Vorinostat Plus Hydroxychloroquine Versus Regorafenib in Colorectal Cancer

Modulation of Autophagy: A Clinical Study of Vorinostat Plus Hydroxychloroquine Versus Regorafenib in Refractory Metastatic Colorectal Cancer (mCRC) Patients (CTMS# 14-2015)

This will be a randomized phase II clinical trial of patients with histologic documentation of metastatic colorectal cancer, who have received local and currently approved standard therapies, excluding RGF.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Vorinostat; Drug: Hydroxychloroquine; Drug: Regorafenib

Detailed Description

The investigators will give VOR 400 mg PO daily and HCQ 600 mg PO daily in 4-week cycles. Patients will require imaging up to 6 weeks prior to enrollment and will be assessed for measureable evidence of mCRC. This will be a randomized, controlled phase II clinical trial of patients with histological documentation of metastatic colorectal cancer, who have received locally and currently approved standard therapies, excluding RGF. Patients will be randomized 1:1 to RGF or VOR/HCQ (see schema below). Also, crossover is optional after first progression on the initial therapy, and based on physician discretion and in the best interest of the patient. If crossover is not done, then the patient will be off study and can go on to receive other treatments.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center University of Texas Health Science Center San Antonio

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histological documentation of metastatic colorectal cancer (mCRC)
• ECOG performance status of 0-2
• Radiographical documentation of metastatic disease with imaging up to 6 weeks prior to enrollment
• Patients with mCRC must have been previously treated with irinotecan and/or oxaliplatin and/or VEGF/EGFR therapy or intolerant to these agents
• Documentation of K-Ras mutational status
• Adequate hematologic, renal and liver function (i.e. absolute neutrophil count > 1000/mm3, platelets > 75,000/mm3); creatinine < 2 times the upper limits of normal (ULN) total bilirubin < 1.5 mg/dl, ALT and AST< 3 times above the ULN, ALT and AST can be < 5 times ULN if patients have hepatic involvement.
• Able to provide written informed consent
• Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative pregnancy test within 72 hours prior to receiving the investigational product
• Tumor blocks available from previous surgery/biopsy, or if not available, patients willing to have biopsy

Exclusion Criteria:

• Patients receiving prior therapy with RGF, VOR, and/or HCQ
• Patients with uncontrolled brain metastases. Patients with brain metastases must be asymptomatic and off corticosteroids for at least one week
• Due to risk of disease exacerbation, patients with porphyria are not eligible
• Due to risk of disease exacerbation, patients with psoriasis are ineligible unless the disease is well controlled, and they are under the care of a specialist for the disorder who agrees to monitor the patient for exacerbations
• Patients with previously documented macular degeneration or diabetic retinopathy
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. For targeted therapies, patients will need to clear for 5 half-lives
• Patients may not be receiving any other investigational agents
• Patients should not have taken valproic acid or another histone deacetylase inhibitor for at least 2 weeks prior to enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to VOR or HCQ
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Major surgery or significant traumatic injury occurring within 21 days prior to treatment
• QTc > 500 ms at baseline (average of 3 determinations at 10 minutes interval)
• Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease. Patients with NG-tube, J-tube, or G-tube will not be allowed to participate
• Pregnant women are excluded from this study because vorinostat has the potential for teratogenic or abortifacient effects. For this reason, women of childbearing potential and men must also agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation
• Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with vorinostat, breastfeeding should be discontinued
• Informed Consent - No study specific procedures will be performed without a written and signed informed consent document. Patients who do not demonstrate the ability to understand or the willingness to sign the written informed consent document will be excluded from study entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study Arm - VOR with HCQ; Patients will be given vorinostat 400 mg daily and hydroxychloroquine 600 mg daily in 4 week cycles.	Drug: Vorinostat; 400mg by mouth daily; Other Names: SAHA; Zolinza; VOR; Drug: Hydroxychloroquine; 600mg by mouth daily; Other Names: plaquenil; HCQ
Active Comparator: Control Arm - Regorafenib; Patients will be given oral RGF 160 mg daily for 3 weeks in 4 week cycles.	Drug: Regorafenib; 160 mg by mouth daily; Other Names: Stivarga; RGF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Based on Progression Free Survival of Vorinostat and Hydroxychloroquine Compared to Regorafenib	CT Scan performed every 8 weeks to monitor progression for one year.	Baseline to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Overall Survival (mOS)	Overall survival was measured in months from baseline	Baseline up to 22 months

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Investigators: Principal Investigator: Sukeshi Patel Arora, MD, University of Texas Health Science Center at the Cancer Therapy and Research Center

Publications and helpful links

General Publications

• Arora SP, Tenner L, Sarantopoulos J, Morris J, Liu Q, Mendez JA, Curiel T, Michalek J, Mahalingam D. Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC). Br J Cancer. 2022 Oct;127(6):1153-1161. doi: 10.1038/s41416-022-01892-6. Epub 2022 Jun 23.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2015
• Primary Completion (Actual): March 7, 2018
• Study Completion (Actual): April 16, 2018

Study Registration Dates

• First Submitted: December 9, 2014
• First Submitted That Met QC Criteria: December 11, 2014
• First Posted (Estimated): December 12, 2014

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Histone Deacetylase Inhibitors; Vorinostat; Hydroxychloroquine
• Other Study ID Numbers: CTMS 14-2015