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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

Carcinoma, Adenoid Cystic

Adenocarcinoma

Adenoid Cystic Carcinoma

Micronutrients

Hematinics

Amino Acids

Vitamins

Pemetrexed

Pembrolizumab

Immune Checkpoint Inhibitors

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Glutamic Acid

Folinic Acid

Folate

Vitamin B9

Patients receive pembrolizumab IV over 30 minutes and pemetrexed disodium IV over 10 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Cycles of pemetrexed disodium repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who had stable disease, partial response, or complete response after completion of 35 cycles of pembrolizumab, may continue pembrolizumab for an additional 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients additionally undergo blood sample collection, CT, PET/CT or MRI and may also undergo PSMA PET on study.

Pemetrexed Disodium

Biospecimen Collection

Computed Tomography

Positron Emission Tomography

Magnetic Resonance Imaging

PSMA PET Scan

Clinical Trials Referral Office

Panayiotis (Panos) Savvides, M.D.

Yujie Zhao, M.D.

Katharine A. Price, M.D.

Katherine A. Price, M.D.

This phase II trial studies the effect of pemetrexed and pembrolizumab in treating patients with salivary gland cancer that has come back (recurrent) and/or has spread to other places in the body (metastatic). Chemotherapy drugs, such as pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The purpose of this study is to evaluate whether pembrolizumab, an immunotherapy drug, in combination with the chemotherapy drug, pemetrexed, has an effect on advanced salivary gland cancer.

PRIMARY OBJECTIVE:

I. To determine the response rate of the combination of pembrolizumab and pemetrexed in patients with recurrent or metastatic adenoid cystic salivary gland cancer (adenoid cystic carcinoma \[ACC\]) II. To determine the response rate of the combination of pembrolizumab and pemetrexed in patients with recurrent or metastatic salivary gland cancer (recurrent/metastatic salivary gland cancer \[R/M SGC\]). (Non-ACC)

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS), overall survival (OS), response rate (ACC cohort), CBR rate (non-ACC), and adverse events of the combination of pembrolizumab and pemetrexed in patients with recurrent or metastatic salivary gland cancer (R/M SGC).

II. To assess safety and tolerability of the combination of pembrolizumab and pemetrexed in patients with recurrent or metastatic salivary gland cancer (R/M SGC).

CORRELATIVE RESEARCH OBJECTIVES:

I. To investigate the frequency of MTAP loss by immunohistochemistry in R/M SGC and whether it correlates with enhanced response to pemetrexed.

II. To measure the degree of PDL1 expression using formalin-fixed tumor samples, and determine the extent of PDL1 expression correlates with response to study treatment.

III. To investigate expression of thymidylate synthase by immunohistochemistry in R/M SGC and whether it correlates with enhanced response to pemetrexed.

IV. To investigate circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and correlation with response to study treatment.

V. To prospectively investigate circulating prostate-specific membrane antigen (PSMA) extracellular vesibles (EVs) and correlate with disease burden and treatment response for patients with adenoid cystic carcinoma in Cohort A1.

VI. To prospectively investigate PSMA positron emission tomography (PET)/computed tomography (CT) as an imaging modality for patients with adenoid cystic carcinoma in Cohort A1.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes and pemetrexed disodium IV over 10 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Cycles of pemetrexed disodium repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who had stable disease, partial response, or complete response after completion of 35 cycles of pembrolizumab, may continue pembrolizumab for an additional 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients additionally undergo blood sample collection, CT, PET/CT or magnetic resonance imaging (MRI) and may also undergo PSMA PET on study.

After completion of study intervention, patients are followed up at 30 days, and then every 3 months for up to 3 years.

Pemetrexed and Pembrolizumab for the Treatment of Recurrent and/or Metastatic Salivary Gland Cancer

Phase II Study of Pemetrexed and Pembrolizumab in Recurrent and/or Metastatic Salivary Gland Malignancies

Assessed by immunohistochemistry. Will investigate correlation with enhanced response to pemetrexed. The associations of these markers with response will be done via Chi-square or Fisher's exact tests by cohort for categorical biomarkers and done via 2-sample t-tests (or the Wilcoxon Rank-Sum test) by cohort for continuous biomarker data. Descriptive statistics and tables will be reported.

Will determine the extent of PDL1 expression correlation with response to study treatment. The associations of these markers with response will be done via Chi-square or Fisher's exact tests by cohort for categorical biomarkers and done via 2-sample t-tests (or the Wilcoxon Rank-Sum test) by cohort for continuous biomarker data. Descriptive statistics and tables will be reported.

Evaluated by Response Evaluation Criteria in Solid Tumors version 1.1.

CBR will be defined as the rate of patients with stable disease, partial response or complete response as their best response during treatment.

The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5.0. The frequency and percentage of grade 3+ adverse events will be estimated.

Response rate will be assessed using RECIST 1.1 criteria. The data will be reported descriptively, with frequencies and percentages.

CBR will be reported descriptively, with frequencies and percentages.

Mayo Clinic

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT05408845	Metastatic Sali... Recurrent Saliv... Stage III Major... Stage IV Major ... Unresectable Sa...	Docetaxel Questionnaire A... Trastuzumab Trastuzumab Emt...	18 Years -	NRG Oncology
Pemetrexed and Pembrolizumab for the Treatment of Recurrent and/or Metastatic Salivary Gland Cancer	NCT04895735	Metastatic Sali... Recurrent Saliv... Stage IV Major ... Adenoid Cystic ...	Pembrolizumab Pemetrexed Diso... Biospecimen Col... Computed Tomogr... Positron Emissi... Magnetic Resona... PSMA PET Scan	18 Years -	Mayo Clinic
Pemetrexed and Pembrolizumab for the Treatment of Recurrent and/or Metastatic Salivary Gland Cancer	NCT04895735	Metastatic Sali... Recurrent Saliv... Stage IV Major ... Adenoid Cystic ...	Pembrolizumab Pemetrexed Diso... Biospecimen Col... Computed Tomogr... Positron Emissi... Magnetic Resona... PSMA PET Scan	18 Years -	Mayo Clinic

Spots Global Cancer Trial Database for metastatic salivary gland carcinoma