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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Neoplasms Malignant
• Intervention / Treatment: Drug: Axitinib 5 MG; Drug: Hydroxychloroquine Pill; Procedure: trans arterial chemoembolization

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.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Michael C Soulen, MD; Phone Number: 215-421-8647; Email: michael.soulen@pennmedicine.upenn.edu
• Study Contact Backup: Name: Mark O'Hara, MD; Phone Number: 215-360-0919; Email: mark.ohara@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Abramson Cancer Center
      • Contact: Chief Compiance Officer; Email: vsallee@pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TACE+axitinib+HCQ; 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.	Drug: Axitinib 5 MG; axitinib 5 mg po BID until progression or intolerance; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
objective response rate in the liver	complete and partial response rate by RECIST and modified RECIST	3 months
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
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
Overall survival	Time from initiation of therapy to death or last follow-up alive	24 months
axitinib treatment intensity	Weeks on axitinib therapy multiplied by percentage of initially prescribed dose	12 months

Collaborators and Investigators

• Sponsor: Abramson Cancer Center at Penn Medicine
• Collaborators: Pfizer
• Investigators: Principal Investigator: Michael C Soulen, MD, Abramson Cancer Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2022
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: April 30, 2021
• First Submitted That Met QC Criteria: April 30, 2021
• First Posted (Actual): May 5, 2021

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: colorectal cancer; liver metastases
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Protein Kinase Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Axitinib; Hydroxychloroquine
• Other Study ID Numbers: UPCC03221

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