Pembrolizumab and Vorinostat in Treating Patients With Recurrent Squamous Cell Head and Neck Cancer or Salivary Gland Cancer That Is Metastatic and/or Cannot Be Removed by Surgery

• Sponsor: University of Washington (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02538510
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 50
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 86.8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects of pembrolizumab and vorinostat in treating patients with squamous cell head and neck cancer or salivary gland cancer that has come back, has spread to other places in the body and/or cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab together with vorinostat may be a better treatment for head and neck cancer or salivary gland cancer.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Squamous Cell Carcinoma; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Nasopharynx Carcinoma; Recurrent Salivary Gland Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage III Major Salivary Gland Carcinoma; Stage III Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage III Nasopharyngeal Carcinoma; Stage IV Nasopharyngeal Carcinoma; Stage IVA Major Salivary Gland Carcinoma; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVB Major Salivary Gland Carcinoma; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVC Major Salivary Gland Carcinoma; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma	Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Drug: Vorinostat	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the safety and tolerability of MK-3475 (pembrolizumab) in combination with vorinostat patients with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC) and recurrent metastatic salivary gland cancer (RMSGC).

SECONDARY OBJECTIVES:

1. Determine the objective response rates and disease control rates of the combination of MK-3475 and vorinostat in patients with RMHNSCC and RMSGC.

2. Examine programmed cell death ligand 1 (PD-L1) expression and T cell phenotype in archived tumor, on-treatment tumor biopsies, pre- and post-treatment blood samples and correlate these with clinical response to the drug combination.

3. Determine median overall survival and progression free survival in and RMHNSCC and RMSGC patients enrolled in the study.

TERTIARY OBJECTIVES:

1. Explore peripheral T cell phenotype at baseline and after 3 cycles vorinostat and MK-3475.

2. Measure expression of the proteins in the PD-1 family on baseline tumor samples and on treatment biopsies.

OUTLINE:

Patients receive vorinostat orally (PO) once daily (QD) or via percutaneous endoscopic gastrostomy (PEG) on days 1-5 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 8-12 weeks thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm Phase I/II Study of MK-3475 Combined With Vorinostat for Recurrent Unresectable and/or Metastatic Squamous Cell Head and Neck Cancer and Recurrent Unresectable and/or Metastatic Salivary Gland Malignancies
• Actual Study Start Date: Oct 8, 2015
• Actual Primary Completion Date: Sep 28, 2019
• Anticipated Study Completion Date: Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (vorinostat, pembrolizumab) Patients receive vorinostat PO QD or via PEG on days 1-5 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda Lambrolizumab MK-3475 SCH 900475 ; Drug: Vorinostat; Given PO or via PEG; Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza

Outcome Measures

Primary Outcome Measures

1. Incidence of Toxicity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [Up to 30 days after the completion of study treatment]

   Toxicities will be summarized as the number and percentage of patients with each type of toxicity, per Criteria for Adverse Events version 4.0

Secondary Outcome Measures

1. Objective Response Rate [Up to 2 years]

   Radiologic assessments of measurable disease will be performed using radiographic imaging. RECIST 1.1 and immune response criteria will be used to assess response to therapy. Responses will be summarized as frequencies and percentages.

2. Overall Survival [Up to 2 years]

   The Kaplan Meier methods will be used to estimate overall survival.

3. Progression Free Survival [Up to 2 years]

   The Kaplan Meier methods will be used to estimate progression free survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Phase I run in: biopsy proven RMHNSCC with the following primary sites: nasopharynx, paranasal sinus, nasal cavity, skin/cutaneous sites; patients with unknown head and neck primary sites will be enrolled; patients with recurrent or metastatic squamous cell carcinomas of the head and neck (regardless of primary site) who are either unwilling to receive or have contraindications (deemed by treating physician) to standard systemic chemotherapy will also be eligible; patients with biopsy proven RMSGC be eligible as well

• Phase II expansion: biopsy proven RMHNSCC, of any primary site (including unknown primary) and RMSGC will be eligible

• Have evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria within 3 months prior to study enrollment; if the patient was receiving a prior line of systemic therapy, he/she should have evidence of disease progression on that line of treatment prior to enrollment

• Have received any number lines of prior systemic therapy (including systemic therapy in the curative intent setting)

• Be willing and able to provide written informed consent for the trial and comply with the study visit requirements

• Have measurable disease based on RECIST 1.1

• Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated* creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrC])

• Creatinine clearance should be calculated per institutional standard

• Serum total bilirubin =< 1.5 x ULN

• Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (glutamate pyruvate transaminase [SGPT]) =< 1.5 x ULN

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

• Patient is < 5 years free of another primary malignancy, except: a) if the other malignancy is basal cell carcinoma or cervical carcinoma in situ or b) if the other primary malignancy is not considered clinically significant and is requiring no active intervention

• SECOND COURSE PHASE (RETREATMENT PERIOD FOR POST-COMPLETE RESPONSE RELAPSE ONLY)

• Subjects may be eligible to receive MK-3475 in the second course phase of this study if the study remains open and the subject meets the following conditions:

• Stopped initial treatment with MK-3475 after attaining an investigator-determined confirmed response according to RECIST1.1 response criteria

• Was treated for at least 24 weeks with MK-3475 before discontinuing therapy

• Received at least four treatments with MK-3475 beyond the date when the initial complete response (CR) was declared

• Experienced an investigator-determined confirmed cutaneous or radiographic disease progression after stopping their initial treatment with MK-3475

• Did not receive any anti-cancer treatment since the last dose of MK-3475

• Have a performance status of 0 or 1 on the ECOG performance scale

• Demonstrate adequate organ function as detailed above

• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving retreatment with study medication

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of child bearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 year; male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

• Does not have a history or current evidence of any condition, therapy, or laboratory abnormality that might interfere with the subject's participation for the full duration of the trial or is not in the best interest of the subject to participate, in the opinion of the treating investigator

Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier

• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent

• Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study

• Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment

• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study

• Has evidence of interstitial lung disease or active, non-infectious pneumonitis

• Has an active infection requiring systemic therapy

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

• Has received prior therapy with an anti-programmed cell death 1 (PD-1), PD-L1, anti-programmed cell death ligand 2 (PD-L2), anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways); patients who have previously received MK-3475 or participated in an MK-3475 clinical trial will be ineligible

• Has received prior therapy with vorinostat or other epigenetic agent

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

• Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (HCV) (e.g., HCV RNA [ribonucleic acid] qualitative is detected)

• Has received a live vaccine within 30 days prior to the first dose of trial treatment

• Requires total parenteral nutrition and is unable to swallow pills or unable to take a suspension through a gastrostomy tube

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Cristina Rodriguez, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 16, 2015

More Information

Publications

None provided.

• Responsible Party: University of Washington
• ClinicalTrials.gov Identifier: NCT02538510
• Other Study ID Numbers: 9383; NCI-2015-01310; MK-3475; 9383; P30CA015704; RG1715066
• First Posted: Sep 2, 2015
• Last Update Posted: Feb 4, 2022
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Nasopharyngeal Carcinoma; Squamous Cell Carcinoma of Head and Neck; Salivary Gland Neoplasms; Recurrence; Pembrolizumab; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Head and Neck Squamous Cell Carcinoma	Salivary Gland Carcinoma
Arm/Group Description	MK-3475 combined with vorinostat,HNSCC patients	MK-3475 combined with votinostat, SGC patients
Period Title: Overall Study
STARTED	25	25
COMPLETED	25	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Head and Neck Squamous Cell Carcinoma	Salivary Gland Carcinoma	Total
Arm/Group Description	Head and Neck Squamous Cell Carcinoma patients	Salivary Gland Carcinoma patients	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 56%	18 72%	32 64%
>=65 years	11 44%	7 28%	18 36%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.12 (8.99)	56.84 (13.64)	59.98 (11.91)
Sex: Female, Male (Count of Participants)
Female	2 8%	9 36%	11 22%
Male	23 92%	16 64%	39 78%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4%	0 0%	1 2%
Not Hispanic or Latino	24 96%	24 96%	48 96%
Unknown or Not Reported	0 0%	1 4%	1 2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 8%	0 0%	2 4%
Asian	3 12%	3 12%	6 12%
Native Hawaiian or Other Pacific Islander	0 0%	1 4%	1 2%
Black or African American	0 0%	0 0%	0 0%
White	20 80%	21 84%	41 82%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%	25 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Toxicity Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Description	Toxicities will be summarized as the number and percentage of patients with each type of toxicity, per Criteria for Adverse Events version 4.0
Time Frame	Up to 30 days after the completion of study treatment

Outcome Measure Data

Analysis Population Description

Only G3 toxicities and toxicities requiring dose hold/reduction recorded.

Arm/Group Title	Head and Neck Squamous Cell Carcinoma	Salivary Gland Carcinoma
Arm/Group Description	AEs experienced with MK-3475 combined with vorinostat in HNSCC patients	AEs experienced with MK-3475 combined with vorinostat in salivary gland carcinoma patients
Measure Participants	25	25
Adrenal insufficiency	1 4%	1 4%
ALT increase	0 0%	1 4%
Anorexia	0 0%	1 4%
Arthiritis	0 0%	1 4%
AST increase	0 0%	1 4%
Cough	1 4%	0 0%
Increased Creatinine	2 8%	5 20%
Dermatitis	1 4%	0 0%
Diarrhea	0 0%	1 4%
Fever with leukocytosis	0 0%	1 4%
Fatigue	2 8%	4 16%
Hyponatremia	2 8%	0 0%
Hypothyroidism	1 4%	0 0%
Colitis and Ileitis	1 4%	0 0%
Malaise	1 4%	0 0%
Nausea	1 4%	3 12%
Nephritis	0 0%	1 4%
Pneumonitis	1 4%	0 0%
Neuritis	0 0%	1 4%
Tracheitis/Epiglottitis	1 4%	0 0%
Vomiting	1 4%	2 8%

2. Secondary Outcome

Title	Objective Response Rate
Description	Radiologic assessments of measurable disease will be performed using radiographic imaging. RECIST 1.1 and immune response criteria will be used to assess response to therapy. Responses will be summarized as frequencies and percentages.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

6 patients were not evaluated as they did not have at least 1 set of follow up scans while on study, (N=2 salivary patients, N=4 SCC patients)

Arm/Group Title	Head and Neck Squamous Cell	Salivary Gland Carcinoma
Arm/Group Description	Head and Neck Squamous Cell RECIST 1.1	RECIST 1.1 response rate salivary gland
Measure Participants	21	23
partial response	8 32%	4 16%
stable disease	8 32%	13 52%
progressive disease	5 20%	6 24%

3. Secondary Outcome

Title	Overall Survival
Description	The Kaplan Meier methods will be used to estimate overall survival.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Progression Free Survival
Description	The Kaplan Meier methods will be used to estimate progression free survival.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Head and Neck Squamous Cell Carcinoma	Salivary Gland Carcinoma
Arm/Group Description	Head and Neck Squamous Cell Carcinoma patients	Salivary Gland Carcinoma patients
Measure Participants	25	25
Mean (95% Confidence Interval) [Months]	12.6	14.0

Adverse Events

Time Frame	3 years, 6 months
Adverse Event Reporting Description	Adverse events are collected from the first dose of Mk-3475 or Vorinostat, and are collected through 30 days post the last dose of therapy.
Arm/Group Title	Head and Neck Squamous Cell Carcinoma		Salivary Gland Carcinoma
Arm/Group Description	MK-3475 combined with vorinostat in HNSCC patients		MK-3475 combined with vorinostat in SGC patients
All Cause Mortality
	Head and Neck Squamous Cell Carcinoma		Salivary Gland Carcinoma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/25 (84%)		20/25 (80%)
Serious Adverse Events
	Head and Neck Squamous Cell Carcinoma		Salivary Gland Carcinoma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		1/25 (4%)
Endocrine disorders
Adrenal Insufficiency	0/25 (0%)	0	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/25 (4%)	1	0/25 (0%)	0
Other (Not Including Serious) Adverse Events
	Head and Neck Squamous Cell Carcinoma		Salivary Gland Carcinoma
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/25 (44%)		19/25 (76%)
Gastrointestinal disorders
Nausea	1/25 (4%)	1	3/25 (12%)	4
Vomiting	1/25 (4%)	1	2/25 (8%)	2
General disorders
Fatigue	2/25 (8%)	3	4/25 (16%)	6
Malaise	1/25 (4%)	1	0/25 (0%)	0
Hepatobiliary disorders
alanine amintotransferase (ALT) increased	0/25 (0%)	0	1/25 (4%)	1
asparate aminotransferase (AST) increased	0/25 (0%)	0	1/25 (4%)	1
Immune system disorders
Adrenal insufficiency	1/25 (4%)	1	1/25 (4%)	1
Infections and infestations
Fever with Leukocytosis	0/25 (0%)	0	1/25 (4%)	1
Metabolism and nutrition disorders
Hyponatremia	2/25 (8%)	2	0/25 (0%)	0
Nervous system disorders
Neuritis	0/25 (0%)	0	1/25 (4%)	1
Renal and urinary disorders
creatinine increased	2/25 (8%)	2	5/25 (20%)	6
Respiratory, thoracic and mediastinal disorders
cough	1/25 (4%)	1	0/25 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.