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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Salivary Gland Carcinoma, Recurrent Salivary Gland Carcinoma, Stage III Major Salivary Gland Cancer AJCC v8, Stage IV Major Salivary Gland Cancer AJCC v8, Unresectable Salivary Gland Carcinoma

Intervention / Treatment
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* Drug: Docetaxel
* Other: Questionnaire Administration
* Biological: Trastuzumab
* Biological: Trastuzumab Emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven diagnosis of HER2-positive salivary gland cancer (SGC) Note: The majority of HER2-positive SGCs are salivary duct carcinoma (SDCs), but to a lesser extent, other SGC subtypes can be HER2-positive (e.g., adenocarcinomas, mucoepidermoid carcinomas, etc.) and are eligible to be included on the study. Additionally, pathologists may sign out SDCs under other descriptors (e.g., ex-pleomorphic adenoma, adenocarcinoma), and these would be eligible if they are HER2-positive. Note: HER2 evaluation based on local site immunohistochemistry (IHC), fluorescent in-situ hybridization (FISH), or local/commercial next-generation sequencing (NGS) is required. Any one of the following criteria observed in a primary tumor or metastasis would meet the study definition for HER2-positive: Immunohistochemistry (IHC) (3+) per the College of American Pathologists (CAP) breast cancer guidelines Gene amplification by FISH (HER2/CEP17 ratio >= 2.0) Gene amplification by NGS (fold change > 2) Patients with unresectable disease who are not candidates for curative surgery or radiation OR recurrent OR metastatic disease that is evident on radiologic imaging Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy Measurable or non-measurable disease by the RECIST v1.1 criteria History/physical examination within 30 days prior to registration The following imaging within 60 days prior to registration: Computed tomography (CT) or magnetic resonance imaging (MRI) of the neck (diagnostic quality with contrast, unless contraindicated) AND CT scan of the chest (diagnostic quality with contrast, unless contraindicated) AND CT or MRI of the abdomen and pelvis, if clinically indicated (diagnostic quality with contrast, unless contraindicated) Age >= 18 Left ventricular ejection fraction (LVEF) >= 50% assessed by echocardiogram or multigated acquisition (MUGA) scan within 30 days prior to registration Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 14 days prior to registration) Platelets >= 100,000 cells/mm^3 (within 14 days prior to registration) Hemoglobin >= 9.0 g/dL (within 14 days prior to registration) (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dL is acceptable.) Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance (CrCl) >= 30 mL/min by the Cockcroft-Gault formula (within 14 days prior to registration) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x institutional ULN (within 14 days prior to registration) Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial. Testing is not required for entry into protocol For patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g., patients immunized against hepatitis B) For patients with a known history of hepatitis C virus (HCV) infection, they must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal Willing to use highly effective contraceptives for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 7 months following last dose of study drug; this inclusion is necessary because the treatment in this study may be significantly teratogenic (See Section 9 for definition of highly effective contraception). Women must refrain from donating eggs during this same period Men with partners of childbearing potential must be willing to use a highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner, and to continue the use of contraception for the duration of study treatment and for at least 7 months after the last dose of study treatment. Male patients whose partners are pregnant should use condoms for the duration of the pregnancy. Men must refrain from donating sperm during this same period Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information Exclusion Criteria: Prior systemic therapy for the study cancer in the unresectable or recurrent and/or metastatic disease setting Note: Prior chemotherapy for a different cancer is allowed; prior androgen receptor targeted therapy in any setting is allowed; prior systemic therapy, including HER2-directed therapies given as neoadjuvant therapy, adjuvant therapy, and/or concurrently with radiation is allowed Patients who have had chemotherapy or palliative-intent radiotherapy must have all toxicities related to prior treatment recovered to =< grade 1 prior to registration Severe, active co-morbidity defined as follows: Unstable angina requiring hospitalization in the last 6 months Myocardial infarction within the last 6 months New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.) Persistent grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing Patient must not have an active infection requiring IV antibiotics >= grade 3 peripheral neuropathy Interstitial lung disease or pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on chest CT scan Any hemorrhage or bleeding event grade >= 3 within 28 days prior to registration History of allergic reactions to compounds of similar chemical or biologic composition to ado-trastuzumab emtansine, trastuzumab, and/or docetaxel (or any of their excipients) History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 500 mg/m^2 Epirubicin > 900 mg/m^2 Mitoxantrone > 120 mg/m^2 Note: If another anthracycline, or more than one anthracycline has been used, the cumulative dose must not exceed the equivalent of doxorubicin 500 mg/m^2 Pregnancy and individuals unwilling to discontinue nursing

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (docetaxel, trastuzumab)<br>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. | Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Trastuzumab<br>* Given IV<br>* Other names: Trazimera;|
| Experimental: Arm II (trastuzumab emtansine)<br>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. | Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Trastuzumab Emtansine<br>* Given IV<br>* Other names: Trastuzumab-MCC-DM1 Immunoconjugate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | 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. | From randomization to disease progression or death due to any cause, whichever occurs first. Analysis occurs after 98 PFS events have been reported, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | From randomization to disease progression or last follow-up, assessed up to 5 years | 
| Duration Of Response (DOR) | 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. | From randomization to disease progression or last follow-up, assessed up to 5 years | 
| Overall Survival (OS) | 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. | From randomization until death due to any cause or last follow-up, assessed up to 5 years | 
| Incidence of Adverse Events | 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. | From start of treatment to last follow-up, assessed up to 5 years | 
| Treatment Discontinuations Due to AEs | 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). | From start of treatment to end of treatment | 
| Patient-Reported Toxicity | Patient-reported adverse events will be assessed using selected PRO-CTCAE. | From randomization to 12 months |