AlloStim® In-Situ Vaccine in Pre-Treated Metastatic Colorectal Cancer

A Phase II/III, Randomized, Open Label, Controlled, Two Arm Study Comparing Overall Survival of AlloStim® Combined With Cryoablation to a Physician's Choice Combined With Cryoablation in 3rd Line Treatment for Metastatic Colorectal Cancer

This is a personalized anti-cancer vaccine protocol which includes an in-situ (in the body) cancer vaccine step which 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• Status: Withdrawn
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Biological: AlloStim®; Procedure: cryoablation; Other: Physician's Choice (PC)

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 due to a mutation in KRAS or BRAF.

This is a Phase II/III, randomized, open-label, multicenter, controlled, two arm study designed to determine the efficacy in terms of OS and the safety of the InSituVax (AlloStim+ Cryoablation) personalized in-situ anti-cancer vaccine protocol (Treatment Arm) compared with Physician's Choice (PC) of Treatment + Cryoablation (Control Arm) in Metastatic Colorectal Cancer. Subjects are randomized 2:1 into the treatment or control arms.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand
    • National Cancer Institute of Thailand

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:

1. Adult males and female subjects aged 18 years or older at screening visit
2. Pathological diagnosis of colorectal adenocarcinoma

3. Metastatic disease with at least one lesion in liver

   • Primary can be intact or resected
   • Metastatic lesion(s) in liver non-resectable
   • Extrahepatic disease acceptable
4. KRAS/BRAF mutant disease or KRAS wild type w/previous anti-EGFR treatment
5. At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation

6. Previous treatment failure of at 2 previous lines of active systemic chemotherapy for metastatic disease:

   • Previous chemotherapy must have included one line with oxaliplatin (e.g. FOLFOX) and a previous second line with irinotecan (e.g. FOLFIRI) with or without bevacizumab
   • If KRAS wild type, at least one anti-EGFR therapy in first or second line
   • Treatment failure can be due to disease progression or toxicity
   • Disease progression on 2nd line therapy must be documented radiologically and have occurred during or within 30 days following the last administration of 2nd line chemotherapy
7. ECOG performance score: 0-1
8. 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)
9. Adequate Organ Function: Creatinine ≤ 1.5 mg/dL, Total bilirubin ≤ 1.5 times ULN, Alkaline phosphatase ≤ 2.5 times ULN, AST or SGOT ≤ 2.5 times ULN, ALT or SGPT≤2.5 times ULN
10. EKG without clinically relevant abnormalities
11. Female subjects: Not pregnant or lactating
12. Subjects with child bearing potential must agree to use adequate contraception
13. Study specific informed consent in the native language of the subject

Exclusion Criteria:

1. Peritoneal carcinomatosis
2. Moderate or severe ascites requiring medical intervention
3. Prior hepatectomy, ablation or chemoembolization of liver lesion
4. Prior pelvic radiotherapy
5. Clinical or radiological evidence of brain metastasis/leptomeningeal involvement
6. Symptomatic asthma or COPD or any lung condition requiring treatment with steroids
7. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room air
8. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation
9. No Regorafenib prior to or during the Study Period
10. Anticoagulant medication for concomitant medical condition (unless can be safely discontinued for invasive cryoablation, biopsy and intratumoral injection procedures)
11. Prior allogeneic bone marrow/stem cell or solid organ transplant

12. 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 1st day of study treatment

    o Topical corticosteroids are permitted

13. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes allowed.
14. Prior experimental therapy
15. History of blood transfusion reactions
16. Known allergy to bovine products

17. Progressive viral or bacterial infection

    o All infections must be resolved and the patient must remain afebrile for seven days without antibiotics prior to being placed on study

18. Cardiac disease of symptomatic nature
19. History of HIV positivity or AIDS
20. 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 procedure
21. History of severe hypersensitivity to monoclonal antibody drugs or any contraindication to any of the study drugs
22. Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AlloStim® treatment; The treatment schedule includes: (1) the priming step with two ID AlloStim® injections (Days 0 and 3), an additional two ID injections followed by IV infusion of AlloStim® (Days 7 and 10); (2) the vaccination step with cryoablation of a single metastatic lesion followed by injection of AlloStim® into the ablated tumor and IV infusion of AlloStim® on protocol day 14, followed by IV infusion of AlloStim® on Day 17 (3) the activation step with an IV study drug infusion on Day 21 and (4) the booster step with IV booster infusions of AlloStim® on days 49 and 77. Additional booster infusions can be administered monthly at the discretion of the Investigator.	Biological: AlloStim®; AlloStim® is derived from the blood of normal blood donors and is intentionally mismatched to the recipient. CD4+ T-cells are separated from the blood and differentiated and expanded for 9-days in culture to make an intermediary called T-Stim. AlloStim is made by incubating T-Stim cells for 4h with antibody coated microbeads. The cells with the beads still attached are suspended in infusion media and loaded into syringes. The syringes are shipped refrigerated to the point-of-care.; Procedure: cryoablation; percutaneous ablation of a single metastatic tumor lesion usually in liver. The procedure is conducted under CT or ultrasound image-guidance.
Other: Physician's Choice (PC); All subjects will be assigned Physician's Choice (PC) therapy. PC can consist of best supportive care (BSC) or any US-FDA-approved cancer drug (e.g. Cetuximab) administrated as a monotherapy at the manufacturer's recommended dose. The treatment schedule shall be prospectively determined and administered as tolerated.	Procedure: cryoablation; percutaneous ablation of a single metastatic tumor lesion usually in liver. The procedure is conducted under CT or ultrasound image-guidance.; Other: Physician's Choice (PC); Physician's Choice therapy can consist of best supportive care (BSC) or any US-FDA approved cancer drug (e.g. Cetuximab) administrated as a monotherapy at the manufacturer's recommended dose. The treatment schedule shall be prospectively determined and administered as tolerated; Other Names: best supportive care; monotherapy (e.g.Cetuximab)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	To assess whether cryoablation combined with AlloStim treatment (arm 1) provides an overall survival (OS) advantage when compared to treatment with cryoablation combined with physician's choice (arm 2).	from randomization within 30 days of accrual to death for any cause followed for up to 2 years from date of randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Safety will be evaluated by physical exam, changes in laboratory values and patient reported symptoms	168 days from randomization
Health-Related Quality of Life (HRQoL)	To assess change in HRQoL between treatment arms	168 days from randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological Response	blood samples will be evaluated for immunological response and a determination made as to whether immunological response correlates with survival	168 days from randomization
Longitudinal changes in tumor burden	To document the longitudinal changes in tumor burden by Response Evaluation Criteria in Solid Tumors (RECIST) and Immune-Related Response Criteria (irRC)	168 days from randomization

Collaborators and Investigators

• Sponsor: Immunovative Therapies, Ltd.
• Investigators: Principal Investigator: Wirote Lausoontornsiri, MD, National Cancer Institute of Thailand; Study Director: Thu Bui, BS, Immunovative Therapies, Ltd.

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.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2017
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): October 1, 2020

Study Registration Dates

• First Submitted: November 29, 2012
• First Submitted That Met QC Criteria: November 30, 2012
• First Posted (Estimate): December 4, 2012

Study Record Updates

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

More Information

Terms related to this study

• Keywords: Immunotherapy; Cryoablation; Allogeneic Cell Therapy; Cancer Vaccine; AlloStim®; Immunovative
• 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; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: ITL-008-INSTAVAC-CRC

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No