Window Study of Nivolumab With or Without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02919683
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 89
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This research study is studying nivolumab, an investigational drug, in combination with ipilimumab, also an investigational drug, as a possible treatment for Squamous Cell Carcinoma of the oral cavity.

The following drugs are involved in this study:

• Nivolumab (Opdivo™)

• Ipilimumab (Yervoy™)

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer	Drug: Nivolumab; Drug: Ipilimumab; Procedure: Standard of Care Surgery	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The purpose of this study is to evaluate effectiveness (how well the drug/s work) of Nivolumab or Nivolumab combined with Ipilimumab prior to standard of care surgery.

Nivolumab and Ipilimumab are types of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells. Both nivolumab and Ipilimumab have been demonstrated to activate the immune system to attack cancer cells in laboratory studies and in patients with different types of cancers.

Nivolumab (Opdivo ™) has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma (a type of skin cancer), and specific types of previously treated advanced lung and kidney cancers. Ipilimumab (Yervoy™) is approved by the FDA for the treatment of metastatic melanoma.

Because Nivolumab and Ipilimumab help the immune system work in different ways, the combination of Nivolumab and Ipilimumab was tested in laboratory studies. The data from these studies suggested that giving the two drugs together could be of benefit to patients, and this was indeed found to be the case in patients with melanoma. The combination of Nivolumab and Ipilimumab is now FDA approved as treatment for patients with metastatic melanoma. However, the use of Nivolumab as well as Ipilimumab alone or in combination for the treatment of patients with head and neck cancer is not approved. Results from clinical trials investigating the safety and efficacy of Nivolumab and Ipilimumab in patients with head and neck cancer are not available at this time.

In the proposed study, either Nivolumab or the combination of Nivolumab and Ipilimumab is being tested is being tested prior to surgery to remove cancers of the oral cavity. By stimulating the immune system to attack cancer cells, these drugs may cause the cancer to decrease in size prior to surgery and prevent the cancer from coming back.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Window Study of Nivolumab With or Without Ipilimumab in Squamous Cell Carcinoma of the Oral Cavity
• Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jul 1, 2019
• Anticipated Study Completion Date: Apr 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab With Ipilimumab Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery	Drug: Nivolumab; Other Names: Opdivo ; Drug: Ipilimumab; Other Names: Yervoy ; Procedure: Standard of Care Surgery
Experimental: Nivolumab Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery	Drug: Nivolumab; Other Names: Opdivo ; Procedure: Standard of Care Surgery

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Volumetric Response Rate to Treatment [At time of surgery]

   Response rate to window treatment with single agent nivolumab or nivolumab combined with ipilimumab is determined using bidirectional measurements (product of longest 2 diameters of lesions) of primary and nodal lesions to be removed at the time of surgery. Responders will have demonstrated any reduction in overall tumor volume as determined by the product of the longest perpendicular bidirectional tumor measurements.

2. Safety and Tolerability of Protocol Treatment [At the time of surgery]

   Outcome measure includes number of participants with treatment-related adverse events as assessed by CTCAE v4.0, number of dose-limiting toxicities in safety run-ins following a 3 + 3 design, and delays to surgery.

Secondary Outcome Measures

1. Percentage of Participants Demonstrating Objective Response Using RECIST Criteria [At time of surgery]

   Determining the radiologic response rate following the window treatment as determined by RECIST v1.1.

2. Percentage of Participants Demonstrating Pathological Response [At time of surgery]

   Pathologic response in the primary tumor was assessed using a quantitative grading scheme: pathologic tumor response [nonviable tumor] PTR0 = no or <10% response PTR1 = ≥10% PTR2 = ≥50%

3. Participant One Year Progression-Free Survival Percentage [1 year]

   Progression-free survival is defined as the time between first study treatment and either recurrent disease or death. Recurrent disease includes a local failure, regional failure, or distant metastasis.

4. Participant Overall Survival Percentage [Data Cutoff (14.2 Months Median Follow Up)]

   Overall survival is defined as the time between first study treatment and death.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Pathologically confirmed squamous cell carcinoma of the oral cavity. Clinical stage

=T2 (primary tumor greater than 2 cm in size) and/or evidence of regional nodal involvement by clinical exam or imaging

• Only patients 18 years and older are eligible. There is no upper age limit but the patients must be able to medically tolerate the regimen. Adverse event data are currently unavailable on the use immune checkpoint blockade for participants < 18 years of age, and thus children are excluded from this study

• ECOG performance status <=1

• Patients much be a surgical candidate (e.g. their disease must be considered resectable before any treatment and must have no serious medical contraindications that definitively preclude undergoing general anesthesia) Ability to understand and the willingness to sign a written informed consent document

• Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of contraception (see Appendix B). WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. WOCBP is defined as any woman or adolescent who has begun menstruation and is not post- menopausal. A post-menopausal woman is defined as a woman who is over the age of 45 and has not had a menstrual period for at least 12 months

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab

• Men who are sexually active with WOCBP must agree to use any contraceptive method (see Appendix B) with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks 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)

• Participants must have normal organ and marrow function as defined below:

Laboratory parameters: WBC ≥ 2000/uL, Absolute neutrophil count (ANC) ≥ 1500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin (Hgb) ≥ 9 g/dL; Hgb-A1C ≤ 7.5%; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); Bilirubin ≤ 2.5 × ULN (≤ 4 × ULN for subjects with Gilbert's disease); Alkaline phosphatase ≤ 2.5 × ULN; Creatinine ≤ 1.5 × ULN

Exclusion Criteria:

• Pathologically proven, radiologic or clinical evidence of distant metastatic disease (this includes all disease below the clavicles, as well as disease metastatic to the bone, brain, or in the spinal canal)

• Any prior immunologic cancer therapy with systemic inhibitors of the PD-1 or CTLA-4 pathway

• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Individuals with a history of a different malignancy are ineligible except for the following circumstances: if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; or if diagnosed and treated within the past 2 years for cervical cancer in situ or basal cell or squamous cell carcinoma of the skin

• Prior radiation to the head and neck region

• Prior chemotherapy within the last 2 years

• History of pneumonitis or interstitial lung disease

• Has evidence of active, noninfectious pneumonitis that required treatment with steroids.

• Active, suspected or prior documented autoimmune disease that has required systemic treatment in the last 2 years with immune modifying agents (e.g. replacement therapy such as thyroxine, insulin or physiologic corticosteroids is not an exclusion criteria). This does not include patients with vitiligo or type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger

• The subject is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA

• Lack of availability for follow up assessments

• Concurrent administration of other cancer specific therapy during the course of this study is not allowed

• Patients who require systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease

• History of allergy to study drug components

• History of severe hypersensitivity reaction to any monoclonal antibody

• The investigator's belief that the subject is medically unfit to receive nivolumab, and/or ipilimumab or unsuitable for any other reason

• Has received a live vaccine within 28 days of planned start of study therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Jonathan Schoenfeld, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 9, 2019

More Information

Publications

None provided.

• Responsible Party: Jonathan Schoenfeld, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT02919683
• Other Study ID Numbers: 16-284
• First Posted: Sep 29, 2016
• Last Update Posted: Feb 24, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jonathan Schoenfeld, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute: Head and Neck Cancer
• Additional relevant MeSH terms: Carcinoma, Squamous Cell; Head and Neck Neoplasms; Nivolumab; Ipilimumab

Study Results

Participant Flow

Arm/Group Title	Nivolumab With Ipilimumab	Nivolumab
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery	Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery
Period Title: Pre-Surgery Intervention
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Pre-Surgery Intervention
STARTED	15	15
COMPLETED	12	13
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Nivolumab With Ipilimumab	Nivolumab	Total
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery	Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery	Total of all reporting groups
Overall Participants	15	15	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 46.7%	7 46.7%	14 46.7%
>=65 years	8 53.3%	8 53.3%	16 53.3%
Sex: Female, Male (Count of Participants)
Female	7 46.7%	5 33.3%	12 40%
Male	8 53.3%	10 66.7%	18 60%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 6.7%	0 0%	1 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 6.7%	1 3.3%
White	14 93.3%	14 93.3%	28 93.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Volumetric Response Rate to Treatment
Description	Response rate to window treatment with single agent nivolumab or nivolumab combined with ipilimumab is determined using bidirectional measurements (product of longest 2 diameters of lesions) of primary and nodal lesions to be removed at the time of surgery. Responders will have demonstrated any reduction in overall tumor volume as determined by the product of the longest perpendicular bidirectional tumor measurements.
Time Frame	At time of surgery

Outcome Measure Data

Analysis Population Description

Thirty patients were treated from 2016 to 2019. One patient was excluded from efficacy analyses as she was ineligible because of evidence of distant metastatic disease at baseline.

Arm/Group Title	Nivolumab With Ipilimumab	Nivolumab
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery	Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery
Measure Participants	15	14
Number (80% Confidence Interval) [percentage of participants]	53 353.3%	50 333.3%

2. Primary Outcome

Title	Safety and Tolerability of Protocol Treatment
Description	Outcome measure includes number of participants with treatment-related adverse events as assessed by CTCAE v4.0, number of dose-limiting toxicities in safety run-ins following a 3 + 3 design, and delays to surgery.
Time Frame	At the time of surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolumab With Ipilimumab	Nivolumab
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery	Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery
Measure Participants	15	15
Delays to Surgery	0	0
Dose-Limiting Toxic Effects during Safety Run-In	0	0
Grade 3-4 Events At Least Possibly Related to Protocol Treatment	5	2

3. Secondary Outcome

Title	Percentage of Participants Demonstrating Objective Response Using RECIST Criteria
Description	Determining the radiologic response rate following the window treatment as determined by RECIST v1.1.
Time Frame	At time of surgery

Outcome Measure Data

Analysis Population Description

For this analysis, patients with no radiographically measurable lesions on imaging review were excluded. Thirty patients were treated from 2016 to 2019. One patient was excluded from efficacy analyses as she was ineligible because of evidence of distant metastatic disease at baseline.

Arm/Group Title	Nivolumab With Ipilimumab	Nivolumab
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery	Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery
Measure Participants	13	14
Number [percentage of participants]	38 253.3%	13 86.7%

4. Secondary Outcome

Title	Percentage of Participants Demonstrating Pathological Response
Description	Pathologic response in the primary tumor was assessed using a quantitative grading scheme: pathologic tumor response [nonviable tumor] PTR0 = no or <10% response PTR1 = ≥10% PTR2 = ≥50%
Time Frame	At time of surgery

Outcome Measure Data

Analysis Population Description

Thirty patients were treated from 2016 to 2019. One patient was excluded from efficacy analyses as she was ineligible because of evidence of distant metastatic disease at baseline.

Arm/Group Title	Nivolumab With Ipilimumab	Nivolumab
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery	Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery
Measure Participants	15	14
PTR1	40 266.7%	38 253.3%
PTR2	33 220%	15 100%

5. Secondary Outcome

Title	Participant One Year Progression-Free Survival Percentage
Description	Progression-free survival is defined as the time between first study treatment and either recurrent disease or death. Recurrent disease includes a local failure, regional failure, or distant metastasis.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Thirty patients were treated from 2016 to 2019. One patient was excluded from efficacy analyses as she was ineligible because of evidence of distant metastatic disease at baseline.

Arm/Group Title	All Participants
Arm/Group Description	All participants enrolled in both trial cohorts.
Measure Participants	29
Number (95% Confidence Interval) [percentage of participants]	85 566.7%

6. Secondary Outcome

Title	Participant Overall Survival Percentage
Description	Overall survival is defined as the time between first study treatment and death.
Time Frame	Data Cutoff (14.2 Months Median Follow Up)

Outcome Measure Data

Analysis Population Description

Thirty patients were treated from 2016 to 2019. One patient was excluded from efficacy analyses as she was ineligible because of evidence of distant metastatic disease at baseline.

Arm/Group Title	All Participants
Arm/Group Description	All participants enrolled in both trial cohorts.
Measure Participants	29
Number (95% Confidence Interval) [percentage of participants]	89 593.3%

Adverse Events

Time Frame	All adverse events experienced by participants were collected from the time of the first dose of study treatment, through the study and until the final study visit 1 year after enrollment.
Adverse Event Reporting Description	The descriptions and grading scales found in the CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0) were utilized for AE reporting.
Arm/Group Title	Nivolumab With Ipilimumab		Nivolumab
Arm/Group Description	Nivolumab to be delivered at a pre-determine dose for two weeks Ipilimumab to be delivered at a pre-determine dose for one week Blood Sample Collected Standard of Care Surgery Nivolumab Ipilimumab Standard of Care Surgery		Nivolumab to be delivered at a pre-determine dose for two weeks Blood Sample Collected Standard of Care Surgery Nivolumab Standard of Care Surgery
All Cause Mortality
	Nivolumab With Ipilimumab		Nivolumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		2/15 (13.3%)
Serious Adverse Events
	Nivolumab With Ipilimumab		Nivolumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)		3/15 (20%)
Endocrine disorders
hyperglycemia and diabetic ketoacidosis	0/15 (0%)		1/15 (6.7%)
Infections and infestations
Infection	0/15 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Right knee effusion and fever	1/15 (6.7%)		0/15 (0%)
Surgical and medical procedures
Wound complication - flap thrombosis and failure	1/15 (6.7%)		0/15 (0%)
Vascular disorders
Thromboembolic event	0/15 (0%)		1/15 (6.7%)
Stroke	1/15 (6.7%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Nivolumab With Ipilimumab		Nivolumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/15 (80%)		11/15 (73.3%)
Endocrine disorders
Hyperthyroidism	1/15 (6.7%)		2/15 (13.3%)
Hypothyroidism	0/15 (0%)		2/15 (13.3%)
Gastrointestinal disorders
Dysphagia	1/15 (6.7%)		3/15 (20%)
Diarrhea	2/15 (13.3%)		0/15 (0%)
Mucositis	2/15 (13.3%)		1/15 (6.7%)
Oral ulcer	0/15 (0%)		1/15 (6.7%)
General disorders
Oral pain	3/15 (20%)		5/15 (33.3%)
Fatigue	1/15 (6.7%)		4/15 (26.7%)
Dental caries	1/15 (6.7%)		0/15 (0%)
Edema	3/15 (20%)		1/15 (6.7%)
Dry mouth	1/15 (6.7%)		3/15 (20%)
Paresthesia	0/15 (0%)		2/15 (13.3%)
Lymph node pain	1/15 (6.7%)		0/15 (0%)
Fever	2/15 (13.3%)		0/15 (0%)
Delayed wound healing	0/15 (0%)		1/15 (6.7%)
Anorexia	1/15 (6.7%)		0/15 (0%)
Lymphedema	1/15 (6.7%)		0/15 (0%)
Glucose intolerance	0/15 (0%)		1/15 (6.7%)
Infusion-related reaction	1/15 (6.7%)		0/15 (0%)
Immune system disorders
Autoimmune disorder	1/15 (6.7%)		3/15 (20%)
Allergic Reaction	1/15 (6.7%)		0/15 (0%)
Infections and infestations
Wound infection	0/15 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Osteonecrosis of the jaw	1/15 (6.7%)		0/15 (0%)
Joint effusion	2/15 (13.3%)		0/15 (0%)
Muscle/Joint Pain	0/15 (0%)		2/15 (13.3%)
Trismus	0/15 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/15 (6.7%)		0/15 (0%)
Skin and subcutaneous tissue disorders
Papulopustular rash	1/15 (6.7%)		0/15 (0%)
Pruitus	1/15 (6.7%)		0/15 (0%)
Maculopapular rash	1/15 (6.7%)		0/15 (0%)
Dermatitis	1/15 (6.7%)		1/15 (6.7%)
Rash	2/15 (13.3%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.