T-DM1 and Tucatinib Compared with T-DM1 Alone in Preventing Relapses in People with High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial

Summary

Objectives

PRIMARY OBJECTIVE:
I. To determine if the invasive disease-free survival (iDFS) with T-DM1 and tucatinib is superior to the iDFS in the control arm (T-DM1 + placebo) when administered to high risk patients with HER2-positive breast cancer and residual disease after neoadjuvant HER2-directed therapy.

SECONDARY OBJECTIVES:
I. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus placebo) improves the following:
Ia. Overall survival (OS).
Ib. Breast cancer free survival (BCFS).
Ic. Distant recurrence-free survival (DRFS).
Id. Disease-free survival (DFS).
Ie. Brain metastases-free survival (BMFS).
II. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus placebo) reduces the incidence of brain metastases.

SECONDARY CORRELATIVE OBJECTIVES:
I. To evaluate the association of tumor infiltrating lymphocyte (TIL) levels in both the primary tumor and the residual disease specimen with iDFS.
II. To determine whether there is evidence of differential treatment benefit of T-DM1 and tucatinib compared to T-DM1 and placebo in high TIL cancers compared to low TIL cancers (assessed in both the pre-neoadjuvant tumor tissue and the residual cancer tissue).
III. To evaluate the association between iDFS and the presence of detectable circulating tumor cells (CTC) at baseline, at completion of study therapy and/or 1 year after completion of study therapy.
IV. To determine the difference in absolute magnitude of benefit of tucatinib (in terms of iDFS) in the subgroup of patients with detectable CTC at baseline and the subgroup of patients without detectable CTC at baseline.

LOCAL REGIONAL EXPLORATORY OBJECTIVES:
I. To determine local regional recurrence following breast conservation based on margin width (no ink on tumor, close, > 2 mm).
II. To determine local regional recurrence following breast conservation with or without boost.
III. To compare regional recurrence based on axillary surgery –sentinel lymph node biopsy (SLNB) vs. axillary lymph node dissection (ALND) – among patients with residual nodal disease.

PATIENT-REPORTED OUTCOMES:
I. To compare quality of life (QOL) after approximately 8 cycles of the study as assessed by the Functional Assessment of Cancer Therapy (FACT)-Breast Cancer (B) Trial Outcome Index between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Primary Objective)
II. To compare QOL after approximately 13 cycles of the study as assessed by the FACT-B Trial Outcome Index between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Secondary Objective)
III. To compare various QOL domains after approximately 8 and 13 cycles of the study as assessed by the 5 subscales of the FACT-B questionnaire between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Exploratory Objective)
IV. To compare self-reported patient adherence and reasons for non-adherence after 1, 4, 8, and 13 cycles of the study as assessed by the Voils instrument (Domains of Subjective Extent of Nonadherence [DOSE-Nonadherence]) between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Exploratory Objective)
V. To compare self-reported symptomatic adverse events after 1, 4, 8, and 13 cycles of the study assessed by the Patient-Reported Outcomes (PRO) - Common Terminology Criteria for Adverse Events (CTCAE) between patients randomized to T-DM1 + tucatinib or T-DM1 + placebo. (Exploratory Objective)

TO-BE-DETERMINED CORRELATIVE OBJECTIVES:
I. To evaluate the association of circulating tumor deoxyribonucleic acid (ctDNA) tumor-specific mutations (at baseline and after completion of adjuvant HER2-directed therapy) with iDFS.
II. To evaluate the association of breast cancer intrinsic subtype and other transcriptional signatures in both the primary tumor and the residual disease specimen with iDFS.

PHARMACOKINETIC OBJECTIVES:
I. To characterize the pharmacokinetic (PK) of T-DM1 in all patients.
II. To characterize the PK of tucatinib in tucatinib-treated patients.
III. To investigate exposure–effect (efficacy and safety) relationships in tucatinib-treated patients.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive T-DM1 intravenously (IV) over 30-90 minutes on day 1 and placebo orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study.

ARM II: Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, then every 6 months for 10 years.