Carcinoma, Colorectal
Conditions
Keywords
Vaccinia, Vaccinia Virus, JX-594, Jennerex, Colorectal Carcinoma, Colorectal cancer, Colon Cancer, Rectal Cancer, Pexa-Vec
Brief summary
The purpose of this pilot safety study is to evaluate the safety and tolerability of JX-594 (Pexa-Vec) administered intravenously every 2 weeks in colorectal carcinoma patients who are refractory to or intolerant of oxaliplatin, irinotecan, and Erbitux treatments.
Detailed description
This is a Phase Ib, open-label, dose-escalation study designed to evaluate the safety and tolerability of Pexa-Vec (JX-594), a vaccinia GM-CSF/thymidine kinase-deactivated virus, administered intravenously in patients with advanced/metastatic colorectal carcinoma (CRC) that is refractory to standard therapy. Vaccinia virus, from which Pexa-Vec is derived, shows a natural selectivity toward cancer relative to normal tissues after intravenous (IV) administration. The study utilizes a sequential dose-escalating design to determine the maximum tolerated dose (MTD) and/or maximum feasible dose (MFD). Patients will receive 4 biweekly treatments of Pexa-Vec administered by IV infusion over 60 minutes on Days 1, 15, 29, and 43. Patients will be sequentially enrolled into one of three dose cohorts: * Cohort 1: 1 × 10\^6 pfu/kg * Cohort 2: 1 × 10\^7 pfu/kg * Cohort 3: 3 × 10\^7 pfu/kg Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT) is observed, at which point the cohort may be expanded. All patients will receive hydration and will be observed in the clinic and/or hospital for a minimum of 24 hours after each infusion. In addition to safety endpoints, secondary objectives include the evaluation of Pexa-Vec pharmacokinetics (PK), pharmacodynamics, immune response, and preliminary anti-tumoral activity. Tumor response assessments will be conducted using CT or MRI on Days 29 and 57 (±2 days) based on Response Evaluation Criteria in Solid Tumors (RECIST).
Interventions
Intravenous Dose Range: 1x10\^6 pfu/kg, 1x10\^7 pfu/kg, 3x10\^7 pfu/kg Up to 4 intravenous infusions administered over 60 minutes every 2 weeks.
Sponsors
Jennerex Biotherapeutics
Samsung Medical Center
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
* Histologically-confirmed, advanced/metastatic colorectal carcinoma * Failed both oxaliplatin and irinotecan based regimens for advanced/metastatic disease (if tumor advanced either immediately or within 3 months of the end of treatment) * Resistance to Erbitux: patients with Ras mutations, or for whom Erbitux has failed (if tumor advanced either immediately or within 3 months of the end of treatment, or there is no response to Erbitux therapy due to a lack of expression of EGFR (epidermal growth factor)) * Karnofsky Performance Score (KPS) ≥ 70 * Age ≥18 years * Laboratory Safety: WBC ≥ 3,500 cells/mm3 and ≤ 50,000 cells/mm3, ANC ≥ 1,500 cells/mm3, Hemoglobin ≥ 10 g/dL (transfusion allowed), Platelet count ≥ 100,000 plts/mm3,Total bilirubin ≤ 1.5 X ULN, INR ≤ 1.5, AST, ALT ≤ 2.5x ULN (in case of liver metastasis: AST,ALT ≤5.0 x ULN) * Serum chemistries within normal limits (WNL) or Grade 1 (excluding alkaline phosphatase) - If patients are diabetic, a fasting glucose must be done and patients must be \> 160 mg/dL. * Patients who, if they are sexually active, are willing and able to refrain from sexual activity for 3 weeks following JX-594 administration. Patients who are willing and able to use a permitted contraceptive for 3 months after the final administration of JX-594.
Exclusion criteria
* Significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic corticosteroids) * Known myeloproliferative disorders requiring systemic therapy * History of exfoliative skin condition (e.g. eczema or ectopic dermatitis) requiring systemic therapy * History of acquiring opportunistic infections. * Tumor(s) invading a major vascular structure (e.g. carotid artery) * Tumor(s) in location that would potentially result in significant clinical adverse effects if post-treatment tumor swelling were to occur * Clinically uncontrolled and/or rapidly accumulating ascites, pericardial and/or pleural effusions * History of severe or unstable cardiac disease * Current, known CNS malignancy (history of completely resected or irradiated brain metastases by WBRT or stereotactic radiosurgery allowed) * Administered anti-cancer therapy within 4 weeks prior to first treatment (6 weeks in case of mitomycin C or nitrosoureas) * Use of anti-viral, anti-platelet, or anti-coagulation medication \[Patients who discontinue such medications within 7 days prior to first treatment may be eligible for this study.\] Low dose aspirin (approximately 81 mg) allowed. * Pulse oximetry O2 saturation \<90% Pulse oximetry O2 saturation \<90% at rest * Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination * Pregnant or nursing * Household contact exclusions: * Women who are pregnant or nursing an infant * Children \< 5 years old * People with skin disease (e.g. eczema, atopic dermatitis, and related diseases * Immunocompromised hosts (severe deficiencies in cell-mediated immunity, including AIDS, organ transplant recipients, hematologic malignancies)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) | Up to Day 57 (assessed through 14 days following the 4th and final biweekly JX-594 infusion, an average of 8 weeks). | A DLT is defined as any of the following treatment-related adverse events: Grade 4 toxicity, Grade 3 hematologic toxicity for \> 5 days, or Grade 3 non-hematologic toxicities persisting for \> 7 days except for flu-like symptoms that respond to standard therapies. The number of participants with DLTs was used to determine the Maximally-Tolerated Dose (MTD) and/or Maximum-Feasible Dose (MFD) of JX-594. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to Day 71 (assessed through 28 days following the 4th and final biweekly JX-594 infusion, an average of 10 weeks). | Adverse events were collected and assessed to evaluate safety and tolerability. A Treatment-Emergent Adverse Event (TEAE) is defined as an event with a start date on or after the date of the first dose of study treatment, or an event present at baseline that worsened in severity after the first dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Each Best Overall Tumor Response Category Based on RECIST | Up to Day 57 (Week 8) | Anti-tumoral response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) on CT or MRI. Categories include: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) = \>=30% decrease in the sum of the longest diameters of target lesions; Progressive Disease (PD) = \>=20% increase in the sum of the longest diameters of target lesions or appearance of new lesions; Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. |
| Overall Survival (OS) | From the first dose of Pexa-Vec until death from any cause, assessed up to 24 months | Overall survival (OS) was defined as the time from the first dose of Pexa-Vec until death from any cause. For patients not known to have died at the time of the analysis, OS was censored on the date they were last known to be alive. |
Countries
South Korea
Contacts
PRINCIPAL_INVESTIGATORYoung Suk Park, MD
Samsung Medical Center
Participant flow
Recruitment details
Patients with metastatic, refractory colorectal carcinoma who had failed both oxaliplatin- and irinotecan-based prior chemotherapy regimens were recruited at a single study site (Samsung Medical Center) in Seoul, Republic of Korea. The recruitment and study conduct took place between September 08, 2010, and October 18, 2012
Pre-assignment details
A total of 15 patients were screened for the study. All 15 screened patients (100%) met the eligibility criteria and were successfully enrolled. There were no screen failures or significant events prior to cohort assignment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 56.3 Years STANDARD_DEVIATION 10.97 |
| American Joint Committee on Cancer (AJCC) Staging Stage IVA | 2 Participants |
| American Joint Committee on Cancer (AJCC) Staging Stage IVB | 13 Participants |
| KRAS Mutational Status Mutant | 1 Participants |
| KRAS Mutational Status Not Assessed | 1 Participants |
| KRAS Mutational Status Wild-type | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 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 | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Received Smallpox Vaccine No | 2 Participants |
| Received Smallpox Vaccine Unknown | 1 Participants |
| Received Smallpox Vaccine Yes | 1 Participants |
| Region of Enrollment South Korea | 3 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 3 | 5 / 9 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 9 / 9 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 2 / 9 |
Outcome results
None listed