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Docetaxel

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Trastuzumab

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Trastuzumab biosimilar HLX02

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Patients receive docetaxel IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive trastuzumab IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients receive trastuzumab emtansine IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Questionnaire Administration

Trastuzumab Emtansine

Site Public Contact

Andrew Fuson

Victoria M. Villaflor

Jennifer M. Suga

Alexander D. Colevas

Daniel W. Bowles

Nitya Alluri

Prem Sobti

Joseph J. Merchant

Richard L. Deming

Dan P. Zandberg

Paul L. Swiecicki

Ammar Sukari

Daniel Almquist

Yan Ji

Katharine A. Price

Douglas R. Adkins

Garrett T. Wasp

Alan L. Ho

Marshall R. Posner

Christopher Lemmon

Marcelo R. Bonomi

Minh Phan

Alan L Ho

This phase II trial tests whether ado-trastuzumab emtansine works to shrink tumors in patients with HER2-positive salivary gland cancer that has come back (recurrent), spread to other places in the body (metastatic), or cannot be removed by surgery (unresectable). Trastuzumab emtansine is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug called emtansine. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers emtansine to kill them. Trastuzumab emtansine may work better compared to usual treatment of chemotherapy with docetaxel and trastuzumab in treating patients with salivary gland cancer.

PRIMARY OBJECTIVE:

I. To determine if trastuzumab emtansine (ado-trastuzumab emtansine \[T-DM1\]) shows better progression-free survival (PFS) when compared to docetaxel plus trastuzumab (TH) in recurrent and/or metastatic (R/M) HER2-positive salivary gland cancer (SGC) patients who have not previously received HER2 therapy for unresectable or recurrent and/or metastatic disease, as determined by local assessment.

SECONDARY OBJECTIVES:

I. To compare the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria between arms.

II. To compare overall survival (OS) between arms. III. To compare toxicity using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria between arms.

IV. To assess patient-reported toxicity, as measured by the patient reported outcome (PRO)-CTCAE, between arms, and explore patient-reported symptomatic adverse events (AEs) for tolerability of each treatment arm as measured by the PRO-CTCAE.

EXPLORATORY OBJECTIVES:

I. To assess the ORR in patients who receive crossover treatment to T-DM1/TH following disease progression on the TH arm/T-DM1 arm.

II. To collect blood and tissue specimens for future translational science studies to examine how tumor genetics, HER2 signaling output/expression, and HER2 tumoral heterogeneity impact TH and T-DM1 efficacy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive docetaxel intravenously (IV) over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive trastuzumab IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive trastuzumab emtansine IV over 90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Testing the Use of Ado-Trastuzumab Emtansine Compared to the Usual Treatment (Chemotherapy With Docetaxel Plus Trastuzumab) for Recurrent, Metastatic, or Unresectable HER2-Positive Salivary Gland Cancer

A Controlled, Randomized Phase II Trial of Docetaxel Plus Trastuzumab Versus Ado-Trastuzumab Emtansine for Recurrent, Metastatic, or Treatment-Naive, Unresectable HER2-Positive Salivary Gland Cancer

Overall tumor response will be assessed by RECIST v1.1 (see Section 13). The ORR, defined as the proportion of complete and partial responses (CR+PR) for patients who crossover after disease progression from T-DM1 (TH) to TH (T-DM1) will be calculated with their respective 80% and 95% CIs.

Kaplan-Meier method will be used to estimate PFS rates. A log-rank test will be used to assess whether T-DM1 shows a signal of better PFS than the control arm. Cox proportional hazards models, including the stratification factors and with/out other key covariates (e.g., Zubrod performance status), will be used to estimate the treatment effect hazard ratio along with 80% and 95% confidence intervals.

Overall tumor response in patients will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Only randomized patients who have measurable disease present at baseline will be considered evaluable for response. The ORR, defined as the proportion of complete and partial best overall responses (complete response \[CR\]+partial response \[PR\]) will be calculated with their respective 80% and 95% confidence intervals (CI) based normal approximations.

The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). If the number of responders is sufficient, the Kaplan-Meier method will be used to estimate the DOR rates along with median of DOR and 95% CIs.

OS rates will be estimated using the Kaplan-Meier method, and between-arms comparison will be performed using a logrank test (0.10 one-sided significance level). Cox proportional hazards models with the stratification factors and with/out other key covariates (e.g., Zubrod performance status) will be used to estimate the treatment effect hazard ratio along with 80% and 95% confidence intervals.

Adverse events (AEs) will be graded using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Counts of all adverse events (AEs) by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. The proportion of patients with at least one grade 3 or higher AE will be compared between the treatment arms. All comparisons will be tested using a chi-Square test, or Fisher's exact test if cell frequencies are \< 5, with a significance level of 0.10. In addition, 80% and 95% confidence intervals will be provided for these proportions.

The proportion of treatment discontinuations due to adverse events between arms will be compared using a chi-Square test (two-sided alpha of 0.10). In addition, 80% and 95% confidence intervals will be provided for these proportions. A two-group chi-square test with a 10% two-sided significance level will have 90% power to detect the difference between Arm 2 proportion of 0.15 and Arm 1 proportion of 0.40 (odds ratio of 3.8) when the number of randomized patients in each group is 58. These figures are reasonable based on data from breast cancer trials (40.9% versus \[vs.\] 7.2% for docetaxel plus trastuzumab \[TH\] and ado-trastuzumab emtansine \[T-DM1\] alone).

Patient-reported adverse events will be assessed using selected PRO-CTCAE.

National Cancer Institute (NCI)

NRG Oncology

Spots Global Cancer Trial Database for unresectable salivary gland carcinoma