Cancer of Anus, Cancer of Cervix, Cancer of Head and Neck
Conditions
Keywords
HPV Related Head and Neck, Cervical, Anal Cancer
Brief summary
This research study is studying a therapeutic vaccine, named DPX-E7, as a possible treatment for Human Papilloma Virus or HPV related head and neck, cervical or anal cancer (positive for HLA-A\*02).
Detailed description
This is a phase Ib/II clinical trial. DPX-E7 is a therapeutic vaccine, intended to treat HPV-related head and neck, cervical or anal cancer. DPX-E7 is an investigational vaccine and the FDA (the U.S. Food and Drug Administration) has not approved DPX-E7 vaccine as a treatment for any disease. DPX-E7 is being tested in humans for the first time. DPX-E7 is a kind of immunotherapy that will make the immune system to elicit an anti-tumor response by generating CD8+ T-cells. CD8+ T-cells play a very important role in fighting against viral infections
Interventions
DRUGDPX-E7 vaccine
Therapeutic vaccine for the treatment of incurable HPV16-related oropharyngeal, cervical and anal cancer in HLA-A\*02 positive patients.
DRUGCyclophosphamide
Cyclophosphamide is a medication primarily used in the management and treatment of neoplasms, including multiple myeloma, sarcoma, and breast cancer. Cyclophosphamide is a nitrogen mustard that exerts its anti-neoplastic effects through alkylation.
Sponsors
Stand Up To Cancer
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Each patient must be positive for HLA-A\*02 and meet all of the following inclusion criteria to be enrolled in the study: * Histologically or cytologically proven HPVOC or cervical cancer or anal cancer, based on expression of HPV type16 in immunohistochemistry and/or HPV 16 DNA analysis by ISH of tumor tissue from the primary or metastatic lesions. * Incurable HPVOC, as defined by: * Relapsed or progressive disease at the primary site and/or regional lymph nodes after initial treatment (e.g. Surgery, radiotherapy or chemoradiotherapy) with no potentially curative option (i.e. surgery or radiation); OR * Distant metastasis * Incurable cervical or anal cancer, as defined by: * Relapsed or progressive disease at the primary site and/or regional lymph nodes after initial treatment (e.g. systemic chemotherapy) with no potentially curative option (i.e. surgery or chemoradiotherapy). Chemotherapy administered in conjunction with primary radiation as a radiosensitizer will not be counted as a systemic chemotherapy regimen; OR * Distant metastasis refractory to initial treatment (at least one prior chemotherapeutic regimen which can include a single chemotherapeutic, a combination of chemotherapeutics, or biologic drugs such as bevacizumab). * Accessible tumors for sequential biopsies Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.03) to grade 1 or better (except for \< grade 2 neuropathy, alopecia, xerostomia, dysphagia, or mucositis); * Age ≥ 18 years; * Measurable disease, according to modified RECIST 1.1 and irRECIST (Appendix B & C); * Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 (Appendix A) * Adequate bone marrow, liver and renal function, defined by: * Hemoglobin ≥ 10 g/dL; * Absolute neutrophil count (ANC) ≥ 1000/μL; * Absolute lymphocyte count ≥ 400/μL; * Platelet count ≥ 100,000/μL; * ALT and AST ≤ 2.5 X upper limit of normal (ULN); * Total bilirubin ≤ 1.5 X ULN; and * Serum creatinine ≤ 1.5 X ULN; * Women of child-bearing potential (WOCBP) must be willing to use acceptable means of birth control; * Men who could potentially father a child must also use birth control * Signed informed consent
Exclusion criteria
* Radiotherapy for primary HPVOC within 8 weeks, or radiotherapy for any other reason within 3 weeks prior to the first dose of trial treatment; * Chemotherapy within 3 weeks prior to the first dose of trial treatment;Other cancer in the past 5 years, except for carcinoma in situ of the cervix or bladder, or non-melanomatous skin cancer; * Inaccessible tumor or lack of consent for sequential biopsies * Uncontrolled central nervous system (CNS) metastases (i.e. known CNS lesions that are radiographically unstable, symptomatic and/or requiring escalating doses of corticosteroids); * Active hepatitis, known HIV, or other condition that requires immunosuppressive therapy, including current use of high dose systemic corticosteroids; * Autoimmune disease, such as systemic lupus erythematosis or rheumatoid arthritis, that is active and requires current immunosuppressive therapy; * Active uncontrolled serious infection; * WOCBP who have a positive β-hCG test or are breastfeeding. * Acute or chronic skin disorders that would interfere with subcutaneous injection of the vaccine or subsequent assessment of potential skin reactions; * Allergies to any vaccine, that after discussion with Immunovaccine, are serious enough to warrant exclusion from this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) [Phase 1b] | Patients were followed for 50 days. | A DLT was defined as any grade 3 or greater adverse event at least possibly related to the study agent including injection site reactions; or grade 2 or greater allergic reactions which occur in a subject prior to day 50, will trigger DLT. In addition, to be considered as DLT, the adverse event must be considered at least possibly related to study treatment. Grade 3 or greater abnormal lab values lasting \<= 72 hours might be excluded as DLTs if there are no accompanying clinical signs and symptoms per investigator's discretion. |
| Grade 1-2 Treatment-Related AE Rate | The median follow up was 2.92 months (range 1.25 - 5.88months). | The proportion of participants who experienced grade 1-2 treatment-related adverse events based on the Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAEv4) as reported on case report forms. |
| Changes in CD8+ T Cells in Peripheral Blood and Tumor Tissue | Patients were followed 22 days. | 'Responders' will be defined as patients with at least a two-fold increase in the number of CD 8+ T cells (dextramer, ELISpot or both methods) in the peripheral blood and tissue at the final analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response | The median follow up was 2.92 months (range 1.25 - 5.88months). | Best Overall Response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started) based on modified RECIST 1.1 and irRECIST. Per irRECIST, CR was defined as disappearance of all lesions in two consecutive observations not less than four weeks apart; PR was defined as greater than or equal to 50% decrease in tumor burden compared with baseline in two observations at least four weeks apart. |
| Time to Progression (TTP) | The median follow up was 4.8 months (range 1.6 - 14.9 months). | TTP is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study. Participants alive without PD were censored at the earliest of the date of the last disease evaluation. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study or the appearance of one or more new lesions. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
| Median Overall Survival | The median follow up was 4.8 months (range 1.6 - 14.9 months). | Overall survival based on the Kaplan-Meier method is defined as the time the start of treatment to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant. |
| Median Progression-Free Survival | The median follow up was 4.8 months (range 1.6 - 14.9 months). | PFS is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study or the appearance of one or more new lesions. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from 3/30/17 until 9/10/19.
Participants by arm
| Arm | Count |
|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] Participants received: 1) 50 mg twice per day of cyclophosphamide orally 7 days before the vaccination, continuing for 7 days on and then 7 days off, throughout the treatment period; 2) two 0.25 mL priming doses of DPX-E7 3 weeks apart, followed by 0.1 mL booster dose every 8 weeks until clinical progression. | 6 |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] Participants were enrolled before amendment 10. Participants received: 1) 50 mg twice per day of cyclophosphamide orally 7 days before the vaccination, continuing for 7 days on and then 7 days off, throughout the treatment period; 2) two 0.25 mL priming doses of DPX-E7 3 weeks apart, followed by 0.1 mL booster dose every 8 weeks until clinical progression. | 3 |
| DPX-E7 [Phase II Cohort 2] Participants were enrolled after amendment 10. Participants received two 0.50 mL priming doses of DPX-E7 3 weeks apart, followed by 0.2 mL booster dose every 8 weeks until clinical progression. | 2 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Progression | 6 | 2 | 2 |
Baseline characteristics
| Characteristic | DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | DPX-E7 [Phase II Cohort 2] | DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Total |
|---|---|---|---|---|
| Age, Continuous | 54.1 years STANDARD_DEVIATION 9.29 | 69.5 years STANDARD_DEVIATION 1.76 | 52.5 years STANDARD_DEVIATION 11.9 | 56.1 years STANDARD_DEVIATION 11.5 |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) ECOG PS0 | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) ECOG PS1 | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) ECOG PS2 | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 6 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants | 8 Participants |
| Site of Disease Anal | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Site of Disease Cervical | 1 Participants | 2 Participants | 5 Participants | 8 Participants |
| Site of Disease Oropharyngeal | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 2 / 3 | 0 / 2 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 2 / 6 | 0 / 3 | 1 / 2 |
Outcome results
Primary
Changes in CD8+ T Cells in Peripheral Blood and Tumor Tissue
'Responders' will be defined as patients with at least a two-fold increase in the number of CD 8+ T cells (dextramer, ELISpot or both methods) in the peripheral blood and tissue at the final analysis.
Time frame: Patients were followed 22 days.
Population: Data were not collected for participants who registered after amendment 10.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Changes in CD8+ T Cells in Peripheral Blood and Tumor Tissue | Responders | 16.7 percentage of participants |
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Changes in CD8+ T Cells in Peripheral Blood and Tumor Tissue | Non-responder | 83.3 percentage of participants |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Changes in CD8+ T Cells in Peripheral Blood and Tumor Tissue | Responders | 0 percentage of participants |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Changes in CD8+ T Cells in Peripheral Blood and Tumor Tissue | Non-responder | 100 percentage of participants |
Primary
Grade 1-2 Treatment-Related AE Rate
The proportion of participants who experienced grade 1-2 treatment-related adverse events based on the Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAEv4) as reported on case report forms.
Time frame: The median follow up was 2.92 months (range 1.25 - 5.88months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Grade 1-2 Treatment-Related AE Rate | 0.66 proportion of participants |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Grade 1-2 Treatment-Related AE Rate | 1 proportion of participants |
| DPX-E7 [Phase II Cohort 2] | Grade 1-2 Treatment-Related AE Rate | 1 proportion of participants |
Primary
Number of Participants With Dose Limiting Toxicity (DLT) [Phase 1b]
A DLT was defined as any grade 3 or greater adverse event at least possibly related to the study agent including injection site reactions; or grade 2 or greater allergic reactions which occur in a subject prior to day 50, will trigger DLT. In addition, to be considered as DLT, the adverse event must be considered at least possibly related to study treatment. Grade 3 or greater abnormal lab values lasting \<= 72 hours might be excluded as DLTs if there are no accompanying clinical signs and symptoms per investigator's discretion.
Time frame: Patients were followed for 50 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Number of Participants With Dose Limiting Toxicity (DLT) [Phase 1b] | 0 Participants |
Secondary
Best Overall Response
Best Overall Response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started) based on modified RECIST 1.1 and irRECIST. Per irRECIST, CR was defined as disappearance of all lesions in two consecutive observations not less than four weeks apart; PR was defined as greater than or equal to 50% decrease in tumor burden compared with baseline in two observations at least four weeks apart.
Time frame: The median follow up was 2.92 months (range 1.25 - 5.88months).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Best Overall Response | Unevaluable | 0 Participants |
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Best Overall Response | PD | 4 Participants |
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Best Overall Response | SD | 2 Participants |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Best Overall Response | Unevaluable | 1 Participants |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Best Overall Response | SD | 1 Participants |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Best Overall Response | PD | 1 Participants |
| DPX-E7 [Phase II Cohort 2] | Best Overall Response | PD | 2 Participants |
| DPX-E7 [Phase II Cohort 2] | Best Overall Response | SD | 0 Participants |
| DPX-E7 [Phase II Cohort 2] | Best Overall Response | Unevaluable | 0 Participants |
Secondary
Median Overall Survival
Overall survival based on the Kaplan-Meier method is defined as the time the start of treatment to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant.
Time frame: The median follow up was 4.8 months (range 1.6 - 14.9 months).
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Median Overall Survival | 16.5 Months |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Median Overall Survival | 4.8 Months |
| DPX-E7 [Phase II Cohort 2] | Median Overall Survival | NA Months |
Secondary
Median Progression-Free Survival
PFS is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Participants alive without PD were censored at the earliest of the date of the last disease evaluation or start of new anticancer therapy. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study or the appearance of one or more new lesions. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: The median follow up was 4.8 months (range 1.6 - 14.9 months).
Population: The analysis dataset is comprised of all enrolled participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Median Progression-Free Survival | 2.9 Months |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Median Progression-Free Survival | 3.3 Months |
| DPX-E7 [Phase II Cohort 2] | Median Progression-Free Survival | 1.4 Months |
Secondary
Time to Progression (TTP)
TTP is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study. Participants alive without PD were censored at the earliest of the date of the last disease evaluation. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study or the appearance of one or more new lesions. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
Time frame: The median follow up was 4.8 months (range 1.6 - 14.9 months).
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DPX-E7 + Cyclophosphamide [Phase Ib Cohort] | Time to Progression (TTP) | 2.9 Months |
| DPX-E7 + Cyclophosphamide [Phase II Cohort 1] | Time to Progression (TTP) | 3.3 Months |
| DPX-E7 [Phase II Cohort 2] | Time to Progression (TTP) | 1.4 Months |