| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally-advanced or metastatic HER2+ breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic breast cancer |
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| 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 | 10072740 |
| E.1.2 | Term | Locally advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 | 100000004864 |
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| 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 PFS by investigator assessment per RECIST v1.1 between treatment arms
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| E.2.2 | Secondary objectives of the trial |
- Compare OS between treatment arms
- Compare the ORR by investigator assessment per RECIST v1.1 between treatment arms
- Evaluate PFS by BICR per RECIST v1.1 between treatment arms
- Evaluate PFS by investigator assessment per RECIST v1.1 in subjects with brain metastases at baseline between treatment arms
- Evaluate PFS by BICR per RECIST v1.1 in subjects with brain metastases at baseline between treatment arms
- Evaluate the ORR by BICR per RECIST v1.1 between treatment arms
- Evaluate the DOR by investigator assessment per RECIST v1.1 between treatment arms
- Evaluate the DOR by BICR per RECIST v1.1 between treatment arms
- Evaluate the CBR (SD or non-CR or non-progressive disease[PD] for ≥6 months or best response of CR or PR) by investigator assessment per RECIST v1.1 between treatment arms
- Evaluate the CBR by BICR per RECIST v1.1 between treatment arms
- Evaluate the safety of tucatinib in combination with T-DM1
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A pharmacokinetics (PK) sub-study will assess the effects of tucatinib on the PK of DM1. With additional consent, approximately 50 subjects (enrollment will continue until at least 25 subjects from each treatment arm have completed the sub-study) will participate in a PK sub-study in which additional PK assessments on Days 1, 2, 3, and 5 in Cycle 2 are performed
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| E.3 | Principal inclusion criteria |
1. Histologically confirmed HER2+ metastatic breast carcinoma, as determined by sponsor-designated central laboratory testing on tumor tissue submitted prior to randomization, from archival tissue or a newly-obtained baseline biopsy of an accessible tumor lesion that has not been previously irradiated is required
2. History of prior treatment with a taxane and trastuzumab in any setting, separately or in combination. Prior pertuzumab therapy is allowed, but not required.
3. Have progression of unresectable LA/M breast cancer after last systemic therapy, or be intolerant of last systemic therapy
4. Measureable or non-measurable disease assessable by RECIST v1.1
5. HR (estrogen receptor [ER]/ progesterone receptor [PR]) status must be known prior to randomization
6. Age ≥18 years at time of consent
7. ECOG performance status score of 0 or 1
8. Life expectancy ≥6 months, in the opinion of the investigator
9. Adequate hepatic function (refer to protocol)
10. Adequate baseline hematologic parameters (refer to protocol)
11. Estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable
12. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN, unless on medication known to alter INR and PTT/aPTT.
13. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment
14. For subjects of childbearing potential the following stipulations apply:
a. Must have a negative serum or urine pregnancy test result within 7 days prior to the first dose of study treatment. A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation.
b. Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study drug administration
c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of study drug administration
d. If sexually active in a way that could lead to pregnancy, must consistently use highly effective methods of birth control starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study drug administration.
Please refer to protocol for a list of highly effective methods of birth control.
15. For subjects who can father children, the following stipulations apply:
a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 7 months after the final study drug administration
b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use a barrier method of birth control starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study drug administration
c. If sexually active with a person who is pregnant or breastfeeding, must consistently use a barrier method of birth control starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study drug administration
16. The subject or the subject’s legally acceptable representative must provide written informed consent
17. Subject must be willing and able to comply with study procedures
18. CNS Inclusion – Based on screening contrast brain magnetic resonance imaging (MRI), subjects must have at least one of the following:
a. No evidence of brain metastases
b. Untreated brain metastases not needing immediate local therapy. For subjects with untreated CNS lesions >2.0 cm in diameter on screening contrast brain MRI, approval from the medical monitor is required prior to enrollment.
c. Previously treated brain metastases
i. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator
ii. Subjects treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met:
· Time since SRS is ≥7 days prior to first dose of study treatment, time since whole-brain radiation therapy (WBRT) is ≥14 days prior to first dose of study treatment, or time since surgical resection is ≥28 days
· Other sites of evaluable disease are present
iii. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
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| E.4 | Principal exclusion criteria |
1. Prior treatment with tucatinib, neratinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤21 days and was discontinued for reasons other than disease progression or severe toxicity)
2. Prior treatment with T-DM1
3. History of allergic reactions to trastuzumab or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed, or known allergy to any of the excipients in the study drugs
4. Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation, experimental agent or participation in another interventional clinical trial ≤3 weeks prior to first dose of study treatment. An exception for the washout of hormonal therapies is gonadotropin releasing hormone agonists used for ovarian suppression in premenopausal women, which are permitted concomitant medications.
5. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
- Alopecia;
- Neuropathy, which must have resolved to ≤ Grade 2;
- Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely
6. Clinically significant cardiopulmonary disease such as:
- Ventricular arrhythmia requiring therapy
- Symptomatic hypertension or uncontrolled asymptomatic hypertension as determined by the investigator
- Any history of symptomatic CHF, left ventricular systolic dysfunction or decrease in ejection fraction
- Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or above) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen therapy
- ≥ Grade 2 QTc prolongation on screening electrocardiogram (ECG)
7. Known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
8. Known carrier of Hepatitis B or Hepatitis C or has other known chronic liver disease
9. Known to be positive for human immunodeficiency virus.
10. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of informed consent until 7 months following the last dose of study drug
11. Unable to swallow pills or has significant gastrointestinal disease which would preclude the adequate oral absorption of medications
12. Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study treatment. CYP3A4 or CYP2C8 inducers and inhibitors are also prohibited as concomitant medications within two weeks of discontinuation of tucatinib treatment. Use of sensitive CYP3A substrates should be avoided two weeks before enrollment and during study treatment.
13. Unable to undergo contrast MRI of the brain
14. Other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
15. Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment
16. CNS Exclusion – Based on screening brain MRI, subjects must not have any of the following:
a. Any untreated brain lesions >2.0 cm in size, unless approved by the medical monitor
b. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent). However, subjects on a chronic stable dose of ≤2 mg total daily of dexamethasone (or equivalent) may be eligible with approval of the medical monitor.
c. Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to the subject (e.g., brain stem lesions). Subjects who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS Inclusion 17c (ii).
d. Known or concurrent leptomeningeal disease as documented by the investigator
e. Poorly controlled (>1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- PFS per RECIST v1.1, as determined by investigator assessment
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 5 years |
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| E.5.2 | Secondary end point(s) |
- OS
- ORR per RECIST v1.1, by investigator assessment
- PFS per RECIST v1.1, as determined by BICR
- PFS per RECIST v1.1, by investigator assessment in subjects with brain metastases at baseline
- PFS per RECIST v1.1, by BICR in subjects with brain metastases at baseline
- ORR per RECIST v1.1, by BICR
- DOR per RECIST v1.1, by investigator assessment
- DOR per RECIST v1.1, by BICR
- CBR per RECIST v1.1, by investigator assessment
- CBR per RECIST v1.1, by BICR
- Incidence of AEs
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Up to approximately 5 years
- Up to approximately 3 years
- Up to approximately 5 years
- Up to approximately 5 years
- Up to approximately 5 years
- Up to approximately 3 years
- Up to approximately 5 years
- Up to approximately 5 years
- Up to approximately 3 years
- Up to approximately 3 years
- Through 1 month following last dose; up to approximately 9 months overall per subject |
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| 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 | Yes |
| 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 | 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) | 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 | Yes |
| 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 105 |
| 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 |
| Japan |
| Korea, Republic of |
| Singapore |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
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| 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
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The study ends once the number of events required for analysis of endpoints has been reached (estimated 5 years after first subject enrolled) or when the last subject completes the last visit, or last contact, discontinues from the study, or is lost to follow-up, whichever occurs first.
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| 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 | 15 |
| 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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