Colorectal Cancer Metastatic
Conditions
Keywords
colorectal cancer, KRAS mutant, BRAF mutant, metastatic, liver metastasis, AlloStim®, cryoablation, cancer vaccine, immunotherapy, MSI-S
Brief summary
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.
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.
Interventions
BIOLOGICALAlloStim
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.
PROCEDURECryoablation
Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance
Sponsors
Mirror Biologics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Overall Survival | from time of signing informed consent for up to 18 months or until death | Subjects are followed for survival monthly after completion of dosing |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dosing Schedule A (With Cryoablation) * 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
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.
Cryoablation: Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance | 4 |
| Dosing Schedule B Without Cryoablation 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
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. | 9 |
| Total | 13 |
Baseline characteristics
| Characteristic | Total | Dosing Schedule A (With Cryoablation) | Dosing Schedule B Without Cryoablation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 3 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment United States | 13 participants | 4 participants | 9 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 6 Participants |
| third-line MSS metastatic colorectal cancer | 13 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 9 / 9 |
| other Total, other adverse events | 3 / 3 | 7 / 9 |
| serious Total, serious adverse events | 2 / 3 | 1 / 9 |
Outcome results
Primary
Evaluate the Overall Survival
Subjects are followed for survival monthly after completion of dosing
Time frame: from time of signing informed consent for up to 18 months or until death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dosing Schedule A (With Cryoablation) | Evaluate the Overall Survival | 97 days |
| Dosing Schedule B Without Cryoablation | Evaluate the Overall Survival | 368 days |