AlloStim® Immunotherapy Dosing Alone or in Combination With Cryoablation in Metastatic Colorectal Cancer

In-Situ Cancer Vaccine: Phase IIA, Open-Label Study to Assess the Safety of AlloStim® Immunotherapy Alone and in Combination With Cryoablation as Third Line Therapy for Metastatic Colorectal Cancer

This is a single center, open label dose frequency escalation study of CryoVax®. 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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Biological: AlloStim; Procedure: Cryoablation

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: CryoVax; 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 Names: CryoVax; 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, 7, 10 and day 14; IV 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 Names: CryoVax; 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 (reducing dose); The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14; IV 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 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 Names: CryoVax; Procedure: Cryoablation; Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the safety of increased frequency of dosing (Part 1) (whether a Dose Limiting Toxicity (DLT) has occurred)	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.	Window is defined from baseline until 28 days after the last dose administration ("Safety Evaluation Period")
To evaluate the anti-tumor effect of AlloStim combined with cryoablation at the new proposed dose and frequency schedule (Part 2)	Subjects at the new proposed dose and frequency schedule will be monitored for radiological, pathological and immunological response	28 days after last dose administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess change from baseline in Health-Related Quality of Life (HRQoL)	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)	From enrollment to 28 days after last dose administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-Tumor Response	Longitudinal changes in tumor burden by RECIST and compare these changes with the histopathological analysis of corresponding biopsies	28 days after last dose administration
Immunological response 9whether immune response correlates with Overall Survival (OS), RECIST and histopathology)	To assess whether immune response correlates with Overall Survival (OS), RECIST and histopathology	28 days after last dose administration

Collaborators and Investigators

• Sponsor: Immunovative Therapies, Ltd.
• Investigators: Principal Investigator: Madappa Kundranda, MD PHD, Banner MD Anderson Cancer Center

Publications and helpful links

General Publications

• Har-Noy M, Slavin S. The anti-tumor effect of allogeneic bone marrow/stem cell transplant without graft vs. host disease toxicity and without a matched donor requirement? Med Hypotheses. 2008;70(6):1186-92. doi: 10.1016/j.mehy.2007.10.008. Epub 2007 Dec 3.
• Har-Noy M, Zeira M, Weiss L, Fingerut E, Or R, Slavin S. Allogeneic CD3/CD28 cross-linked Th1 memory cells provide potent adjuvant effects for active immunotherapy of leukemia/lymphoma. Leuk Res. 2009 Apr;33(4):525-38. doi: 10.1016/j.leukres.2008.08.017. Epub 2008 Oct 1.
• Har-Noy M, Zeira M, Weiss L, Slavin S. Completely mismatched allogeneic CD3/CD28 cross-linked Th1 memory cells elicit anti-leukemia effects in unconditioned hosts without GVHD toxicity. Leuk Res. 2008 Dec;32(12):1903-13. doi: 10.1016/j.leukres.2008.05.007. Epub 2008 Jun 18.
• Epple LM, Bemis LT, Cavanaugh RP, Skope A, Mayer-Sonnenfeld T, Frank C, Olver CS, Lencioni AM, Dusto NL, Tal A, Har-Noy M, Lillehei KO, Katsanis E, Graner MW. Prolonged remission of advanced bronchoalveolar adenocarcinoma in a dog treated with autologous, tumour-derived chaperone-rich cell lysate (CRCL) vaccine. Int J Hyperthermia. 2013 Aug;29(5):390-8. doi: 10.3109/02656736.2013.800997. Epub 2013 Jun 20.
• Mayer-Sonnenfeld T, Har-Noy M, Lillehei KO, Graner MW. Proteomic analyses of different human tumour-derived chaperone-rich cell lysate (CRCL) anti-cancer vaccines reveal antigen content and strong similarities amongst the vaccines along with a basis for CRCL's unique structure: CRCL vaccine proteome leads to unique structure. Int J Hyperthermia. 2013 Sep;29(6):520-7. doi: 10.3109/02656736.2013.796529. Epub 2013 Jun 4.
• LaCasse CJ, Janikashvili N, Larmonier CB, Alizadeh D, Hanke N, Kartchner J, Situ E, Centuori S, Har-Noy M, Bonnotte B, Katsanis E, Larmonier N. Th-1 lymphocytes induce dendritic cell tumor killing activity by an IFN-gamma-dependent mechanism. J Immunol. 2011 Dec 15;187(12):6310-7. doi: 10.4049/jimmunol.1101812. Epub 2011 Nov 9.
• Janikashvili N, LaCasse CJ, Larmonier C, Trad M, Herrell A, Bustamante S, Bonnotte B, Har-Noy M, Larmonier N, Katsanis E. Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia. Blood. 2011 Feb 3;117(5):1555-64. doi: 10.1182/blood-2010-06-288621. Epub 2010 Dec 1.
• Zeng Y, Stokes J, Hahn S, Hoffman E, Katsanis E. Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD. Bone Marrow Transplant. 2014 Aug;49(8):1076-83. doi: 10.1038/bmt.2014.91. Epub 2014 Apr 28.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): March 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: March 2, 2015
• First Submitted That Met QC Criteria: March 4, 2015
• First Posted (Estimate): March 5, 2015

Study Record Updates

• Last Update Posted (Actual): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 17, 2020
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: colorectal cancer; immunotherapy; liver metastasis; metastatic; cancer vaccine; cryoablation; KRAS mutant; BRAF mutant; MSI-S; AlloStim®
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: ITL-019-CORK-CRYVAC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO