimates and confidence intervals.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease evaluation will be performed every 2 cycles by CT (or MRI) and PET/CT. PET/CT is mandatory for all breast cancer patients and optional for RECIST-evaluable patients with other cancers. Radiological response by RECIST v1.1 and metabolic response by PET Response Criteria will be reported and analyzed separately.
For patients who switch from monotherapy to combination therapy, the disease assessment performed immediately prior to the addition of the combination therapy will constitute the new baseline of measurable disease for the combination. This should be used as the comparator for future response assessments performed at 2-cycle intervals.
Radiographic tumor assessments use CT (or MRI) and PET/CT and will be performed in accordance with the Schedule of Procedures per protocol. |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Belgium |
| Finland |
| France |
| Israel |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 |
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