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

Recurrent Salivary Gland Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05408845
• Other study ID #: NRG-HN010
• Secondary ID: NCI-2022-04353NR
• Status: Recruiting
• Phase: Phase 2
• Start date: September 30, 2022
• Est. completion date: July 31, 2028

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 116
• Est. completion date: July 31, 2028
• Est. primary completion date: July 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Recurrence
• Recurrent Salivary Gland Carcinoma
• Salivary Gland Neoplasms

Intervention

Drug:
• Docetaxel
Given IV

Other:
• Questionnaire Administration
Ancillary studies

Biological:
• Trastuzumab
Given IV
• Trastuzumab Emtansine
Given IV

Locations

Country	Name	City	State
United States	UPMC Altoona	Altoona	Pennsylvania
United States	McFarland Clinic - Ames	Ames	Iowa
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	UPMC Hillman Cancer Center at Butler Health System	Butler	Pennsylvania
United States	UPMC Camp Hill	Camp Hill	Pennsylvania
United States	Carlisle Regional Cancer Center	Carlisle	Pennsylvania
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UPMC Hillman Cancer Center - Passavant - Cranberry	Cranberry Township	Pennsylvania
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	UPMC Western Maryland	Cumberland	Maryland
United States	Carle at The Riverfront	Danville	Illinois
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Kaiser Permanente Dublin	Dublin	California
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania
United States	Kaiser Permanente-Fremont	Fremont	California
United States	Kaiser Permanente-Fresno	Fresno	California
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	UCHealth Highlands Ranch Hospital	Highlands Ranch	Colorado
United States	Kaiser Permanente Moanalua Medical Center	Honolulu	Hawaii
United States	IRMC Cancer Center	Indiana	Pennsylvania
United States	City of Hope at Irvine Lennar	Irvine	California
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Kaiser Permanente-Modesto	Modesto	California
United States	UPMC Hillman Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	UPMC Hillman Cancer Center in Coraopolis	Moon	Pennsylvania
United States	UPMC Hillman Cancer Center - Part of Frick Hospital	Mount Pleasant	Pennsylvania
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Arnold Palmer Cancer Center Medical Oncology Norwin	N. Huntingdon	Pennsylvania
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	UPMC Cancer Center-Natrona Heights	Natrona Heights	Pennsylvania
United States	UPMC Hillman Cancer Center - New Castle	New Castle	Pennsylvania
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Chelsea	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Kaiser Permanente-Oakland	Oakland	California
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Mercy Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Kaiser Permanente-Roseville	Roseville	California
United States	Kaiser Permanente Downtown Commons	Sacramento	California
United States	Kaiser Permanente-South Sacramento	Sacramento	California
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Kaiser Permanente San Leandro	San Leandro	California
United States	Kaiser San Rafael-Gallinas	San Rafael	California
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	Trinity's Tony Teramana Cancer Center	Steubenville	Ohio
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	UPMC Cancer Center-Uniontown	Uniontown	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	UPMC Cancer Center-Washington	Washington	Pennsylvania
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Divine Providence Hospital	Williamsport	Pennsylvania
United States	UPMC Memorial	York	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Objective Response Rate (ORR) for patients who receive crossover treatment to T-DM1/TH following disease progression on the TH/T-DM1 arm	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.	From start of crossover treatment to disease progression, assessed up to 5 years
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Patient-Reported Toxicity	Patient-reported adverse events will be assessed using selected PRO-CTCAE.	From randomization to 12 months