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

Phase 2

Withdrawn

• Conditions: Metastatic Colorectal Cancer
• Interventions: Biological: AlloStim®; Procedure: cryoablation; Other: Physician's Choice (PC)

• Registration Number: NCT01741038
• Lead Sponsor: Mirror Biologics, Inc.

Brief Summary

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.

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 Timeline

• Study First Submitted: 2012-11-29
• Study First Submitted QC: 2012-11-30
• Study First Posted: 2012-12-04
• Status Verified: 2016-08
• Study Start: 2017-12
• Primary Completion: 2019-12
• Last Update Submitted: 2020-01-17
• Last Update Posted: 2020-01-22
• Study Completion: 2020-10

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AlloStim® treatment	cryoablation	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.
Physician's Choice (PC)	cryoablation	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.
AlloStim® treatment	AlloStim®	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.
Physician's Choice (PC)	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.

Primary Outcome Measures

Name	Time	Method
Overall Survival	from randomization within 30 days of accrual to death for any cause followed for up to 2 years from date of randomization	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).

Secondary Outcome Measures

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

Trial Locations

Locations (1)

National Cancer Institute of Thailand; 🇹🇭 Bangkok, Thailand