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

NCT04873895 | Terminated Phase 1 FDA Drug FDA Device

• 1 other identifier: UPCC03221
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Colorectal Neoplasms Malignant

Keywords

colorectal cancer; liver metastases

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• objective response rate in the liver

  3 months

• Hepatic progression-free survival

  12 months

• Progression-free survival

  12 months

• Overall survival

  24 months

• axitinib treatment intensity

  12 months

Study Arms (1)

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.

Drug: Axitinib 5 MG; Drug: Hydroxychloroquine Pill; Procedure: trans arterial chemoembolization

Interventions

Axitinib 5 MG DRUG

axitinib 5 mg po BID until progression or intolerance

TACE+axitinib+HCQ

Hydroxychloroquine Pill DRUG

hydroxychloroquine 600 mg po BID until progression or intolerance

TACE+axitinib+HCQ

trans arterial chemoembolization PROCEDURE

segmental or lobar TACE at 4-8 week intervals until entire tummy burden is treated.

TACE+axitinib+HCQ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or more.
• Pathologically-verified diagnosis of colorectal adenocarcinoma.
• Measurable metastasis to liver with at least one dimension ≥ 1.0 cm.
• Liver dominant metastases as judged by multidisciplinary team consensus review of cross-sectional imaging of the chest, abdomen and pelvis.
• 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.
• Subjects must be at least 2 weeks beyond prior radiotherapy or surgery, and have recovered from all therapy associated toxicities.
• Eastern Cooperative Oncology Group (ECOG) Performance status must be 0-1 (see Appendix II).
• Absolute granulocyte count \> 1,500/ul, platelet count \> 75,000/ul, International Normalized Ratio (INR) \< 1.6
• Serum creatinine \< 2.0 mg/dl; serum bilirubin \< 2.0 mg/dl.
• Urine protein:creatinine ratio \< 1 or 24-hour urine protein \< 1 gm/day
• Liver function Child-Pugh A
• Competent and willing to provide informed consent
• Patients of reproductive potential agree to use approved contraceptive methods per section 5.4

You may not qualify if:

• Contraindications to angiography and selective visceral catheterization:
• severe allergy or intolerance to contrast media not controllable with prophylaxis.
• bleeding diathesis not correctable by usual forms of therapy.
• severe peripheral vascular disease precluding catheterization.
• Contraindications to hepatic artery embolization:
• 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.
• tumor volume \>75% of total liver volume.
• portal vein occlusion without hepatopetal collateral flow demonstrated by angiography; or portal hypertension with hepatofugal flow.
• hepatic encephalopathy.
• Prior hepatic arterial infusion chemotherapy or hepatic radiation therapy. Prior surgical resection or ablation of liver metastases is acceptable.
• No more than two prior lines of systemic chemotherapy.
• Pregnancy or lactation
• Known allergic reactions to irinotecan, HCQ or axitinib
• Allergy to contrast not mitigated by usual prophylaxis
• Serious infection requiring intravenous therapy.

Sponsors & Collaborators

• Abramson Cancer Center at Penn Medicine: lead
• Pfizer: collaborator

Study Sites (1)

Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (4)

• 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.

  PMID: 32273974 BACKGROUND

• 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.

  PMID: 28253108 BACKGROUND

• 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.

  PMID: 32111770 BACKGROUND

• 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.

  PMID: 28640364 BACKGROUND

MeSH Terms

Conditions

Colonic Neoplasms; Colorectal Neoplasms

Interventions

Axitinib; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Chloroquine; Aminoquinolines; Quinolines

Study Officials

• Michael C Soulen, MD

  Abramson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: single-center open-label Phase 1B trial

Study Record Dates

• First Submitted: April 30, 2021
• First Posted: May 5, 2021
• Study Start: January 24, 2022
• Primary Completion: April 25, 2024
• Study Completion: April 25, 2024
• Last Updated: April 26, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)