Description:
Liver metastases are a leading cause of death among patients with metastatic colorectal
cancer. Duration of disease control is short following 2nd-line or later systemic therapy.
Liver-directed therapy such as TACE has a higher response rate and improves progression-free
survival (PFS), but the benefit is still limited. Cancer cells escape ischemic cell death via
autophagy and hypoxia-inducible factor (HIF) activation. We hypothesize that blocking
autophagy and the vascular endothelial growth factor (VEGF) pathway will improve both
response and PFS following TACE.
Title
- Brief Title: TACE Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Colorectal Cancer (CRC)
- Official Title: Phase 1B Study of Hepatic Chemoembolization Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Adenocarcinoma Of The Colon And Rectum
Clinical Trial IDs
- ORG STUDY ID:
UPCC03221
- NCT ID:
NCT04873895
Conditions
- Colorectal Neoplasms Malignant
Interventions
Drug | Synonyms | Arms |
---|
Axitinib 5 MG | | TACE+axitinib+HCQ |
Hydroxychloroquine Pill | | TACE+axitinib+HCQ |
Purpose
Liver metastases are a leading cause of death among patients with metastatic colorectal
cancer. Duration of disease control is short following 2nd-line or later systemic therapy.
Liver-directed therapy such as TACE has a higher response rate and improves progression-free
survival (PFS), but the benefit is still limited. Cancer cells escape ischemic cell death via
autophagy and hypoxia-inducible factor (HIF) activation. We hypothesize that blocking
autophagy and the vascular endothelial growth factor (VEGF) pathway will improve both
response and PFS following TACE.
Detailed Description
Subjects with liver-dominant colorectal cancer metastases failing at least one line of
systemic therapy will receive 2 weeks of axitinib 5mg twice daily (BID) and HCQ 600 mg BID
followed by lobar or segmental TACE monthly until the entire tumor burden is treated, then
continue axitinib/HCQ until progression or intolerable toxicity. Response and hepatic
progression-free survival (HPFS) will be assessed one month post-TACE, then every 3 months.
Trial Arms
Name | Type | Description | Interventions |
---|
TACE+axitinib+HCQ | Experimental | 2 weeks of axitinib 5mg BID and hydroxychloroquine 600 mg BID followed by lobar or segmental trans arterial chemoembolization monthly until the entire tumor burden is treated, then continue axitinib/HCQ until progression or intolerable toxicity. | - Axitinib 5 MG
- Hydroxychloroquine Pill
|
Eligibility Criteria
Inclusion Criteria:
1. Age 18 years or more.
2. Pathologically-verified diagnosis of colorectal adenocarcinoma.
3. Measurable metastasis to liver with at least one dimension ≥ 1.0 cm.
4. Liver dominant metastases as judged by multidisciplinary team consensus review of
cross-sectional imaging of the chest, abdomen and pelvis.
5. At least 2 weeks must have elapsed from the last dose of chemotherapy before starting
HCQ and at least 4 weeks must have elapsed from the last dose of VEGF/VEGFR therapy
prior to starting axitinib.
6. Subjects must be at least 2 weeks beyond prior radiotherapy or surgery, and have
recovered from all therapy associated toxicities.
7. Eastern Cooperative Oncology Group (ECOG) Performance status must be 0-1 (see Appendix
II).
8. Absolute granulocyte count > 1,500/ul, platelet count > 75,000/ul, International
Normalized Ratio (INR) < 1.6
9. Serum creatinine < 2.0 mg/dl; serum bilirubin < 2.0 mg/dl.
10. Urine protein:creatinine ratio < 1 or 24-hour urine protein < 1 gm/day
11. Liver function Child-Pugh A
12. Competent and willing to provide informed consent
13. Patients of reproductive potential agree to use approved contraceptive methods per
section 5.4
Exclusion Criteria:
1. Contraindications to angiography and selective visceral catheterization:
1. severe allergy or intolerance to contrast media not controllable with
prophylaxis.
2. bleeding diathesis not correctable by usual forms of therapy.
3. severe peripheral vascular disease precluding catheterization.
2. Contraindications to hepatic artery embolization:
1. high risk of hepatic failure, indicated by the constellation of greater than 50%
liver replacement by tumor, lactate dehydrogenase (LDH) >425 mU/ml, aspartate
aminotransferase (AST) >100mU/ml. and bilirubin >2 mg/dl.
2. tumor volume >75% of total liver volume.
3. portal vein occlusion without hepatopetal collateral flow demonstrated by
angiography; or portal hypertension with hepatofugal flow.
4. hepatic encephalopathy.
3. Prior hepatic arterial infusion chemotherapy or hepatic radiation therapy. Prior
surgical resection or ablation of liver metastases is acceptable.
4. No more than two prior lines of systemic chemotherapy.
5. Pregnancy or lactation
6. Known allergic reactions to irinotecan, HCQ or axitinib
7. Allergy to contrast not mitigated by usual prophylaxis
8. Serious infection requiring intravenous therapy.
9. Known retinal disease
10. Poorly controlled hypertension, defined as a blood pressure > 150/100 at the time of
enrollment. Patients with a preexisting hypertension must be on a stable
anti-hypertensive regimen
11. History of abdominal fistula, gastrointestinal perforation, or serious non-healing
wounds, ulcers, or bone fractures
12. Known New York Heart Association class II or greater congestive heart failure (defined
as symptoms of fatigue, dyspnea, or other symptoms with ordinary physical activity)
13. Known untreated brain metastases. History of treated metastases off steroids allowed.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Serious adverse event (SAE) rate |
Time Frame: | 12 months |
Safety Issue: | |
Description: | SAE is scored by CTCAE v5 (G3 or higher) and the 2017 revision of the Society of Interventional Radiology (SIR) Complications Classification categories 3-5. |
Secondary Outcome Measures
Measure: | objective response rate in the liver |
Time Frame: | 3 months |
Safety Issue: | |
Description: | complete and partial response rate by RECIST and modified RECIST |
Measure: | Hepatic progression-free survival |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Time from initiation of therapy to progression in the liver by RECIST, death from any cause, or last documented progression-free status. |
Measure: | Progression-free survival |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Time from initiation of therapy to progression anywhere by RECIST, death from any cause, or last documented progression-free status. |
Measure: | Overall survival |
Time Frame: | 24 months |
Safety Issue: | |
Description: | Time from initiation of therapy to death or last follow-up alive |
Measure: | axitinib treatment intensity |
Time Frame: | 12 months |
Safety Issue: | |
Description: | Weeks on axitinib therapy multiplied by percentage of initially prescribed dose |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | Abramson Cancer Center of the University of Pennsylvania |
Trial Keywords
- colorectal cancer
- liver metastases
Last Updated
May 5, 2021