Pancreatic Cancer
Conditions
Keywords
Metastatic, Pancreas, Adenocarcinoma
Brief summary
The purpose of the study is to assess the safety of injections of talimogene laherparepvec into patients with pancreatic cancer that cannot be removed by surgery. The study will also test whether the injections are effective in treating the tumor.
Detailed description
Talimogene laherparepvec is a conditionally replication competent herpes simplex type-1 virus designed for use in solid tumors. It has been specifically modified to replicate in tumors and to provide a local source of the immune-stimulating cytokine, granulocyte macrophage colony stimulating factor (GM-CSF). It is injected directly into cancer tumors and is believed to destroy tumor cells by direct infection of the tumor cells and an enhanced immune response due to the release of tumor antigens and GM-CSF expression. This was an open-label, dose-escalation study evaluating the safety and efficacy of talimogene laherparepvec administered by direct injection into pancreatic tumors using endoscopic ultrasound (EUS)-guided fine needle injection (FNI). Only 1 tumor mass within the body and tail of the pancreas was injected in any participant. The protocol called for evaluation of 4 dosing regimens in sequential cohorts of participants; however, cohort 4 was not opened for enrollment.
Interventions
BIOLOGICALTalimogene Laherparepvec
Talimogene laherparepvec administered by direct injection into pancreatic tumors using EUS-guided FNI, up to a maximum of 4 mL per treatment.
Sponsors
BioVex Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* cytological or histological proof of adenocarcinoma of the pancreas * unresectable, locally advanced disease (isolated liver metastases are permitted) * tumors of at least 1 cm diameter at screening * measurable disease using Response Evaluation Criteria In Solid Tumors (RECIST) criteria * failure of either standard therapy, OR any one of the following: * no alternative therapeutic of higher curative potential is available; * investigator determination that patient could not tolerate alternative therapeutic due to unacceptable toxicity; or, * patient refusal to be treated with available alternative therapeutic * age \> 18 years * life expectancy \> 3 months * adequate bone marrow function as indicated by: * White blood cells (WBC) ≥ 3.0 x 10\^9/L * platelets ≥ 100 x 10\^9/L * hemoglobin ≥ 8.5 gm/dL * adequate liver function as indicated by: * bilirubin \< 1.5 x upper limit of normal (ULN) * alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \< 5 x ULN in case of presence of liver metastasis * ALT or AST \< 2.5 x ULN in case of absence of liver metastasis * adequate renal function as indicated by a serum creatinine level \< 1.5 x ULN. * adequate hemostasis indicated by international normalized ratio (INR) ≤ 1.5 * mentally, physically and geographically able to undergo treatment and follow-up * provided written informed consent * first patient in each cohort only: seropositive for herpes simplex virus type 1 (HSV1)
Exclusion criteria
* history of other malignancy within two years prior to screening, except for prostate cancer (T1c, T2ab with definitive treatment, prostate-specific antigen (PSA) \< 1 ng/ml, and without ongoing hormone suppression) or adequately treated in situ carcinoma of the cervix, basal cell carcinoma, or squamous cell carcinoma of the skin * cystic form of pancreatic cancer; microcystic disease may be eligible upon discussion with Medical Monitor * Common Terminology Criteria for Adverse Events (CTCAE) version 3 grade 2 or greater clinical pancreatitis within 8 weeks prior to dosing with OncoVEX\^GM-CSF * other than metastases limited to the liver, imaging evidence of metastatic disease to any other organ or tissue * any serious concomitant systemic disorder that would compromise the safety of the patient, at the discretion of the investigator * evidence of compromised immune function including but not limited to: * clinically significant absolute lymphocyte count \< Lower Limit of Normal (LLN) * known human immunodeficiency virus (HIV), acute or chronic active hepatitis B, or hepatitis C infection; * concurrently taking HIV antiviral medications (e.g. protease inhibitors, azidothymidine, etc.) * received intravenous (IV), intramuscular (IM) or subcutaneous (SC) human gamma globulin within 6 months prior to dosing with OncoVEX\^GM-CSF * patients taking immunosuppressive agents (e.g. cyclosporine, tacrolimus, or oral or systemic corticosteroids at a dose of \> 10 mg/day of prednisone or equivalent). * pregnancy, lactation or lack of effective contraception in women of child-bearing potential (e.g., not post menopausal for \> 2 years, or had tubal ligation); lack of effective contraception in men if the partner is of child-bearing potential; women must have been practicing an effective contraceptive method for at least three months prior to entry in to the trial (hormonal contraception or intrauterine device in conjunction with a barrier method); men must use a condom or be surgically sterilized * patients with active bacterial or viral infections that require treatment with systemic antibiotics or antiviral agents within 2 weeks prior to the first dose of OncoVEX\^GM-CSF); (note: patients with active cold sores or other HSV1 infections must wait until those lesions have crusted over before receiving OncoVEX\^GM-CSF) * surgery requiring general or spinal anesthesia within four weeks prior to dosing with OncoVEX\^GM-CSF * Treatment with an investigational agent within 4 weeks prior to the first dose of OncoVEX\^GM-CSF * serum carbohydrate antigen (CA)19.9 levels \> 3000 U/mL at screening * evidence of ascites on screening abdominal computed tomography (CT) scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From first dose of talimogene laherparepvec until 30 days after the last dose; the median duration of treatment was 44.0 days, 22.0 days, and 11.5 days in each group respectively. | A serious adverse event is defined as any untoward medical occurrence that at any dose results in death, is life threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important and significant medical event that, based upon appropriate medical judgment, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed above. |
| Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Treatment Day 1 predose and 2, 6, 12 and 24 hours postdose, and Week 3 and 6 at (predose and 2 hours postdose. | Samples of blood and urine collected before and up to 24 hours after dosing were tested for the presence of talimogene laherparepvec deoxyribonucleic acid (DNA) using a validated quantitative polymerase chain reaction (qPCR) assay. |
| Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Week 0 (Day 1, predose) and Week 3 | Anti-HSV-1 antibodies were detected using an enzyme-linked immunosorbent assay (ELISA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sum of Longest Diameters of Injected Tumors | Baseline and Week 6, 12 and 18 | Spiral computed tomography (CT) scans were performed to assess tumors at screening and at Weeks 6, 12 and 18 after the initial dose. |
| Number of Participants With Overall Objective Response | Every 6 weeks until 12 weeks after the last dose; the median duration of treatment was 44.0 days, 22.0 days, and 11.5 days in each group respectively. | Tumor response was assessed via CT scan by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 guidelines. Objective response is defined as a complete response (CR) or partial response (PR). CR: Disappearance of all target and non-target lesions, normalization of tumor marker level and no new lesions and with confirmation no less than 4 weeks after the criteria for CR is first met. PR: At least a 30% decrease in the sum of longest diameters of target lesions taking as reference the baseline sum of the longest diameters, absence of non-target lesion progression, and no new lesions. These criteria must be confirmed no less than 4 weeks after they are first met. |
| Change From Baseline in Pain Intensity | Baseline and Weeks 3 and 6 | Pain was assessed by the participant using a validated Visual Analog Scale (VAS) pain assessment instrument. A single 10-cm line was used with the leftmost end (0 cm) representing no pain and the rightmost end (10 cm) representing worst pain. The distance was measured from the leftmost part of the scale to the mark made by the participant indicating pain level. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled sequentially into each dose cohort.
Participants by arm
| Arm | Count |
|---|---|
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL Participants received 3 doses of talimogene laherparepvec; an initial dose of 10⁴PFU/mL followed by 2 doses of 10⁵ PFU/mL, each 3 weeks apart.
At the discretion of the investigator, treatment with talimogene laherparepvec could continue beyond the third dose until Week 15 in a regimen of at least 3 weeks between doses. | 3 |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL Participants received 3 doses of talimogene laherparepvec; an initial dose of 10⁵ PFU/mL followed by 2 doses of 10⁶ PFU/mL, each 3 weeks apart.
At the discretion of the investigator, treatment with talimogene laherparepvec could continue beyond the third dose until Week 15 in a regimen of at least 3 weeks between doses. | 4 |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL Participants received 3 doses of talimogene laherparepvec; an initial dose of 10⁶ PFU/mL followed by 2 doses of 10⁷ PFU/mL, each 3 weeks apart.
At the discretion of the investigator, treatment with talimogene laherparepvec could continue beyond the third dose until Week 15 in a regimen of at least 3 weeks between doses. | 10 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 |
| Overall Study | Death | 0 | 1 | 5 |
| Overall Study | Disease Progression | 1 | 1 | 2 |
| Overall Study | Participant Decision | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Total |
|---|---|---|---|---|
| Age, Continuous | 54.7 years STANDARD_DEVIATION 10.97 | 63.8 years STANDARD_DEVIATION 10.21 | 50.8 years STANDARD_DEVIATION 6.68 | 54.5 years STANDARD_DEVIATION 9.47 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 1 participants | 0 participants | 2 participants | 3 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 1 participants | 3 participants | 7 participants | 11 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 1 participants | 1 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White | 2 participants | 3 participants | 8 participants | 13 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 10 / 10 |
| serious Total, serious adverse events | 2 / 3 | 3 / 4 | 9 / 10 |
Outcome results
Primary
Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies
Anti-HSV-1 antibodies were detected using an enzyme-linked immunosorbent assay (ELISA).
Time frame: Week 0 (Day 1, predose) and Week 3
Population: ITT population with available antibody results (indicated by N)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Baseline (predose) (N= 3, 3, 8) | 2 participants |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Week 3 (N=3, 3, 6) | 3 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Baseline (predose) (N= 3, 3, 8) | 3 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Week 3 (N=3, 3, 6) | 3 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Baseline (predose) (N= 3, 3, 8) | 6 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants Positive for Anti-herpes Simplex Virus-1 (HSV-1) Antibodies | Week 3 (N=3, 3, 6) | 6 participants |
Primary
Number of Participants With Adverse Events
A serious adverse event is defined as any untoward medical occurrence that at any dose results in death, is life threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an important and significant medical event that, based upon appropriate medical judgment, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed above.
Time frame: From first dose of talimogene laherparepvec until 30 days after the last dose; the median duration of treatment was 44.0 days, 22.0 days, and 11.5 days in each group respectively.
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Adverse Events | Any adverse event | 3 participants |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Adverse Events | Serious adverse events | 2 participants |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Adverse Events | Deaths | 1 participants |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Adverse Events | Discontinued study treatment due to adverse event | 0 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Adverse Events | Discontinued study treatment due to adverse event | 0 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Adverse Events | Any adverse event | 4 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Adverse Events | Deaths | 1 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Adverse Events | Serious adverse events | 3 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Adverse Events | Discontinued study treatment due to adverse event | 2 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Adverse Events | Serious adverse events | 9 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Adverse Events | Deaths | 6 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Adverse Events | Any adverse event | 10 participants |
Primary
Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine
Samples of blood and urine collected before and up to 24 hours after dosing were tested for the presence of talimogene laherparepvec deoxyribonucleic acid (DNA) using a validated quantitative polymerase chain reaction (qPCR) assay.
Time frame: Treatment Day 1 predose and 2, 6, 12 and 24 hours postdose, and Week 3 and 6 at (predose and 2 hours postdose.
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Blood | 0 participants |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Urine | 1 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Blood | 4 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Urine | 2 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Blood | 1 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Talimogene Laherparepvec Detected in Blood and Urine | Urine | 4 participants |
Secondary
Change From Baseline in Pain Intensity
Pain was assessed by the participant using a validated Visual Analog Scale (VAS) pain assessment instrument. A single 10-cm line was used with the leftmost end (0 cm) representing no pain and the rightmost end (10 cm) representing worst pain. The distance was measured from the leftmost part of the scale to the mark made by the participant indicating pain level.
Time frame: Baseline and Weeks 3 and 6
Population: ITT population with available VAS data; this assessment was added in the third protocol amendment and change from baseline could only be assessed for participants in cohort 3.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Change From Baseline in Pain Intensity | Week 3 (N=0, 0, 6) | 1.250 cm | Standard Deviation 2.456 |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Change From Baseline in Pain Intensity | Week 6 (N=0, 0, 4) | 2.575 cm | Standard Deviation 3.305 |
Secondary
Change From Baseline in Sum of Longest Diameters of Injected Tumors
Spiral computed tomography (CT) scans were performed to assess tumors at screening and at Weeks 6, 12 and 18 after the initial dose.
Time frame: Baseline and Week 6, 12 and 18
Population: ITT population with available data at each time point (indicated by N).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 12 (N=1, 1, 0) | 0.0 mm | — |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 6 (N=2, 1, 4) | 2.5 mm | Standard Deviation 3.54 |
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 18 (N=2, 2, 1) | 11.5 mm | Standard Deviation 9.19 |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 12 (N=1, 1, 0) | 18.0 mm | — |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 6 (N=2, 1, 4) | 18.0 mm | — |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 18 (N=2, 2, 1) | 25.5 mm | Standard Deviation 10.61 |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 6 (N=2, 1, 4) | -3.3 mm | Standard Deviation 12.42 |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 18 (N=2, 2, 1) | 37.0 mm | — |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Change From Baseline in Sum of Longest Diameters of Injected Tumors | Week 12 (N=1, 1, 0) | NA mm | — |
Secondary
Number of Participants With Overall Objective Response
Tumor response was assessed via CT scan by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 guidelines. Objective response is defined as a complete response (CR) or partial response (PR). CR: Disappearance of all target and non-target lesions, normalization of tumor marker level and no new lesions and with confirmation no less than 4 weeks after the criteria for CR is first met. PR: At least a 30% decrease in the sum of longest diameters of target lesions taking as reference the baseline sum of the longest diameters, absence of non-target lesion progression, and no new lesions. These criteria must be confirmed no less than 4 weeks after they are first met.
Time frame: Every 6 weeks until 12 weeks after the last dose; the median duration of treatment was 44.0 days, 22.0 days, and 11.5 days in each group respectively.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Talimogene Laherparepvec 10⁴/ 10⁵ PFU/mL | Number of Participants With Overall Objective Response | 0 participants |
| Talimogene Laherparepvec 10⁵ / 10⁶ PFU/mL | Number of Participants With Overall Objective Response | 0 participants |
| Talimogene Laherparepvec 10⁶ / 10⁷ PFU/mL | Number of Participants With Overall Objective Response | 0 participants |