Head and Neck Cancer
Conditions
Brief summary
This study is being done to evaluate the efficacy of Pembrolizumab, concomitant with and following standard of care definitive radiation, for locally advanced squamous cell carcinoma of the head and neck patients who are not good candidates for Cisplatin.
Detailed description
This open label, phase II trial will enroll 29 subjects in order to evaluate the efficacy of Pembrolizumab, concomitant with and following standard of care definitive radiation for locally advanced squamous cell carcinoma head and neck patients who are not good candidates for Cisplatin. Objectives include estimating progression free survival and overall survival, response rates, safety and toxicity, and quality of life in these patients. Correlative studies, based on serial blood collections and tumor samples, may be done under a separate protocol based on availability of archival diagnostic tissue.
Interventions
DRUGPembrolizumab
Pembrolizumab, 200 mg IV during cycle visits every 3-weeks for up to 6 cycles, or until toxicities are no longer tolerable
RADIATIONIntensity Modulated Radiation Therapy
Eligible participants will receive Intensity Modulated Radiation Therapy daily x 7 weeks
Sponsors
Merck Sharp & Dohme LLC
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Be willing and able to provide written informed consent/assent for the trial * Be greater than or equal to 18 years of age * Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 1 * Histologically or cytologically confirmed stage III-IV (non-metastatic) squamous cell carcinoma of the head and neck as defined by American Joint Committee on Cancer. Nasopharyngeal cancer patients will be excluded. * Ineligible for high dose cisplatin therapy; the reason for ineligibility must be defined. * Demonstrate adequate organ function. All screening labs should be performed within 14 days of treatment initiation. * No prior curative attempts for this cancer (i.e., surgery, radiation and/or other). * Female patients of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. Serum pregnancy test may be required. * Female patients 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. * Male patients 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. * As determined by the enrolling physician or protocol designee, ability of the patient to understand and comply with study procedures for the entire length of the study. * Consent for the use of any residual material from biopsy (archival tissue) and serial blood draws will be required for enrollment.
Exclusion criteria
* If 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 from adverse events due to agents administered more than 4 weeks earlier * Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from adverse events due to a previously administered agent. * Has a known additional malignancy that is metastatic, progressing or requires active treatment. * Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease even if resolved; patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. * Has clinical or radiologic 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 patient's participation for the full duration of the trial, or is not in the best interest of the patient 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. * Has inadequate home environment or social support to safely complete the trial procedures. * 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 (PD-1), anti-PD-L1, anti-PD-L1, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. * Has a known history of Human Immunodeficiency Virus (HIV) HIV 1/2 antibodies) Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C )e.g., HCV RNA \[qualitative\] is detected). * Has received a live vaccine within 30 days prior to the first dose of trial treatment. * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 20 Week Progression Free Survival Rate | 20 weeks after D1 of treatment | the proportion of patients who are alive and free of progression from disease at 20 weeks from the start of treatment |
| One Year Progression Free Survival Rate | 1 years after D1 of treatment | the proportion of patients who are alive and free of progression from disease atoneyears from the start of treatment |
| Two Year Progression Free Survival Rate | 2 years after D1 of treatment | the proportion of patients who are alive and free of progression from disease at two years from the start of treatment |
| Median Progression Free Survival | up to 5 years after D1 of treatment | Progression-free survival is defined as the time from D1 of treatment to progression or death from any cause. The median was not reached, thus Kaplan Meier's estimated rate at 5 years is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 2 years after start of treatment | Overall response rate will be determined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) which defines Complete Response (CR) as Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Overall Response Rate (ORR) = CR + PR/total number of subjects. |
| Complete Response Rate | 2 years after start of treatment | complete response rate will be determined using RECIST 1.1 and is defined as the percentage of participants who achieve a Complete response (CR)-Disappearance of all target lesions. Any pathological lymph node (LN) (whether target or non-target) must have decreased in short axis to \<10mm. |
| One Year Overall Survival Rate | 1 year after Day 1 of treatment | the proportion of patients who are alive at one year after Day 1 of treatment |
| Five Years Distant Metastasis Rate | 5 years from start of treatment | Time to distant metastasis is defined as the time from day 1 of treatment to progression of disease at a distant site; deaths or other progressions will be censored |
| Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | At baseline, 10 and 20 weeks after initiation of treatment | The FACT-HN is the FACT-General (FACT-G) and a head and neck cancer specific (HNC) subscale given at baseline, at end of treatment, and at first follow-up visit. The FACT-G is a measure of general QOL with Items rated by patients on a Likert scale from 0 to 4, assessing function in 4 domains: physical well-being (PWB) (7 items, score range 0-28), social-family well-being (SFWB) (7 items, score range 0-28), emotional well-being (EWB) (6 items, score range 0-24) and functional well-being (FWB) (7 items, score range 0-28). The HNC subscale has 12 items and a score range from 0 to 48. Higher scores represent better QOL. |
| Five Years Locoregional Recurrence Rate | 5 years from start of treatment | Time to locoregional recurrence is defined from Day 1 of treatment until the first locoregional progression |
| Two Year Overall Survival Rate | 2 years after Day 1 of treatment | the proportion of patients who are alive at two years after Day 1 of treatment |
| Proportion of Participants Who Received <95% of Intended Dose of Radiation | 7 weeks | Evaluate the safety of the proposed regimen by Estimating the proportion of patients who receive \<95% of the intended dose of radiation (i.e., \<67 Gray) |
| Number of Participants With Clinically Relevant Adverse Events | Monitored continuously from D1 of treatment through 40 weeks. | Safety was assessed by documenting clinically relevant adverse events, defined as events reported by both the clinician and participant related to concurrent radiation plus pembrolizumab. Clinicians classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The grading (severity) scale for each AE term: Grade (G) 1 Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; G 2 Moderate; G 3 Severe or medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated; disabling; G 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. Patient assessed toxicity were classified based on the Patient-Reported Outcome version of the CTCAE (PRO-CTCAE) which measures the severity, interference, and frequency of events on a 5 point likert scale (0-4) with a higher score indicating worse or more bothersome event |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the University of North Carolina (Chapel Hill, NC), Fox Chase Cancer Center (Philadelphia, PA), and Johns Hopkins (Baltimore,MD) between February 2016 and July 2018.
Pre-assignment details
One potential participant was deemed ineligible during screening and therefore did not start the trial.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation All patients will receive Intensity Modulated Radiotherapy Treatments (IMRT) as per standard of care. The total dose will be 70 Gray(Gy) at 2Gy/fraction, 35 fractions, Monday to Friday, for 7 weeks.
Starting on the first day of radiotherapy, patients will be treated with pembrolizumab 200 milligrams (mg) intravenous (IV) every 3 weeks for 6 doses. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab Concomitant With and Post 7 Weeks of Radiation |
|---|---|
| Age, Continuous | 63.1 years |
| Charleson comorbidity index score 0 | 6 Participants |
| Charleson comorbidity index score 1 | 6 Participants |
| Charleson comorbidity index score 2 | 11 Participants |
| Charleson comorbidity index score 3 | 2 Participants |
| Charleson comorbidity index score 4 | 3 Participants |
| Charleson comorbidity index score 5 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Performance status 0 | 12 Participants |
| Performance status 1 | 17 Participants |
| Primary site Base of tongue | 10 Participants |
| Primary site Hypopharynx | 2 Participants |
| Primary site Oral tongue | 1 Participants |
| Primary site Supraglottic larynx | 3 Participants |
| Primary site Tonsil | 10 Participants |
| Primary site Unknown primary | 2 Participants |
| Primary site Uvula | 1 Participants |
| Programmed cell Death Ligand-1 (PD-L1) modified H-score (MHS) | 105 units on a scale |
| Programmed cell Death Ligand-1 (PD-L1) Modified Percent Score (MPS) | 60 percent staining |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Reason for cisplatin ineligibility Diabetes | 2 Participants |
| Reason for cisplatin ineligibility Hearing | 14 Participants |
| Reason for cisplatin ineligibility Neuropathy | 2 Participants |
| Reason for cisplatin ineligibility Renal function | 5 Participants |
| Reason for cisplatin ineligibility Tinnitus | 6 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 28 Participants |
| Smoking pack years <10 pack years | 13 Participants |
| Smoking pack years >=10 pack years | 16 Participants |
| Smoking status Current | 3 Participants |
| Smoking status Former | 15 Participants |
| Smoking status Never | 11 Participants |
| Stage I | 5 Participants |
| Stage II | 3 Participants |
| Stage III | 11 Participants |
| Stage IVA | 8 Participants |
| Stage IVB | 2 Participants |
| Tumor-Infiltrating Lymphocytes (TIL) | 3 units on a scale |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 29 |
| other Total, other adverse events | 29 / 29 |
| serious Total, serious adverse events | 6 / 29 |
Outcome results
Primary
20 Week Progression Free Survival Rate
the proportion of patients who are alive and free of progression from disease at 20 weeks from the start of treatment
Time frame: 20 weeks after D1 of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | 20 Week Progression Free Survival Rate | 0.90 proportion of participants |
Primary
Median Progression Free Survival
Progression-free survival is defined as the time from D1 of treatment to progression or death from any cause. The median was not reached, thus Kaplan Meier's estimated rate at 5 years is reported.
Time frame: up to 5 years after D1 of treatment
Population: Participants started the study treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Median Progression Free Survival | 58.6 Proportion of participants |
Primary
One Year Progression Free Survival Rate
the proportion of patients who are alive and free of progression from disease atoneyears from the start of treatment
Time frame: 1 years after D1 of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | One Year Progression Free Survival Rate | 0.76 proportion of participants |
Primary
Two Year Progression Free Survival Rate
the proportion of patients who are alive and free of progression from disease at two years from the start of treatment
Time frame: 2 years after D1 of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Two Year Progression Free Survival Rate | 0.71 proportion of participants |
Secondary
Complete Response Rate
complete response rate will be determined using RECIST 1.1 and is defined as the percentage of participants who achieve a Complete response (CR)-Disappearance of all target lesions. Any pathological lymph node (LN) (whether target or non-target) must have decreased in short axis to \<10mm.
Time frame: 2 years after start of treatment
Population: Two participants did not complete follow-up radiographic measurements to assess for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Complete Response Rate | 23 Participants |
Secondary
Five Years Distant Metastasis Rate
Time to distant metastasis is defined as the time from day 1 of treatment to progression of disease at a distant site; deaths or other progressions will be censored
Time frame: 5 years from start of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Five Years Distant Metastasis Rate | 3.8 percentage |
Secondary
Five Years Locoregional Recurrence Rate
Time to locoregional recurrence is defined from Day 1 of treatment until the first locoregional progression
Time frame: 5 years from start of treatment
Population: Subjects started to the study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Five Years Locoregional Recurrence Rate | 19.8 percentage |
Secondary
Number of Participants With Clinically Relevant Adverse Events
Safety was assessed by documenting clinically relevant adverse events, defined as events reported by both the clinician and participant related to concurrent radiation plus pembrolizumab. Clinicians classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The grading (severity) scale for each AE term: Grade (G) 1 Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; G 2 Moderate; G 3 Severe or medically significant but not immediately life-threatening; hospitalization/prolongation of hospitalization indicated; disabling; G 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. Patient assessed toxicity were classified based on the Patient-Reported Outcome version of the CTCAE (PRO-CTCAE) which measures the severity, interference, and frequency of events on a 5 point likert scale (0-4) with a higher score indicating worse or more bothersome event
Time frame: Monitored continuously from D1 of treatment through 40 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Number of Participants With Clinically Relevant Adverse Events | Dry mouth | 24 participants |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Number of Participants With Clinically Relevant Adverse Events | Fatigue | 18 participants |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Number of Participants With Clinically Relevant Adverse Events | Pain | 10 participants |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Number of Participants With Clinically Relevant Adverse Events | Decreased appetite | 5 participants |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Number of Participants With Clinically Relevant Adverse Events | Swallowing difficulty | 12 participants |
Secondary
One Year Overall Survival Rate
the proportion of patients who are alive at one year after Day 1 of treatment
Time frame: 1 year after Day 1 of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | One Year Overall Survival Rate | 0.86 proportion of participants |
Secondary
Overall Response Rate
Overall response rate will be determined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) which defines Complete Response (CR) as Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Overall Response Rate (ORR) = CR + PR/total number of subjects.
Time frame: 2 years after start of treatment
Population: Two participants did not complete follow-up radiographic measurements to assess for response
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Overall Response Rate | 26 Participants |
Secondary
Proportion of Participants Who Received <95% of Intended Dose of Radiation
Evaluate the safety of the proposed regimen by Estimating the proportion of patients who receive \<95% of the intended dose of radiation (i.e., \<67 Gray)
Time frame: 7 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Proportion of Participants Who Received <95% of Intended Dose of Radiation | 0 proportion of participants |
Secondary
Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN)
The FACT-HN is the FACT-General (FACT-G) and a head and neck cancer specific (HNC) subscale given at baseline, at end of treatment, and at first follow-up visit. The FACT-G is a measure of general QOL with Items rated by patients on a Likert scale from 0 to 4, assessing function in 4 domains: physical well-being (PWB) (7 items, score range 0-28), social-family well-being (SFWB) (7 items, score range 0-28), emotional well-being (EWB) (6 items, score range 0-24) and functional well-being (FWB) (7 items, score range 0-28). The HNC subscale has 12 items and a score range from 0 to 48. Higher scores represent better QOL.
Time frame: At baseline, 10 and 20 weeks after initiation of treatment
Population: Three subjects did not complete the FACT assessments and are therefore not included
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | EWB | 18.12 score on a scale |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | HNC | 24.57 score on a scale |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | SFWB | 22.26 score on a scale |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | FWB | 19.00 score on a scale |
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | PWB | 23.26 score on a scale |
| Week 10 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | FWB | 14.04 score on a scale |
| Week 10 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | HNC | 14.75 score on a scale |
| Week 10 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | PWB | 17.63 score on a scale |
| Week 10 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | EWB | 17.85 score on a scale |
| Week 10 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | SFWB | 21.54 score on a scale |
| Week 20 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | PWB | 19.81 score on a scale |
| Week 20 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | SFWB | 23.40 score on a scale |
| Week 20 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | EWB | 17.59 score on a scale |
| Week 20 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | FWB | 16.74 score on a scale |
| Week 20 Assessment - Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Quality of Life Measured by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN) | HNC | 18.92 score on a scale |
Secondary
Two Year Overall Survival Rate
the proportion of patients who are alive at two years after Day 1 of treatment
Time frame: 2 years after Day 1 of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Concomitant With and Post 7 Weeks of Radiation | Two Year Overall Survival Rate | 0.75 proportion of participants |