Post-op T-DM1 in HER-2+ Salivary Gland Carcinomas

Study Overview
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Brief Summary
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This research is being done to see how safe and effective the use of the study drug Ado-trastuzumab (T) emtansine (DM1), T-DM1, and standard of care chemoradiation are when used together in treating HER2-positive salivary gland cancer. It will also examine the effectiveness of study drug Ado-trastuzumab (T) emtansine (DM1) on cancer recurrence.

Detailed Description
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This is a phase II, open-label, non-randomized, multi-institutional study investigating postoperative or adjuvant human epidermal growth factor receptor (HER2)-directed therapy with adjuvant ado-trastuzumab emtansine (T-DM1) in HER2-positive salivary gland carcinomas (SGC). This research study is: Studying the use of T-DM1 in combination with radiation and chemotherapy; and the use of maintenance T-DM1 alone for up to a year after surgery Evaluating the effectiveness, safety, and toxicity of T-DM1 T-DM1 is a specialized antibody targeting HER-2 (a protein that is expressed in some breast and salivary gland cancers). The drug is a HER-2 antibody that is bound to a chemotherapy agent (DM1) and delivered intravenously. T-DM1 then binds cancer cells that express HER-2 and is taken up into the cell to allow DM1 to kill cancer cells in a more targeted way. This allows the use of a targeted treatment along with chemoradiation to treat HER-2 expressing salivary cancers. The U.S. Food and Drug Administration (FDA) has not approved T-DM1 for HER2-positive salivary gland cancer but it has been approved for other uses (for breast cancers that express HER2 protein). The research study procedures include: screening for eligibility and study treatment including evaluations and follow up visits. This research study involves radiation, chemotherapy, and targeted therapy given after surgery for up to 1-year, and participants will be followed for 3 years. It is expected that about 55 people will take part in this research study. Genentech is supporting this research study by providing the research study drug, T-DM1.

Official Title
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A Phase II Study of Adjuvant Ado-trastuzumab Emtansine (T-DM1) in HER2-positive Salivary Gland Carcinomas

Conditions
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Salivary Gland Cancer, HER2 Gene Mutation

Intervention / Treatment
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* Drug: Ado-trastuzumab (T) emtansine (T-DM1)
* Radiation: Standard of Care Radiotherapy
* Drug: Standard of Care Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have histologically or cytologically confirmed, resectable stage II (with positive margins), III, IVA, or IVB locoregionally advanced salivary gland carcinoma (including any histologic subtype), as defined by 2017 American Joint Committee on Cancer (AJCC), 8th edition. Willing to provide tissue from a diagnostic biopsy or at the time of cancer resection, and blood samples before, during, and after treatment. HER2 positive disease as defined by any of the following: Tumor HER2 expression staining intensity of 2 or 3+ by IHC (from either a preoperative biopsy or resection specimen at the time of oncologic surgery) HER2 amplification as determined by FISH (HER2/CEP 17 ratio greater than or equal to 2.0 or HER2 mean copy number greater than or equal to 4.0) HER2 or ERBB2 mutated on tumor genomic sequencing assay (see Section 9.1 for permitted HER2 mutations) Age 18 years or older ECOG performance status ≤ 1 (Karnofsky ≥ 60%, see Appendix A) Participant must have normal organ and marrow function as defined below within 14 days prior to study registration: leukocytes ≥ 3,000/mcL absolute neutrophil count ≥ 1,000/mcL hemoglobin ≥ 9.0 g/dL platelets ≥ 100,000/mcL total bilirubin ≤ 2.0 g/dL AST(SGOT)/ALT(SGPT) ≤ 2.5× institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥50 mL/min/1.73 m2 for participants with creatinine levels above institutional normal Serum calcium (corrected for albumin value), magnesium, and potassium levels within normal limits per institutional standards. Assessment of cardiac function either by an echocardiogram or a multi-gated acquisition (MUGA) scan prior to the therapy initiation, with a baseline left systolic ventricular ejection fraction (LVEF) ≥ 50% within 1 month prior to study registration. Ability to understand and the willingness to sign a written informed consent document. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of T-DM1. Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 6 months after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception. See Appendix B for further guidance on contraception. Exclusion Criteria: Patient with AJCC 2017 8th edition stage I or stage IVC (metastatic) disease, or unresectable disease. Subject who has had prior radiation and/or chemotherapy for head and neck cancer. Any history of prior HER2 directed therapy. Active or uncontrolled infection. Pregnant or lactating women. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, and low risk prostate adenocarcinoma being managed with active surveillance. A history of another separate malignancy in remission without evidence of active disease in the last 2 years is permitted.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard of Care + T-DM1 in HER2-Positive Salivary Gland Cancer<br>Participants will undergo standard of care surgery followed by standard of care radiation and chemotherapy with the addition of T-DM1. Study cycles are 21 days (3 weeks): Participants will be given the study treatment T-DM1 at a predetermined dose (3.6 mg/kg) intravenously once (1x) every 3 weeks for up to 52 weeks (or about 1 year). Participants will be given standard of care radiation and chemotherapy Radiation will be given on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, and Cycle 3 Day 1 Chemotherapy (cisplatin 40 mg/m2 intravenously or carboplatin AUC 2 intravenously) will be given on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 8, Cycle 2 Day 15, and Cycle 3 Day 1 Participants will be followed for 3 years. | Drug: Ado-trastuzumab (T) emtansine (T-DM1)<br>* Intravenous infusion ever 21 days (3weeks) for 1 year (52 weeks)<br>* Other names: Kadcyla;Radiation: Standard of Care Radiotherapy<br>* Radiotherapy to shrink or kill tumors<br>* Other names: Radiation;Drug: Standard of Care Chemotherapy<br>* Intravenous injection<br>* Other names: carboplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 Year Disease-free survival (DFS) Rate | Kaplan-Meier method will be used to estimate 2 Year Disease-free survival (DFS) Rate | Time from the date of study registration to first invasive local, regional, distant recurrence, or death due to any cause assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Evaluate adverse events for patient receiving T-DM1, defined as adverse events of all grades utilizing CTCAE v5 | Time from study registration to death due to any cause, or censored at date last known alive assessed up to 36 months | 
| Overall survival (OS) Rate | Overall Survival (OS) estimated using a Kaplan-Meier or competing risk methodology (whichever is appropriate). | Time from study registration to death due to any cause, or censored at date last known alive assessed up to 36 months | 
| Distant metastatic-free survival (DMFS) Rate | Distant metastatic-free survival (DMFS) Rate estimated using a Kaplan-Meier or competing risk methodology (whichever is appropriate). | Time from study registration to the earlier of the first occurrence of distant or metastatic disease, or death due to any cause assessed up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Salivary Gland Cancer, HER2 Gene Mutation