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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04873895
Recruitment Status : Not yet recruiting
First Posted : May 5, 2021
Last Update Posted : May 5, 2021
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Abramson Cancer Center of the University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Malignant Drug: Axitinib 5 MG Drug: Hydroxychloroquine Pill Procedure: trans arterial chemoembolization Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: single-center open-label Phase 1B trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1B Study of Hepatic Chemoembolization Plus Axitinib and Hydroxychlorquine for Liver-Dominant Metastatic Adenocarcinoma Of The Colon And Rectum
Estimated Study Start Date : June 2021
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Serious adverse event (SAE) rate [ Time Frame: 12 months ]
    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 :
  1. objective response rate in the liver [ Time Frame: 3 months ]
    complete and partial response rate by RECIST and modified RECIST

  2. Hepatic progression-free survival [ Time Frame: 12 months ]
    Time from initiation of therapy to progression in the liver by RECIST, death from any cause, or last documented progression-free status.

  3. Progression-free survival [ Time Frame: 12 months ]
    Time from initiation of therapy to progression anywhere by RECIST, death from any cause, or last documented progression-free status.

  4. Overall survival [ Time Frame: 24 months ]
    Time from initiation of therapy to death or last follow-up alive

  5. axitinib treatment intensity [ Time Frame: 12 months ]
    Weeks on axitinib therapy multiplied by percentage of initially prescribed dose



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04873895


Contacts
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Contact: Michael C Soulen, MD 215-421-8647 michael.soulen@pennmedicine.upenn.edu
Contact: Mark O'Hara, MD 267-804-0691 mark.ohara@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
Abramson Cancer Center
Philadelphia, Pennsylvania, United States, 19104
Contact: Chief Compiance Officer       vsallee@pennmedicine.upenn.edu   
Sponsors and Collaborators
Abramson Cancer Center of the University of Pennsylvania
Pfizer
Investigators
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Principal Investigator: Michael C Soulen, MD Abramson Cancer Center
Publications:
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Responsible Party: Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier: NCT04873895    
Other Study ID Numbers: UPCC03221
First Posted: May 5, 2021    Key Record Dates
Last Update Posted: May 5, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Abramson Cancer Center of the University of Pennsylvania:
colorectal cancer
liver metastases
Additional relevant MeSH terms:
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Colorectal Neoplasms
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Hydroxychloroquine
Axitinib
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents
Antineoplastic Agents
Protein Kinase Inhibitors