Induction TPN Followed by Nivolumab With Radiation in Locoregionally Advanced Laryngeal and Hypopharyngeal Cancer

Sequential Therapy With Induction TPN Followed by Nivolumab With Radiation in Locoregionally Advanced Laryngeal and Hypopharyngeal Cancer

This research is being performed to treat patient for head and neck cancer patients who have not received prior chemotherapy.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Drug: Docetaxel; Drug: Cisplatin; Drug: Nivolumab; Radiation: Intensity-modulated radiotherapy

Detailed Description

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

Nivolumab is approved by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent or advanced head and neck cancer (head and neck cancer that has come back or is incurable) but is considered investigational for head and neck cancer patients who have not received prior chemotherapy.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Winship Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10029
      • The Tisch 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 or cytologically confirmed, resectable or unresectable, Stage III or Stage IV locoregionally advanced squamous cell carcinoma of the larynx or hypopharynx, as defined by 2017 American Joint Committee on Cancer (AJCC), 8th edition
• Willing to provide tissue from diagnostic biopsy and blood samples before, during, and after treatment
• Any smoking history is permitted
• Patients must have HPV negative disease. Those patients with a supraglottic primary are required to undergo HPV testing with p16 immunohistochemistry and/or confirmatory HPV PCR or ISH testing to rule out oropharyngeal origin with laryngeal extension
• Age 18 years or older
• ECOG performance status ≤ 1 (Karnofsky ≥ 80%, 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 ≥1,500/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) within 24 hours prior to the start of nivolumab
• 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:

• Existing severe autoimmune conditions (at the discretion of the treating physician). Patients with a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not excluded. Short-term corticosteroid dosing is permitted (i.e. dexamethasone for chemotherapy-induced nausea prevention during induction chemotherapy) as long as steroids are discontinued within 1 week (7 days) of receiving the first dose of nivolumab during the induction phase of treatment.
• Subject who has had prior chemotherapy for head and neck cancer and/or radiotherapy to the head and neck.
• 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 immune 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 negative).
• Known non-infectious pneumonitis or any history of interstitial lung disease.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, and low-risk prostate adenocarcinoma being managed with active surveillance. A history of another separate malignancy in remission without evidence of active disease in the last 5 years is permitted.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: Induction Docetaxel (T)+Cisplatin (P)+Nivolumab (N) then Radioimmunotherapy (IMRT+N) then adjuvant N; Participants received 3 cycles of induction with docetaxel, cisplatin and nivolumab (TPN) every 3 weeks (or 21 days): docetaxel 75 mg/m2 IV day 1, cisplatin 100 mg/m2 IV day 1, and nivolumab 240 mg IV flat dose day 1. Induction was followed by clinical and radiologic assessment of response. Participants without partial response or better based on RECIST 1.1 were offered salvage laryngectomy and/or pharyngectomy. Participants with partial or complete response per RECIST 1.1 proceeded with immunoradiotherapy concurrently with nivolumab. Intensity-modulated radiotherapy (IMRT) was preferred and proton beam radiotherapy not permitted. Nivolumab 240 mg IV flat dose day 1 was repeated every 2 weeks concurrently with IMRT (for a total of 3-4 doses). Participants then received adjuvant nivolumab (480 mg IV flat dose day 1) every 4 weeks within 3-8 weeks from the last day of IMRT for up to 6 cycles or until disease progression or recurrence.

Drug: Docetaxel; Docetaxel is a chemotherapy drug.; Other Names: Taxotere; Drug: Cisplatin; Cisplatin is a chemotherapy drug.; Other Names: Platinol; Drug: Nivolumab; Nivolumab is a type of immunotherapy.; Other Names: OPDIVO®; Radiation: Intensity-modulated radiotherapy; IMRT is definitive treatment for head and neck cancer.; Other Names: IMRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Laryngectomy-free Survival (LFS)	LFS defined as time from study registration to earlier of surgical removal of larynx and/or hypopharynx, or death due to any cause. Participants alive with intact larynx and hypopharynx are censored at date of last disease evaluation. Given limited sample size and zero events, the Kaplan-Meier method was not used for estimate of LFS.	Disease was assessed following the completion of 2-3 cycles of induction TPN, 10-12 weeks after the completion of immunoradiotherapy or surgery and every 3 months until disease progression (PD). Participants were followed up to 18.9 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Radiologic Response	Best radiologic response on treatment was evaluated per RECIST 1.1 criteria. For target lesions: complete response (CR) is complete disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Non-CR/Non-PD defined as persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.	Disease evaluation following the completion of the induction phase of treatment on cycle 3 day 43-63.
Median Censoring Time for Overall Survival (OS)	Overall Survival (OS) is defined as the time from study entry to death or censored at date last known alive. Given limited sample size and zero events, the Kaplan-Meier method was not used for the estimate of OS. The empirical median is provided which represents median time to date last known alive (all 6 participants were censored).	Participants were observed for OS up to 23.2 months.
Median Laryngo-esophageal Dysfunction-free Survival (LEDFS)	LEDFS is defined as time from study registration to earlier of surgical removal of larynx and/or hypopharynx, non-functioning larynx and/or hypopharynx (inability to swallow, speak, and/or breath on own), or death from any cause. Participants alive with intact and functioning larynx and hypopharynx and esophagus are censored at date of last disease evaluation. Given limited sample size and zero events, the Kaplan-Meier method was not used for estimate of LEDFS.	Disease was assessed following the completion of 2-3 cycles of induction TPN, 10-12 weeks after the completion of immunoradiotherapy or surgery and every 3 months until disease progression (PD). Participants were observed for LEDFS up to 18.9 months.
EORTC QLQ-C30 Change in Emotional Functional Score From Baseline to Post IMRT+Nivolumab	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. The emotional functional (EF) scale has 3 items (v3 items 21-24). Scores are standardized to range from 0-100. Higher scores indicate better emotional health.	At baseline and post IMRT+Nivolumab approximately 22 weeks from start of induction treatment.
Number of Participants With Grade 3-5 Treatment-related Adverse Events	All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 The number of treated participants experiencing at least one of these adverse events as defined during the time of observation was counted.	AEs were evaluated up to 9.6 months, representing maximum treatment duration for this study cohort.
EORTC QLQ-C30 Change in Fatigue Score From Baseline to Post IMRT+Nivolumab	The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. The fatigue scale has 3 items (v3 items 10,12,18). Scores are standardized to range from 0-100. Higher scores indicate more symptomatology.	At baseline and post IMRT+Nivolumab approximately 22 weeks from start of induction treatment.

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2019
• Primary Completion (Actual): October 31, 2022
• Study Completion (Actual): December 16, 2022

Study Registration Dates

• First Submitted: March 27, 2019
• First Submitted That Met QC Criteria: March 27, 2019
• First Posted (Actual): March 29, 2019

Study Record Updates

• Last Update Posted (Estimated): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Head and Neck Cancer
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Head and Neck Neoplasms; Hypopharyngeal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Docetaxel; Nivolumab
• Other Study ID Numbers: 18-652

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No