Head and Neck Cancer
Conditions
Keywords
Head and Neck Cancer
Brief summary
This research study is studying immunotherapy in combination with radiation therapy as a possible treatment for head & neck cancer that has worsened or spread to another organ or part of your body. The immunotherapy involved in this study is: MK-3475 (pembrolizumab or KEYTRUDA).
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational treatment to learn whether the treatment works in treating a specific disease. "Investigational" means that the treatment is being studied. MK-3475 is a humanized monoclonal antibody. An antibody is a common type of protein made in the body in response to a foreign substance (particles not typically found in the body such as bacteria or viruses). Antibodies attack foreign substances and protect against infection. Antibodies can also be produced in the laboratory for use in treating patients. MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells. The FDA recently granted approval to MK-3475 as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). This study is testing whether using radiation in combination with MK-3475 will make this drug work better in participants that might otherwise be unlikely to benefit from this drug because they have not responded to either this same drug given without radiation or another similar drug.
Interventions
DRUGPembrolizumab
Keytruda is designed to restore the natural ability of the immune system to recognize and target cancer cells
RADIATIONRadiation
Radiation is used to shrink the cancer
Sponsors
Dana-Farber Cancer Institute
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed squamous cell carcinoma of the head and neck with evidence of metastatic disease considered incurable by local therapies. Patients without pathologic or cytologic evidence of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation. * Patients must have evidence of radiologic or clinical disease progression during previous treatment with systemic PD-1 directed therapy, or have stable disease on prior PD-1 therapy (at least 6 doses) and/or have been deemed not to derive clinical benefit from PD-1 directed treatment. * Patients must have least 3 measurable non-CNS based lesions that have not previously been irradiated. Palliative radiation must be potentially indicated for at least one of these lesions. * Patients must agree to undergo a research biopsy, if tumor is accessible, at baseline (mandatory) and at the end of cycle 2 of pembrolizumab (optional). . * Prior systemic therapy: Patients must be at least 2 weeks from prior chemotherapy, biological agents, immunotherapy or any investigational drug product, with adequate recovery of toxicity. For investigational agents, the minimum time from prior therapy is 5 half-lives if this is longer than 2 weeks in duration. * Prior radiation therapy: Patients must be at least 2 weeks from prior radiation therapy * Concurrent administration of other cancer specific therapy during the course of this study is not allowed. * 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 (see Appendix A). * Ability to understand and the willingness to sign a written informed consent document * Female subjects of childbearing potential must have a negative serum pregnancy test at screening. * Female and male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in section 5.7.1. Contraception is required prior to study entry and for the duration of study participation and 4 months after completion of pembrolizumab administration. --Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. * Participants must have normal organ and marrow function as defined below: * leukocytes ≥3,000/mcl * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * hemoglobin \>= 9 g/dl * total bilirubin ≤1.5 × institutional upper limit of normal (ULN) * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN * AST(SGOT)/ALT(SGPT) For patients with documented liver metastases, ≤ 5 × institutional ULN * creatinine ≤1.5 ×within normal institutional ULN OR * creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional ULN. * International normalized ratio (INR) or Prothrombin Time (PT) \<1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants. * Activated Partial Thromboplastin Time (aPTT) \<1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants. * Laboratory tests required for eligibility must be completed within 14 days prior study entry. Baseline tumor measurements must be documented from tests within 28 days of study entry. Other non-laboratory tests must be performed within 28 days of study entry.
Exclusion criteria
* Metastatic disease impinging on the spinal cord or threatening spinal cord compression. * Surgical fixation of bone lesion to be irradiated is required and indicated to provide mechanical stability. * Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least 2 weeks prior to trial therapy initiation, are neurologically stable, and have recovered from the acute effects of radiotherapy or surgery. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks before the initiating protocol therapy. Treatment for brain metastases may include surgery, whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician. * Participants who are receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or previous toxicity attributed to pembrolizumab or other PD-1 directed therapy that led to drug discontinuation. * 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. * Clinically significant electrocardiogram (ECG) abnormality, including a marked Baseline prolonged QT/QTc (\[QT interval/corrected QT interval\], e.g., a repeated demonstration of a QTc interval \>500 ms). * Pregnant women are excluded from this study because immunotherapy has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with immunotherapy, breastfeeding should be discontinued if the mother is treated on this protocol. * 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 for cervical cancer in situ or basal cell or squamous cell carcinoma of the skin. * HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for interaction between immunotherapy and these medications. * Has history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non infectious pneumonitis. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Surival | 1 year | The primary endpoint of this study is progression-free survival (PFS) rate at 3 months. Patients are considered progression-free at 3 months if progression is not observed at the 3-month disease assessment. PFS is defined as the time from registration to disease progression per RECIST or death, whichever occurred first. Progressive Disease is defined as at least a 20% increase in the sum of diameters of target lesions, which must also demonstrate an absolute increase of at least 5 mm (with reference to the smallest sum on study). The appearance of one or more new lesions is also considered progressions (RECIST guidelines version 1.1). |
Secondary
| Measure | Time frame |
|---|---|
| Overall Survival | 1 year |
| Overall Response Rate | 1 year |
| Number of Patients With Treatment Related Adverse Events as Assessed by CTCAE v4.0 | 1 year |
| Objective Response by Immune Related Response Criteria (irRC) | 1 year |
| Local Response Determined Using CT Imaging | 1 year |
| Clinical Benefit Rate | 1 year |
| Abscopal Response Determined Using CT Imaging | 1 year |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJonathan D. Schoenfeld, MD MPH
Dana-Farber Cancer Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High Dose Radiation + Pembrolizumab * High dose radiation will be given in 3 fractions
* Pembrolizumab administered intravenously on day one of each cycle.
Pembrolizumab: Keytruda is designed to restore the natural ability of the immune system to recognize and target cancer cells
Radiation: Radiation is used to shrink the cancer | 6 |
| High Dose + Low Dose Radiation + Pembrolizumab * High Dose radiation will be given in 3 fractions
* Low Dose Radiation will be given in 2 fractions
* Pembrolizumab administered intravenously on day one of each cycle.
Pembrolizumab: Keytruda is designed to restore the natural ability of the immune system to recognize and target cancer cells
Radiation: Radiation is used to shrink the cancer | 12 |
| Total | 18 |
Baseline characteristics
| Characteristic | High Dose Radiation + Pembrolizumab | High Dose + Low Dose Radiation + Pembrolizumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 9 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 3 Participants | 8 Participants |
| Age, Continuous | 59 years | 67 years | 65.5 years |
| Disease Site Hypopharynx | 1 Participants | 2 Participants | 3 Participants |
| Disease Site Larynx | 1 Participants | 1 Participants | 2 Participants |
| Disease Site Oral Cavity | 1 Participants | 2 Participants | 3 Participants |
| Disease Site Oropharynx | 3 Participants | 6 Participants | 9 Participants |
| Disease Site Other | 0 Participants | 1 Participants | 1 Participants |
| Disease Stage Missing | 0 Participants | 1 Participants | 1 Participants |
| Disease Stage Stage III | 1 Participants | 2 Participants | 3 Participants |
| Disease Stage Stage IV | 5 Participants | 9 Participants | 14 Participants |
| ECOG PS 0 | 0 Participants | 2 Participants | 2 Participants |
| ECOG PS 1 | 6 Participants | 9 Participants | 15 Participants |
| ECOG PS 2 | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 11 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HIV Status Negative | 6 Participants | 11 Participants | 17 Participants |
| HIV Status Unknown | 0 Participants | 1 Participants | 1 Participants |
| HPV Status Negative | 1 Participants | 3 Participants | 4 Participants |
| HPV Status Positive | 3 Participants | 5 Participants | 8 Participants |
| HPV Status Unknown | 2 Participants | 4 Participants | 6 Participants |
| M Stage M0 | 3 Participants | 6 Participants | 9 Participants |
| M Stage M1 | 1 Participants | 5 Participants | 6 Participants |
| M Stage Missing | 2 Participants | 1 Participants | 3 Participants |
| N Stage Missing | 0 Participants | 1 Participants | 1 Participants |
| N Stage N0 | 0 Participants | 1 Participants | 1 Participants |
| N Stage N1 | 0 Participants | 1 Participants | 1 Participants |
| N Stage N2 | 6 Participants | 7 Participants | 13 Participants |
| N Stage N3 | 0 Participants | 1 Participants | 1 Participants |
| N Stage NX | 0 Participants | 1 Participants | 1 Participants |
| Pathology Other | 0 Participants | 0 Participants | 0 Participants |
| Pathology Squamous Cell Carcinoma | 6 Participants | 12 Participants | 18 Participants |
| Prior IO Therapy Type Nivolumab | 3 Participants | 3 Participants | 6 Participants |
| Prior IO Therapy Type Nivolumab/Lirilumab | 1 Participants | 8 Participants | 9 Participants |
| Prior IO Therapy Type Other | 0 Participants | 1 Participants | 1 Participants |
| Prior IO Therapy Type Pembrolizumab | 2 Participants | 0 Participants | 2 Participants |
| Prior Treatment Chemotherapy | 5 Participants | 12 Participants | 17 Participants |
| Prior Treatment Radiation Therapy | 6 Participants | 11 Participants | 17 Participants |
| Prior Treatment Surgery | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 9 Participants | 14 Participants |
| Region of Enrollment United States | 6 Participants | 12 Participants | 18 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 16 Participants |
| Smoking Status Current Smoker | 0 Participants | 3 Participants | 3 Participants |
| Smoking Status Former Smoker | 5 Participants | 4 Participants | 9 Participants |
| Smoking Status Never Smoked | 1 Participants | 5 Participants | 6 Participants |
| T Stage Missing | 0 Participants | 1 Participants | 1 Participants |
| T Stage T1 | 1 Participants | 1 Participants | 2 Participants |
| T Stage T2 | 1 Participants | 2 Participants | 3 Participants |
| T Stage T3 | 2 Participants | 3 Participants | 5 Participants |
| T Stage T4 | 1 Participants | 3 Participants | 4 Participants |
| T Stage TX | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 10 / 12 |
| other Total, other adverse events | 4 / 6 | 12 / 12 |
| serious Total, serious adverse events | 3 / 6 | 7 / 12 |
Outcome results
Primary
Progression-Free Surival
The primary endpoint of this study is progression-free survival (PFS) rate at 3 months. Patients are considered progression-free at 3 months if progression is not observed at the 3-month disease assessment. PFS is defined as the time from registration to disease progression per RECIST or death, whichever occurred first. Progressive Disease is defined as at least a 20% increase in the sum of diameters of target lesions, which must also demonstrate an absolute increase of at least 5 mm (with reference to the smallest sum on study). The appearance of one or more new lesions is also considered progressions (RECIST guidelines version 1.1).
Time frame: 1 year
Population: The groups of 'High Dose Radiation + Pembrolizumab' and 'High Dose + Low Dose Radiation + Pembrolizumab' listed under Primary Outcome were the predefined groups in the study protocol; this was not a dose escalation study for pembrolizumab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Radiation + Pembrolizumab | Progression-Free Surival | 1 Participants |
| High Dose + Low Dose Radiation + Pembrolizumab | Progression-Free Surival | 8 Participants |
Secondary
Abscopal Response Determined Using CT Imaging
Time frame: 1 year
Secondary
Clinical Benefit Rate
Time frame: 1 year
Secondary
Local Response Determined Using CT Imaging
Time frame: 1 year
Secondary
Number of Patients With Treatment Related Adverse Events as Assessed by CTCAE v4.0
Time frame: 1 year
Secondary
Objective Response by Immune Related Response Criteria (irRC)
Time frame: 1 year
Secondary
Overall Response Rate
Time frame: 1 year
Secondary
Overall Survival
Time frame: 1 year