A Trial of JX-594 in Refractory Colorectal Carcinoma

A Phase 1b Dose Escalation Study of JX-594 (Thymidine Kinase-Inactivated Vaccinia Virus Plus GM-CSF) Administered by Biweekly (Every Two Weeks) Intravenous Infusion in Patients With Metastatic, Refractory Colorectal Carcinoma

The purpose of this study is to:

• determine the maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of JX-594 administered by biweekly intravenous (IV) infusion.
• determine the safety of JX-594(TK- GM-CSF+ Wyeth strain vaccinia) administered by biweekly IV infusion.

Study Overview

• Status: Completed
• Conditions: Colorectal Carcinoma
• Intervention / Treatment: Biological: JX-594

Detailed Description

This is a Phase 1b, open-label, dose-escalation trial in patients with advanced colorectal carcinoma (CRC) that have failed both oxaliplatin based and irinotecan based prior chemotherapy regimens for metastatic disease. Patients will receive treatment at one of three dose levels in a sequential dose-escalating design.

Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT) is observed. Enrollment will proceed to the next dose level if 0 of 3 patients experiences a DLT; if one of the first 3 patients experiences a DLT, additional patients will be enrolled until a second patient experiences a DLT (which defines the toxic dose) or until six total patients have been treated at that dose level, whichever comes first. If a second DLT is not experienced within that cohort, dose escalation may continue.

Patients will be enrolled a minimum of 14 days after the first treatment of the immediately preceding patient for the first patient in any cohort or all remaining patients in a cohort with DLT.

If 2 DLTs are observed within a cohort, enrollment into the cohort will cease and the dose level immediately preceding that dose will be determined to be the MTD. Regulatory Authorities and the IRB will be notified as required if any patient dies within 28 days of product administration due to a serious and unexpected ADR that is determined by the Investigator to be possibly or probably related to JX-594.

Once the MTD and/or MFD is defined, an additional 3-6 patients may be enrolled at that dose level. Note: once the MTD and/or MFD is defined, treatment of additional patients at this dose level will no longer require inter-patient delays of 14 days.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Samsung Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically-confirmed, advanced/metastatic colorectal carcinoma
• Failed both oxaliplatin and irinotecan based regimens for advanced/metastatic disease (tumor progression on or within 3 months of treatment completion)
• Erbitux therapy resistant: Ras mutant tumor status, and/or failed Erbitux therapy (tumor progression on or within 3 months of treatment completion or Erbitux treatment not indicated due to lack of epidermal growth factor (EGFR) expression)
• At least one measurable tumor mass by PET-CT/CT/MRI (lesion that can accurately be measured in at least one dimension with longest diameter > 1 cm)
• Expected survival for approximately 12 weeks or longer
• Karnofsky Performance Score (KPS) ≥ 70
• Age ≥18 years
• 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 ULN
• AST, ALT ≤2.5 ULN (if liver metastases(+): AST,ALT ≤5.0 x ULN)
• Serum chemistries within normal limits (WNL) or Grade 1 (excluding alkaline phosphatase) - If patients are diabetic or have a screening random glucose > 160 mg/dL, a fasting glucose must be done and patients must be WNL or Grade 1 in order to be eligible for the study.

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 (e.g. tumors impinging on the upper airway or affecting biliary tract drainage, etc.)
• Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or pleural effusions
• Severe or unstable cardiac disease, including (for example) coronary artery disease requiring increased doses of anti-anginal mediation and/or coronary angioplasty (including stent placement) within the preceding 24 months
• Current, known CNS malignancy (history of completely resected or irradiated brain metastases by WBRT or stereotactic radiosurgery allowed)
• Received 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% at rest
• Experienced a severe systemic reaction or side-effect as a result of a previous smallpox vaccination

Household contact exclusions:

• Women who are pregnant or nursing an infant
• Children < 12 months 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)Patients with household contacts meeting any of the above criteria will be excluded unless alternate living arrangements can be made during the patient's dosing period and for at least 7 days following the last dose of study medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: JX-594; Infusion Procedure:JX-594 will be administered on the designated treatment days at a dose of either 1 x 106, 1 x 107 or 3 x 107 pfu per kg. Virus infusion should occur over 60 minutes (+/- 5 minutes). The final infusion volume of virus plus diluent will be approximately 250 mL.	Biological: JX-594; Infusion Procedure:JX-594 will be administered on the designated treatment days at a dose of either 1 x 106, 1 x 107 or 3 x 107 pfu per kg. Virus infusion should occur over 60 minutes (+/- 5 minutes). The final infusion volume of virus plus diluent will be approximately 250 mL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determine the maximally-tolerated dose	18 months
Determine the maximum-feasible dose	18months

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Young suk park, MD, Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2010
• Primary Completion (ACTUAL): October 1, 2012
• Study Completion (ACTUAL): January 1, 2015

Study Registration Dates

• First Submitted: November 7, 2011
• First Submitted That Met QC Criteria: November 9, 2011
• First Posted (ESTIMATE): November 10, 2011

Study Record Updates

• Last Update Posted (ACTUAL): February 17, 2017
• Last Update Submitted That Met QC Criteria: February 15, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: advanced/metastatic colorectal carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Carcinoma; Colorectal Neoplasms
• Other Study ID Numbers: SMC IRB 2009-06-055