Squamous Cell Carcinoma of the Head and Neck
Conditions
Keywords
Head and Neck Cancer, Immunotherapy, IRX-2, Mouth Cancer, Throat Cancer
Brief summary
This was a Phase 2a trial to investigate the safety and biological activity of the RIX-2 Regimen in patients with untreated, resectable squamous cell cancer of the head and neck (HNSCC).
Detailed description
IRX-2 is a primary cell-derived biologic that reduces the immune suppression that is often seen in the cancer tumor micro-environment, restores immune function and activates a coordinated immune response against the tumor. IRX-2 is a complex proprietary therapeutic containing numerous active cytokine components, which restores and activates multiple immune cell types including T cells, dendritic cells, and natural killer cells to recognize and destroy tumors. The present study administered the IRX-2 Regimen to 27 patients as a neoadjuvant (before surgery) therapy, and the main objective of the study was to determine the safety and tolerability of the IRX-2 regimen.
Interventions
BIOLOGICALIRX-2
IRX-2 for 10 days (2 s.c. injections of 1 mL each day) into bilateral mastoid insertion regions.
DRUGCyclophosphamide
Single i.v. injection of low-dose (300 mg/m2) on Day 1
DRUGIndomethacin
21 days of oral indomethacin, 25 mg. 3 times daily
DRUGZinc
21 days of zinc gluconate (65 mg) as part of an oral multivitamin
DRUGOmeprazole
21 days of 20 mg. orally
Sponsors
Brooklyn ImmunoTherapeutics, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open Label
Intervention model description
Open Label Single Arm Phase 2a trial of Safety of IRX-2 in Patients with Operable Head and Neck Cancer
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed (histology) Squamous Cell Carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. * No prior surgery, radiation therapy or chemotherapy of this tumor other than biopsy or emergency procedure required for supportive care. * Clinically staged Stage II, III, or IVA cancer, assessed to be surgically resectable with curative intent. * Life Expectancy of greater than 6 months
Exclusion criteria
* Stage IVB Squamous Cell Carcinoma * Use of any investigational agent within the previous 30 days * Uncontrolled cardiovascular disease * Myocardial infarction within the last 3 months * Abnormal hemoglobin, neutrophil, lymphocyte or platelet counts * Positive for hepatitis B or C or HIV * Evidence of distant metastases * Clinical gastritis or peptic ulcer within the last 6 months * Stroke within the last six months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events and Serious Adverse Events | Enrollment through 30 days post-surgery | The frequency of all Adverse Events (greater than 5%) is reported. All Serious Adverse Events were described. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Tolerance of Surgery and Post-operative Adjuvant Therapy; | Following surgery and post-operative therapy (up to 39 days post surgery) | Patient Tolerance of Surgery and Post-operative Adjuvant Therapy as measured by median days spent in the hospital, intensive care unit, and step down unit. |
| Immune Competence as Measured by Skin Test Reactivity | At approx. 21 days, prior to surgery | To assess measures of immune competence following administration of the IRX-2 regimen, including skin test reactivity. |
| Disease-free Survival | Time from surgery to death or clinically apparent, biopsy confirmed recurrent or progressive disease after the completion of initial therapy, assessed up to 3 years; margins of resection positive for tumor will not be considered disease recurrence | Estimate disease-free survival (DFS) (time from surgery to death or clinically apparent, biopsy confirmed recurrent or progressive disease after the completion of initial therapy, assessed up to 3 years; margins of resection positive for tumor will not be considered disease recurrence). |
| Clinical and Histological Tumor Responses | On approximately Day 21 (last day of treatment) prior to undergoing post-treatment surgery | Number of participants with the specified percent change in size of target lesion is presented |
| Number of Participants With High Lymphocyte Infiltration (LI) According to the Visual Analog Scale (VAS) | On approximately Day 21 (last day of treatment) prior to undergoing post-treatment surgery | Immunologic response features were extracted and quantified using a VAS of 0-100 mm to provide for a more continuous variable than the 0-4+ scale that is often used to assess histological responses. The scoring was such that 100 represented the maximum for any sample and 0 represented the lack of any parameter of interest. See publication of Berinstein, et al., 2012 for complete details. |
| Relationship Between Overall Survival (OS) and Immune Competence (Lymphocyte Infiltration, LI) in Participants With High LI and Low LI | At time of surgery, after treatment with IRX-2 Regimen, assessed up to 5 years | After participants completed the IRX-2 regimen and the tumor resection was performed, tumor pathology was evaluated from tissue specimens obtained at tumor resection. Formalin-fixed, paraffin-embedded blocks, or unstained slides from the primary tumor were submitted to an independent pathology laboratory for hematoxylin and eosin staining, and evaluation of lymphocyte infiltration (LI). Participants were grouped into a low LI and high LI group based on the change in lymphocyte infiltration from the pretreatment tumor biopsy to the post-treatment tumor surgical resection. 5-year overall survival probabilities were then estimated (Kaplan-Meier) between the low LI and high LI groups |
| Overall Survival | Time from surgery to death or confirmed recurrent or progressive disease, assessed up to 3 years | Estimate overall survival (OS) in patients receiving the IRX-2 regimen. IRX-2 is currently being studied in an on-going Phase 2b clinical trial in patients with newly diagnosed Stage II, III, and IVA squamous cell carcinoma of the oral cavity (INSPIRE) |
Participant flow
Recruitment details
The first subject was enrolled July 2005 and the last subject visit was August 2009.
Pre-assignment details
Pathologically confirmed (by histology) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. No prior surgery, radiation therapy, or chemotherapy of this tumor other than biopsy or emergency procedure required for supportive care. No medical contraindications to surgical resection and reconstruction required.
Participants by arm
| Arm | Count |
|---|---|
| IRX-2 Regimen The IRX-2 regimen is the combination of a 2-week course of IRX-2 itself, an initial dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | IRX-2 Regimen |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age, Continuous | 57.4 years STANDARD_DEVIATION 9.4 |
| Region of Enrollment Mexico | 1 participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 27 |
| other Total, other adverse events | 23 / 27 |
| serious Total, serious adverse events | 7 / 27 |
Outcome results
Primary
Number of Participants With Adverse Events and Serious Adverse Events
The frequency of all Adverse Events (greater than 5%) is reported. All Serious Adverse Events were described.
Time frame: Enrollment through 30 days post-surgery
Population: 27 participants were entered into study and treated. All participants were included in the safety analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Injection Site Pain | 6 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Headache | 8 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Nausea | 6 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Constipation | 4 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Dizziness | 4 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Fatigue | 3 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Pneumonia Aspiration | 3 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Anaemia | 3 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Injection Site Discomfort | 3 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Myalgia | 2 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Contusion | 2 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Dry Mouth | 2 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Adverse Event: Vomiting | 2 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Additional AE Categories w lower frequency | 4 Participants |
| IRX-2 Regimen | Number of Participants With Adverse Events and Serious Adverse Events | Serious Adverse Events | 7 Participants |
Secondary
Clinical and Histological Tumor Responses
Number of participants with the specified percent change in size of target lesion is presented
Time frame: On approximately Day 21 (last day of treatment) prior to undergoing post-treatment surgery
Population: A total of 23 subjects who received the IRX-2 regimen were evaluated for tumor response based on the RECIST criteria
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IRX-2 Regimen | Clinical and Histological Tumor Responses | -20% to < -10% | 4 Participants |
| IRX-2 Regimen | Clinical and Histological Tumor Responses | -10% to < 0% | 7 Participants |
| IRX-2 Regimen | Clinical and Histological Tumor Responses | 0% to < 10% | 9 Participants |
| IRX-2 Regimen | Clinical and Histological Tumor Responses | 10% to < 20% | 1 Participants |
| IRX-2 Regimen | Clinical and Histological Tumor Responses | 20% to < 30% | 0 Participants |
| IRX-2 Regimen | Clinical and Histological Tumor Responses | >= 30% | 2 Participants |
p-value: <0.1Spearman Rank
Secondary
Disease-free Survival
Estimate disease-free survival (DFS) (time from surgery to death or clinically apparent, biopsy confirmed recurrent or progressive disease after the completion of initial therapy, assessed up to 3 years; margins of resection positive for tumor will not be considered disease recurrence).
Time frame: Time from surgery to death or clinically apparent, biopsy confirmed recurrent or progressive disease after the completion of initial therapy, assessed up to 3 years; margins of resection positive for tumor will not be considered disease recurrence
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IRX-2 Regimen | Disease-free Survival | 1-year disease free survival probability | 0.721 DFS Probability |
| IRX-2 Regimen | Disease-free Survival | 2-year disease free survival probability | 0.641 DFS Probability |
| IRX-2 Regimen | Disease-free Survival | 3-year disease free survival probability | 0.620 DFS Probability |
Secondary
Immune Competence as Measured by Skin Test Reactivity
To assess measures of immune competence following administration of the IRX-2 regimen, including skin test reactivity.
Time frame: At approx. 21 days, prior to surgery
Population: Skin response (erythema) was evaluated at Baseline and Day 21 on 26 subjects treated with IRX-2 Regimen
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| IRX-2 Regimen | Immune Competence as Measured by Skin Test Reactivity | Positive at both Baseline and at Day 21 (%) | 12 Participants |
| IRX-2 Regimen | Immune Competence as Measured by Skin Test Reactivity | Negative at both Baseline and Day 21 (%) | 6 Participants |
| IRX-2 Regimen | Immune Competence as Measured by Skin Test Reactivity | Positive at Baseline and Negative Day 21 (%) | 6 Participants |
| IRX-2 Regimen | Immune Competence as Measured by Skin Test Reactivity | Negative at Baseline and Positive at Day 21 | 2 Participants |
| IRX-2 Regimen | Immune Competence as Measured by Skin Test Reactivity | Induration at Day 21 | 3 Participants |
Secondary
Number of Participants With High Lymphocyte Infiltration (LI) According to the Visual Analog Scale (VAS)
Immunologic response features were extracted and quantified using a VAS of 0-100 mm to provide for a more continuous variable than the 0-4+ scale that is often used to assess histological responses. The scoring was such that 100 represented the maximum for any sample and 0 represented the lack of any parameter of interest. See publication of Berinstein, et al., 2012 for complete details.
Time frame: On approximately Day 21 (last day of treatment) prior to undergoing post-treatment surgery
Population: Number of patients with high lymphocyte infiltration (LI).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IRX-2 Regimen | Number of Participants With High Lymphocyte Infiltration (LI) According to the Visual Analog Scale (VAS) | 18 participants with high LI (>34 mm) VAS |
Secondary
Overall Survival
Estimate overall survival (OS) in patients receiving the IRX-2 regimen. IRX-2 is currently being studied in an on-going Phase 2b clinical trial in patients with newly diagnosed Stage II, III, and IVA squamous cell carcinoma of the oral cavity (INSPIRE)
Time frame: Time from surgery to death or confirmed recurrent or progressive disease, assessed up to 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IRX-2 Regimen | Overall Survival | First Year (%) | 92 percentage of subjects |
| IRX-2 Regimen | Overall Survival | Second Year (%) | 73 percentage of subjects |
| IRX-2 Regimen | Overall Survival | Third Year (%) | 69 percentage of subjects |
Secondary
Patient Tolerance of Surgery and Post-operative Adjuvant Therapy;
Patient Tolerance of Surgery and Post-operative Adjuvant Therapy as measured by median days spent in the hospital, intensive care unit, and step down unit.
Time frame: Following surgery and post-operative therapy (up to 39 days post surgery)
Population: Following surgery the median days spent in the hospital, intensive care unit and step down unit was determined for 26 subjects
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IRX-2 Regimen | Patient Tolerance of Surgery and Post-operative Adjuvant Therapy; | Median Days in hospital | 8.5 days |
| IRX-2 Regimen | Patient Tolerance of Surgery and Post-operative Adjuvant Therapy; | Median Days in intensive care unit | 0.5 days |
| IRX-2 Regimen | Patient Tolerance of Surgery and Post-operative Adjuvant Therapy; | Median Days in step-down unit | 0.5 days |
Secondary
Relationship Between Overall Survival (OS) and Immune Competence (Lymphocyte Infiltration, LI) in Participants With High LI and Low LI
After participants completed the IRX-2 regimen and the tumor resection was performed, tumor pathology was evaluated from tissue specimens obtained at tumor resection. Formalin-fixed, paraffin-embedded blocks, or unstained slides from the primary tumor were submitted to an independent pathology laboratory for hematoxylin and eosin staining, and evaluation of lymphocyte infiltration (LI). Participants were grouped into a low LI and high LI group based on the change in lymphocyte infiltration from the pretreatment tumor biopsy to the post-treatment tumor surgical resection. 5-year overall survival probabilities were then estimated (Kaplan-Meier) between the low LI and high LI groups
Time frame: At time of surgery, after treatment with IRX-2 Regimen, assessed up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IRX-2 Regimen | Relationship Between Overall Survival (OS) and Immune Competence (Lymphocyte Infiltration, LI) in Participants With High LI and Low LI | 0.80 5-Year OS Probability |
| Low Lymphocyte Infiltration | Relationship Between Overall Survival (OS) and Immune Competence (Lymphocyte Infiltration, LI) in Participants With High LI and Low LI | 0.50 5-Year OS Probability |