Safety and Efficacy of Nivolumab in Treating Oral Proliferative Verrucous Leukoplakia

This research study is studying an immunotherapy drug, as a possible treatment for oral proliferative verrucous leukoplakia (OPVL).

Study Overview

• Status: Active, not recruiting
• Conditions: Leukoplakia, Oral
• Intervention / Treatment: Drug: Nivolumab

Detailed Description

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

The purpose of this study is to evaluate effectiveness (how well the drug works) of nivolumab in treating OPVL and or prolonging the onset of possible malignancy.

Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells. Nivolumab has been demonstrated to activate the immune system to attack cancer cells in participants with different types of cancers. OPVL has a high risk for turning into cancer and the investigators are testing if nivolumab may help to shrink the white lesions in the participant's mouth and reduce cancer risk.

In November 2016, the Food and Drug Administration (FDA) approved nivolumab for the treatment of participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Squamous cell carcinoma is the kind of cancer that OPVL can transform into.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject must have histologically confirmed oral proliferative verrucous leukoplakia (OPVL), as defined by: multifocal lesions (≥ 2) or contiguous lesions ≥ 3 cm or a single lesion ≥ 4 cm in largest diameter (at least one lesion with any degree of dysplasia). (Note: no restriction on the length of time that patients have had one or more existing lesions)
• Willing to provide blood and tissue from diagnostic biopsies
• Any smoking history is permitted. A history of prior or current tobacco use is not an exclusion criteria. While discouraged, patients are permitted to continue tobacco use while on the study.
• Age 18 years or older
• ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A)

• Participant must have normal organ and marrow function as defined below within 21 days prior to study registration:

  • leukocytes ≥3,000/mcL
  • absolute neutrophil count ≥1,000/mcL
  • 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 ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal
• 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. WOCBP should plan to use an adequate method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 iu/l or equivalent units of hcg) at screening. Pregnancy test will be repeated on the day of the first dose of study drug (before administration), although results of this test are not required for registration.
• "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 7 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

Exclusion Criteria:

• Known carcinoma in situ (CIS) or invasive squamous cell carcinoma of the oral cavity. A history of a prior stage III (T1-2N1, T3N0) or IV (T1-3N2, T4N0) invasive head & neck squamous cell carcinoma treated with surgery and radiation with or without chemotherapy. Patients with prior locoregionally advanced tumors treated with surgery alone are eligible.
• Existing significant autoimmune conditions. Patients with a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not excluded. Patients cannot be on long-term (> 4 weeks) corticosteroids at doses exceeding prednisone 20 mg (or its equivalent) prior to enrollment. Short-term corticosteroid dosing is permitted as long as steroids are discontinued within 2 weeks of study registration.
• Subject who has had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Subject who has been treated with immunotherapy. This includes prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• 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.
• Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency.
• Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA is negative).
• A personal history of hematopoietic stem cell or solid organ transplant.
• Known non-infectious pneumonitis or any history of interstitial lung disease.
• A personal history of other active malignancies, with the exception of non-melanomatous skin cancers, low-risk prostate adenocarcinoma on active surveillance, or treated cancers in remission for the last 5 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab; Nivolumab will be administered by IV infusion on Day 1 of each 28-day cycle; Treatment with the study drug will continue for a maximum of 4 cycles or until unacceptable toxicity or withdrawal of consent	Drug: Nivolumab; Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells.; Other Names: Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response Rate (BORR)	BORR on treatment is the percentage of participants who achieved CR or PR. Best overall response is the best response recorded from study registration until the first disease progression/diagnosis of invasive OSCC (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Best overall response was determined by using composite scores based on both measurement and histology, matching to the response grid as following, (1)CR, a decrease of >80% or more; (2)PR, a decrease of 40-80%; (3)SD, neither PR or PD, (4)PD, an increase of 10% or more.	Participants were followed up to 164 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COMD QLQ Score Change From Baseline to End of Treatment	Quality of Life was evaluated using COMD QLQ (chronic oral mucosal diseases quality of life questionnaire). The range of the possible total score is 0-104, and low score is a good QoL.	Assessed at baseline and end of treatment. Treatment duration in days was a median (range) of 105 (21-164).
Grade 1/2 Toxicity Rate	The proportion of participants who experienced a maximum grade 1 or 2 adverse events regardless of treatment attribution based on the Common Toxicity Criteria for Adverse events Version 5.0 (CTCAEv5) as reported on case report forms.	Participants were followed up to 194 days.
Grade 3/4 Toxicity Rate	The proportion of participants who experienced a maximum grade 3 or 4 adverse events regardless of treatment attribution based on the Common Toxicity Criteria for Adverse events Version 5.0 (CTCAEv5) as reported on case report forms.	Participants were followed up to 194 days.
Time to the Next Surgery for a Head and Neck Malignancy	Time to Next Surgery is defined as time from the first study treatment to any head & neck surgery or resection for biopsy-proven carcinoma in situ (CIS) or invasive oral carcinoma.	Participants were followed up to 13.3 months.
Cancer Free Survival at 2 Years (CFS2)	CFS2 is the probability of participants remaining alive and cancer-free at 2 years based on Kaplan-Meier methodology. Cancer-Free Survival (CFS) is defined as the time from study registration to development of invasive oral cancer or death due to any cause. Participants alive without disease progression or recurrence (of invasive oral cancer) are censored at date of last disease evaluation.	Participants were followed up to 2 years.
2-year Overall Survival (OS) Rate	2-year OS rate was defined as the percentage of participants alive at 2 years.	Participants were followed up to 2 years.
PD-L1 Combined Positive Scores (CPS)	PD-L1 CPS (programmed death-1 ligand 1 combined positive score) was calculated by dividing the number of PD-L1 staining cells by the total number of viable tumor cells and then multiplying by 100. Its range of possible values was 0-100, where higher scores were better when participants received PD-L1 targeted therapy.	PD-L1 CPS assessed at baseline.

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Glenn Hanna, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2018
• Primary Completion (Actual): September 1, 2022
• Study Completion (Estimated): August 30, 2024

Study Registration Dates

• First Submitted: September 27, 2018
• First Submitted That Met QC Criteria: October 1, 2018
• First Posted (Actual): October 2, 2018

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Stomatognathic Diseases; Mouth Diseases; Pathological Conditions, Anatomical; Precancerous Conditions; Mouth Neoplasms; Leukoplakia; Leukoplakia, Oral; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 18-387

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No