Clinical Trials /

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

NCT04873895

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

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

DrugSynonymsArms
Axitinib 5 MGTACE+axitinib+HCQ
Hydroxychloroquine PillTACE+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

NameTypeDescriptionInterventions
TACE+axitinib+HCQExperimental2 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