| 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 | 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 | 27.0 |
| 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 PFS by investigator assessment per RECIST v1.1 between treatment arms
|
|
| E.2.2 | Secondary objectives of the trial |
- Compare OS between treatment arms
- Compare PFS by investigator assessment per RECIST v1.1 in subjects
with brain metastases at baseline (PFS.BM per investigator) between treatment arms
- Compare the ORR by investigator assessment per RECIST v1.1 between
treatment arms
- Compare overall survival in subjects with brain metastases at baseline
(OS.BM) between treatment arms.
- Evaluate PFS by BICR per RECIST v1.1 between treatment arms
- Evaluate PFS by BICR per RECIST v1.1 in subjects with brain
metastases at baseline (PFS.BM by BICR) 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
Please see protocol for additional objectives. |
|
| 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
|
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed HER2+ 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. Measurable 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 or ≥ the age of majority in the
geographic location
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
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 2 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.
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 2 highly effective
methods 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 1 of 2 highly effective methods 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 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 retreatment
with local therapy in the opinion of the investigator
ii. Subjects treated with CNS local therapy for newly identified lesions or
previously treated and progressing 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 |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-
8201a), or any other investigational anti-HER2, anti-EGFR, or HER2 TKI
agent. Prior treatment with lapatinib or neratinib within 12 months of
starting study treatment (except in cases where they were given for ≤21
days and discontinued for reasons other than disease progression or
severe toxicity). Prior treatment with pyrotinib for recurrent or mBC
(except in cases where pyrotinib was given for ≤21 days and
discontinued for reasons other than disease progression or severe
toxicity)
2. Prior treatment with T-DM1 in any treatment setting
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 (palliative or therapeutic), 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, symptomatic left ventricular systolic
dysfunction or symptomatic decrease in ejection fraction
- For France and Italy only: Any history of interstitial lung disease or
pneumonitis
- 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
- For Italy: positive for 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 12
weeks. 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 therapy are not eligible for the trial.
9. Subjects Known to be positive for human immunodeficiency virus
(HIV) if they meet any of the following criteria:
● CD4+ T-cell count of <350 cells/μL
● Detectable HIV viral load
● History of an opportunistic infection within the past 12 months
● On stable antiretroviral therapy for <4 weeks
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 cytochrome P450 (CYP) 3A4 or CYP2C8 inhibitor within 1 week, 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 1 week of discontinuation
of tucatinib treatment. Use of sensitive CYP3A substrates should be
avoided 1 week 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. Systemic therapy for another malignancy within 2 years of the start
of study treatment
16. CNS Exclusion – Based on screening brain MRI
Please refer to protocol for the full criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- PFS per RECIST v1.1, as determined by investigator assessment
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 5 years |
|
| E.5.2 | Secondary end point(s) |
- OS
- PFS.BM per RECIST v1.1, as determined by investigator assessment
- ORR per RECIST v1.1, by investigator assessment
- OS.BM
- PFS per RECIST v1.1, as determined by BICR
- PFS.BM per RECIST v1.1, by BICR
- 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 |
|
| 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 |
|
| 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 | 3 |
| 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 |
| Singapore |
| Switzerland |
| Taiwan |
| Australia |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
|
| 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
|
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.
|
|
| 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 | 17 |
| 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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