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Increased Frequency of AlloStim® Immunotherapy Dosing in Combination With Cryoablation in Metastatic Colorectal Cancer

This study is currently recruiting participants.
See Contacts and Locations
Verified October 2016 by Immunovative Therapies, Ltd.
Sponsor:
Information provided by (Responsible Party):
Immunovative Therapies, Ltd.
ClinicalTrials.gov Identifier:
NCT02380443
First received: March 2, 2015
Last updated: October 19, 2016
Last verified: October 2016
  Purpose
This is a single center, open label dose frequency escalation study of InSituVax personalized anti-tumor vaccine protocol combining the cryoablation of a selected metastatic lesion with intra-lesional immunotherapy with AlloStim®. The in-situ (in the body) cancer vaccine step combines killing a single metastatic tumor lesion by use of cryoablation in order to cause the release of tumor-specific markers to the immune system and then injecting bioengineered allogeneic immune cells (AlloStim®) into the lesion as an adjuvant in order to modulate the immune response and educate the immune system to kill other tumor cells where ever they reside in the body.

Condition Intervention Phase
Colorectal Cancer Metastatic Biological: AlloStim Procedure: Cryoablation Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: In-Situ Cancer Vaccine: Phase I/IIb, Open-Label Study to Assess the Safety of AlloStim® Immunotherapy in Combination With Cryoablation as Third Line Therapy for Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Immunovative Therapies, Ltd.:

Primary Outcome Measures:
  • To determine the safety of increased frequency of dosing (Part 1) (whether a Dose Limiting Toxicity (DLT) has occurred) [ Time Frame: Window is defined from baseline until 28 days after the last dose administration ("Safety Evaluation Period") ]
    Three patients are enrolled at each frequency schedule in the absence of dose limiting toxicity (DLT).Two types of toxicity are assessed for determination of whether a Dose Limiting Toxicity (DLT) has occurred. An acute dose limiting toxicity (ADLT) is assessed within 48h of a dose administration. Cumulative dose limiting toxicity (CDLT) is assessed during the complete Safety Evaluation Period.

  • To evaluate the anti-tumor effect of AlloStim combined with cryoablation at the new proposed dose and frequency schedule (Part 2) [ Time Frame: 28 days after last dose administration ]
    Subjects at the new proposed dose and frequency schedule will be monitored for radiological, pathological and immunological response


Secondary Outcome Measures:
  • To assess change from baseline in Health-Related Quality of Life (HRQoL) [ Time Frame: From enrollment to 28 days after last dose administration ]
    Health-Related Quality of Life (HRQoL) will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30)


Other Outcome Measures:
  • Anti-Tumor Response [ Time Frame: 28 days after last dose administration ]
    Longitudinal changes in tumor burden by RECIST and compare these changes with the histopathological analysis of corresponding biopsies

  • Immunological response 9whether immune response correlates with Overall Survival (OS), RECIST and histopathology) [ Time Frame: 28 days after last dose administration ]
    To assess whether immune response correlates with Overall Survival (OS), RECIST and histopathology


Estimated Enrollment: 18
Study Start Date: September 2016
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dosing Schedule A
  • The priming step with ID injections of AlloStim on Days 0, 7, and 14
  • The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 21
  • The activation step with IV infusion of AlloStim on Day 28
  • The booster step with two IV booster infusions of AlloStim on Days 56 and 84

Protocol follow-up procedures continue until day 112. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Biological: AlloStim
AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.
Other Name: InSituVax
Procedure: Cryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance
Experimental: Dosing Schedule B
  • The priming step with ID injections of AlloStim on Days 0, 3 and days 7 and 10
  • The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 14
  • The activation step with IV infusion of AlloStim on Day 21
  • The booster step with two IV booster infusions of AlloStim on Days 49 and 77

Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Biological: AlloStim
AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.
Other Name: InSituVax
Procedure: Cryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance
Experimental: Dosing Schedule C
  • The priming step with ID injections of AlloStim on Days 0, 3 and days 7 and 10
  • The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 14 and an additional IT injection of AlloStim on Day 17
  • The activation step with IV infusion of AlloStim on Day 21
  • The booster step with two IV booster infusions of AlloStim on Days 49 and 77

Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Biological: AlloStim
AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.
Other Name: InSituVax
Procedure: Cryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance
Experimental: Dosing Schedule D
  • The priming step with ID and IV injections of AlloStim on Days 0, 3 and days 7 and 10
  • The vaccination step with cryoablation and IT injection of AlloStim on Day 14
  • The activation step with IV infusion of AlloStim on Day 21
  • The booster step with two IV booster infusions of AlloStim on Days 49 and 77

Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Biological: AlloStim
AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.
Other Name: InSituVax
Procedure: Cryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance
Experimental: Dosing Schedule E
  • The priming step with ID and IV injections of AlloStim on Days 0, 3 and days 7 and 10
  • The vaccination step with cryoablation and IT and IV injections of AlloStim on Day 14
  • The activation step with IV infusion of AlloStim on Day 21
  • The booster step with two IV booster infusions of AlloStim on Days 49 and 77

Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Biological: AlloStim
AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.
Other Name: InSituVax
Procedure: Cryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance
Experimental: Dosing Schedule F
  • The priming step with ID and IV injections of AlloStim on Days 0, 3 and days 7 and 10
  • The vaccination step with cryoablation and IT injection of AlloStim on Day 14 and IV injection of AlloStim on Day 17
  • The activation step with IV infusion of AlloStim on Day 21
  • The booster step with two IV booster infusions of AlloStim on Days 49 and 77

Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up

Biological: AlloStim
AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.
Other Name: InSituVax
Procedure: Cryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance

Detailed Description:
Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Metastasis is the main reason of death in CRC patients. The current drugs used to treat colorectal cancer provide important treatment options for patients, their limitations including drug resistance, poor efficacy and severe side effects. Development of new therapeutic strategies for KRAS mutant as well as BRAF mutant tumors are therefore highly needed in order to offer a new category of drug (immunotherapy). This study targets the population of mCRC patients that have progressed after two lines of chemotherapy and are not eligible for targeted therapies. The study will assess six different dosing schedules. A standard 3 plus 3 study design will be used. The starting frequency for each dosing schedule will be escalated in subsequent groups of patients. The study will evaluate safety of increased frequency of AlloStim® dosing and anti-tumor effect of the new proposed dose and frequency schedule.
  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult males and female subjects aged 18-80 years at screening visit
  2. Pathologically confirmed diagnosis of colorectal adenocarcinoma
  3. Presenting with metastatic disease:

    • Primary can be intact or previously resected
    • Metastatic lesion(s) in liver must be non-resectable
    • Extrahepatic disease acceptable
  4. At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation
  5. Previous treatment failure of two previous lines of active systemic chemotherapy:

    • Previous chemotherapy must have included an oxaliplatin-containing (e.g. FOLFOX) and an irinotecan-containing (e.g. FOLFIRI) regimen
    • with or without bevacizumab
    • administered in adjuvant setting or for treatment of metastatic disease
    • If KRAS wild type, must have at least one prior anti-EGFR therapy
    • Treatment failure can be due to disease progression or toxicity
    • Disease progression on second line therapy must be documented radiologically and must have occurred during or within 30 days following the last administration of treatment for metastatic disease
  6. ECOG performance score: 0-1
  7. Adequate hematological function:

    • Absolute granulocyte count ≥ 1,200/mm3
    • Platelet count ≥ 100,000/mm3
    • PT/INR ≤ 1.5 or correctable to <1.5 at time of interventional procedures
    • Hemoglobin ≥ 9 g/dL (may be corrected by transfusion)
  8. Adequate Organ Function:

    • Creatinine ≤ 1.5 mg/dL
    • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
    • Alkaline phosphatase ≤ 2.5 times ULN
    • Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN
    • Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN
  9. EKG without clinically relevant abnormalities
  10. Female subjects: Not pregnant or lactating
  11. Patients with child bearing potential must agree to use adequate contraception
  12. Study specific informed consent in the native language of the subject.

Exclusion Criteria:

  1. Bowel obstruction or high risk for obstruction
  2. Moderate or severe ascites requiring medical intervention
  3. Clinical evidence or radiological evidence of brain metastasis or leptomeningeal involvement
  4. Symptomatic asthma or COPD
  5. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room air
  6. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation procedure
  7. Regorafenib prior to the Study Period
  8. Taking anticoagulant medication for concomitant medical condition (unless can be safely discontinued for invasive cryoablation, biopsy and intratumoral injection procedures)
  9. Prior allogeneic bone marrow/stem cell or solid organ transplant
  10. Chronic use (> 2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to > 5 mg/day of prednisone) within 30 days of the first day of study drug treatment

    • Topical corticosteroids are permitted
  11. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes allowed
  12. Prior experimental therapy
  13. History of blood transfusion reactions
  14. Known allergy to bovine products
  15. Progressive viral or bacterial infection

    • All infections must be resolved and the subject must remain afebrile for seven days without antibiotics prior to being placed on study
  16. Cardiac disease of symptomatic nature
  17. History of HIV positivity or AIDS
  18. Concurrent medication known to interfere with platelet function or coagulation (e.g., aspirin, ibuprofen, clopidogrel, or warfarin) unless such medications can be discontinued for an appropriate time period based on the drug half-life and known activity (e.g., aspirin for 7 days) prior to cryoablation and biopsy procedures
  19. History of severe hypersensitivity to monoclonal antibody drugs or any contraindication to any of the study drugs
  20. Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation.
  21. Subjects that lack ability to provide consent for themselves
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02380443

Contacts
Contact: Andrea Horstman 1-480-440-7458 BMDACCResearch@bannerhealth.com
Contact: Thu Bui, M.A. 1-619-227-4872 thu@immunovative.com

Locations
United States, Arizona
Banner MD Anderson Medical Center Recruiting
Gilbert, Arizona, United States, 85234
Sponsors and Collaborators
Immunovative Therapies, Ltd.
Investigators
Principal Investigator: Madappa Kundranda, MD PHD Banner MD Anderson Cancer Center
  More Information

Publications:

Responsible Party: Immunovative Therapies, Ltd.
ClinicalTrials.gov Identifier: NCT02380443     History of Changes
Other Study ID Numbers: ITL-019-CORK-CRYVAC
Study First Received: March 2, 2015
Last Updated: October 19, 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Immunovative Therapies, Ltd.:
colorectal cancer
KRAS mutant
BRAF mutant
metastatic
liver metastasis
AlloStim®
cryoablation
cancer vaccine
immunotherapy

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases

ClinicalTrials.gov processed this record on August 18, 2017