TACE Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Colorectal Cancer (CRC)

Colorectal Neoplasms Malignant Clinical Trial

— TACE-Ax-HCQ  

Official title:

Phase 1B Study of Hepatic Chemoembolization Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Adenocarcinoma Of The Colon And Rectum

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04873895
• Other study ID #: UPCC03221
• Status: Terminated
• Phase: Phase 1
• Start date: January 24, 2022
• Est. completion date: April 25, 2024

Study information

• Verified date: April 2024
• Source: Abramson Cancer Center at Penn Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: April 25, 2024
• Est. primary completion date: April 25, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Colorectal Neoplasms Malignant
• Neoplasms

Intervention

Drug:
• Axitinib 5 MG
axitinib 5 mg po BID until progression or intolerance
• Hydroxychloroquine Pill
hydroxychloroquine 600 mg po BID until progression or intolerance

Procedure:
• trans arterial chemoembolization
segmental or lobar TACE at 4-8 week intervals until entire tummy burden is treated.

Locations

Country	Name	City	State
United States	Abramson Cancer Center	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Abramson Cancer Center at Penn Medicine	Pfizer

Country where clinical trial is conducted

United States, 

References & Publications (4)

Chan SL, Yeo W, Mo F, Chan AWH, Koh J, Li L, Hui EP, Chong CCN, Lai PBS, Mok TSK, Yu SCH. A phase 2 study of the efficacy and biomarker on the combination of transarterial chemoembolization and axitinib in the treatment of inoperable hepatocellular carcinoma. Cancer. 2017 Oct 15;123(20):3977-3985. doi: 10.1002/cncr.30825. Epub 2017 Jun 22. — View Citation

Fiorentini G, Sarti D, Nani R, Aliberti C, Fiorentini C, Guadagni S. Updates of colorectal cancer liver metastases therapy: review on DEBIRI. Hepat Oncol. 2020 Jan 21;7(1):HEP16. doi: 10.2217/hep-2019-0010. — View Citation

Fiorentini G, Sarti D, Nardella M, Inchingolo R, Nestola M, Rebonato A, Guadagni S. Chemoembolization Alone or Associated With Bevacizumab for Therapy of Colorectal Cancer Metastases: Preliminary Results of a Randomized Study. In Vivo. 2020 Mar-Apr;34(2):683-686. doi: 10.21873/invivo.11824. — View Citation

Gade TPF, Tucker E, Nakazawa MS, Hunt SJ, Wong W, Krock B, Weber CN, Nadolski GJ, Clark TWI, Soulen MC, Furth EE, Winkler JD, Amaravadi RK, Simon MC. Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma. Radiology. 2017 Jun;283(3):702-710. doi: 10.1148/radiol.2017160728. Epub 2017 Mar 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serious adverse event (SAE) rate	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.	12 months
Secondary	objective response rate in the liver	complete and partial response rate by RECIST and modified RECIST	3 months
Secondary	Hepatic progression-free survival	Time from initiation of therapy to progression in the liver by RECIST, death from any cause, or last documented progression-free status.	12 months
Secondary	Progression-free survival	Time from initiation of therapy to progression anywhere by RECIST, death from any cause, or last documented progression-free status.	12 months
Secondary	Overall survival	Time from initiation of therapy to death or last follow-up alive	24 months
Secondary	axitinib treatment intensity	Weeks on axitinib therapy multiplied by percentage of initially prescribed dose	12 months