| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally-advanced or metastatic HER2+ breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic breast cancer |
|
| 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 | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10072740 |
| E.1.2 | Term | Locally advanced breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Compare progression-free survival (PFS) by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 between treatment arms |
|
| E.2.2 | Secondary objectives of the trial |
- Compare overall survival (OS) between treatment arms
- Evaluate PFS by blinded independent central review (BICR) per RECIST v1.1
- Assess the change in health-related quality of life (HRQoL)
- Evaluate PFS in the brain
- Evaluate the safety and tolerability of tucatinib in combination with trastuzumab and pertuzumab
- Evaluate the pharmacokinetics (PK) of tucatinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have centrally confirmed HER2+ breast carcinoma according to 2018 American Society of Clinical Oncologists (ASCO)-College of American Pathologists (CAP) guidelines prior to randomization (defined as a 3+ score on immunohistochemistry (IHC) and/or 2+ IHC and concurrent positive by ISH).
2. Have unresectable locally advanced or metastatic (hereafter referred to as “advanced”) disease; if recurrent (after [neo]adjuvant therapy), there must be a minimum 6-month treatment-free interval from any trastuzumab and pertuzumab received in the early breast cancer setting to the diagnosis of advanced HER2+ disease. Prior standard of care therapy for early breast cancer is permitted (eg, prior T-DM1); however, Exclusion Criterion 1 should be noted.
3. Have received 4-8 cycles of pre-study induction therapy including only with trastuzumab, pertuzumab, and taxane as first-line therapy for the treatment of advanced breast cancer prior to study enrollment. Subjects are eligible provided they are without evidence of disease progression (per investigator judgement) ie, CR, PR, or SD) following completion of induction therapy.
a. Subjects receiving <6 cycles (ie, 4-5 cycles) of taxane are only eligible if the taxane was stopped early due to intolerable toxicity (eg, documented neuropathy impacting function).
b. Subjects are permitted to receive trastuzumab and pertuzumab for 2 additional cycles (after completion of chemotherapy) to allow completion of screening procedures. Study treatment should begin within 6 weeks (± 3 days) from the start of the last cycle of trastuzumab and pertuzumab.
c. Subjects are permitted to receive up to 2 cycles of carboplatin during the start of induction therapy in combination with trastuzumab, pertuzumab , and taxane (eg, to obtain confirmation of metastatic breast cancer diagnosis)
d. Subjects who received traditional medications (eg, traditional Chinese medication) and/or supplements with potential anti-cancer effects during induction therapy will remain eligible if they discontinue these treatments at least 4 weeks prior to the start of study treatment
4. Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-])
5. Be at least 18 years of age, and legally an adult at time of consent and ≥ the age of majority per regional requirements
6. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
7. Have adequate hepatic function as defined in the protocol
8. Have adequate baseline hematologic parameters as defined in the protocol
9. Have a serum or plasma creatinine ≤1.5 X institutional ULN.
10. Have left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment.
11. Subjects of childbearing potential must meet the conditions as per protocol
12. Male subjects must meet the conditions as per protocol
13. Provide signed informed consent per a consent document that has been approved by an institutional review board or independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the subject’s disease
14. Be willing and able to comply with study procedures
15. CNS Inclusion – Based on screening contrast -enhanced brain magnetic resonance imaging (MRI), subjects may have any of the following:
a. No evidence of brain metastases
b. Untreated brain metastases which are asymptomatic , not needing immediate local treatment and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane
c. Previously treated brain metastases which are asymptomatic
i. Brain metastases previously treated with local therapy must not have progressed since treatment
a. Time since whole brain radiation therapy (WBRT) is ≥ 14 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥7 days prior to first dose of study treatment, or time since surgical resection is ≥28 days prior to first dose of study treatment
ii. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
|
|
| E.4 | Principal exclusion criteria |
1. Have previously been treated with any tyrosine kinase inhibitor targeting anti-HER2 and/or epidermal growth factor receptor (EGFR) including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and at least 12 months have elapsed from the last neratinib dose to the start of study drug) or are currently participating in another interventional clinical trial
2. Unable for any reason to undergo contrast -enhanced MRI of the brain
3. History of allergic reactions to trastuzumab, pertuzumab, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion-related reactions (IRRs) to trastuzumab that were successfully managed, known allergy to one of the excipients in the study drugs, or hypersensitivity to murine proteins
4. Are positive for active Hepatitis B by surface antigen expression, positive for Hepatitis C infection, or the presence of known chronic liver disease. Subjects who have been treated for Hepatitis C infection are permitted if they have documented sustained virologic response of at least 12 weeks, as documented per local guidelines. The latest local guidelines should be followed regarding the testing of Hepatitis B DNA levels by polymerase chain reaction (PCR). Subjects with Hepatitis B DNA levels by PCR that require nucleoside analogue or other therapies are not eligible for the trial.
5. Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if they meet any of the following criteria:
a. CD4+ T-cell count of <350 cells/μL
b. Detectable HIV viral load
c. History of an opportunistic infection within the past 12 months
d. On stable antiretroviral therapy for <4 weeks
6. Are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug
7. Have inability to swallow pills or have significant GI disease or surgery which would preclude the adequate oral absorption of medications
8. Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
9. Have current conditions of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled hypertension, or cardiac arrhythmia or history of myocardial infarction within 6 months prior to randomization
10. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
11. Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
12. Have ongoing ≥ Grade 2 toxicity from first-line induction therapy (ie, trastuzumab, pertuzumab, and taxane) with the exceptions of alopecia, neuropathy, and nail toxicity
13. Have ongoing ≥ Grade 2 diarrhea
14. CNS Exclusion – Based on screening brain MRI and clinical assessment, subjects must not have any of the following:
a. Symptomatic brain metastasis after CNS-directed local therapy
b. Progression of brain metastases since starting first-line trastuzumab, pertuzumab, and taxane
c. Ongoing use of systemic corticosteroids at a total daily dose of >2 mg of dexamethasone (or equivalent). For subjects requiring systemic steroids for control of comorbidities (eg, asthma or autoimmune diseases), daily dose must not exceed 2 mg dexamethasone (or equivalent).
d. Any untreated brain lesion in an anatomic site which may pose risk to subject (eg, brain stem lesions). Subjects who successfully undergo local treatment for such lesions may be permitted to rescreen, if otherwise eligible, after discussion with, and approval by, the medical monitor.
e. Known or suspected leptomeningeal disease (LMD) as documented by the investigator
f. Poorly controlled (>1/week) seizures, or other persistent neurologic symptoms despite CNS-directed therapy for brain metastasis |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS per RECIST v1.1 according to investigator assessment, or death from any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Once approximately 331 PFS events per investigator assessment have been observed |
|
| E.5.2 | Secondary end point(s) |
- OS
- PFS per RECIST v1.1, as determined by BICR, or death from any cause, whichever occurs first
- Time to deterioration of HRQoL
- CNS-PFS per RECIST v1.1 according to investigator assessment, or death from any cause, whichever occurs first
- AEs, clinical laboratory assessments, incidence of dose holding and discontinuation of study treatment, incidence of dose reductions of tucatinib
- Plasma concentrations of tucatinib
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS: final analysis will occur when approximately 252 OS events are observed
- PFS by BICR: once approx. 331 PFS events have occurred
- HRQoL: to be assessed on Day 1 of each 21-day cycle, at the end of treatment visit, and first follow-up visit
- CNS-PFS: once approx. 331 PFS events have occurred
- Safety assessments will be collected throughout the study. The safety reporting period for all AEs and SAEs is from study Cycle 1 Day 1 (predose) through 30 days after the last study treatment.
- samples for PK assessment of tucatinib drug levels will be collected on Day 1 of Cycles 2 to 6 (prior to administration of tucatinib), at EOT and on Day 1 of Cycle 3 (after administration of tucatinib)
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient Reported Outcomes, biomarkers. |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 124 |
| 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 |
| Chile |
| Switzerland |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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