Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer

• ClinicalTrials.gov Identifier: NCT03037437
• Recruitment Status: Recruiting
• First Posted: January 31, 2017
• Last Update Posted: September 19, 2022
• Sponsor: The University of Texas Health Science Center at San Antonio
• Information provided by (Responsible Party): Sukeshi Patel, The University of Texas Health Science Center at San Antonio

Study Description

Brief Summary:

The PI is studying if sorafenib/hydroxychloroquine (HCQ) will have improved efficacy when compared to sorafenib alone and in patients progressing of sorafenib the addition of HCQ would lead to disease stability in patients with advanced hepatocellular cancer (HCC).

Condition or disease	Intervention/treatment	Phase
Hepatocellular Cancer	Drug: Sorafenib (SOR); Drug: Hydroxychloroquine (HCQ)	Phase 2

Detailed Description:

Phase 2 study with two cohorts:

Cohort 1: As second-line treatment, we will add HCQ to SOR dose the patient was tolerating at the time of progression.

Cohort 2: SOR-naïve patients receive SOR 400 mg by PO twice daily on Cycle1 Day1 (C1D1). On Cycle 1 Day 15, HCQ 400 mg PO daily will be started. In clinical practice, dose reduction of SOR may be required. On C1D15 SOR maybe kept as starting dose or reduced for toxicity. On Cycle 2 Day 1 of toxicity of HCQ and SOR will be assessed.

Each cycle is 28 days.

Blood samples will be collected at Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 to assess for biomarkers.

Disease evaluation every 2 cycles.

Dose reductions due to adverse events are allowed for both sorafenib per standard of care and/or HCQ for grade 3 or more adverse event was related to study medication. Dose reductions are also permitted based on investigator clinical decision.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 68 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Modulation of Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer
• Actual Study Start Date: February 16, 2017
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: March 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: No prior systemic treatment; Sorafenib (SOR)-naïve patients receive SOR 400 mg by PO twice daily on Cycle1/Day1 (C1D1). In clinical practice, dose reduction of SOR is often required. Therefore, on C1D15, the clinician will dose-reduce sorafenib based on toxicity and hydroxychloroquine (HCQ) 400 mg PO daily will be started. C2D1 of each cohort, toxicity of HCQ will be assessed. Dose reductions due to adverse events (AEs) to each agent are allowed for SOR per standard of care and/or HCQ for grade 3+ AE.	Drug: Sorafenib (SOR); Patients will receive SOR 400 mg by PO twice daily on Cycle1/Day1 (C1D1).; Other Name: Nexavar; Drug: Hydroxychloroquine (HCQ); 400mg by mouth daily; Other Name: Plaquenil
Experimental: Progress on sorafenib; As second-line treatment, we will add hydroxychloroquine (HCQ) to sorafenib (SOR) dose the patient was tolerating at the time of progression.	Drug: Sorafenib (SOR); Patients will receive SOR 400 mg by PO twice daily on Cycle1/Day1 (C1D1).; Other Name: Nexavar; Drug: Hydroxychloroquine (HCQ); 400mg by mouth daily; Other Name: Plaquenil

Outcome Measures

Primary Outcome Measures :

1. Time to tumor progression evaluated via tumor imaging [ Time Frame: Through study completion, an average of 1 year ]
   Computerized axial tomography (CAT) Scan or Magnetic resonance imaging (MRI) will be done at Screening, then every other cycle and evaluated using RECIST version 1.1

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Cytologically or histologically confirmed advanced or metastatic HCC. If no histological diagnosis, patient must have imaging studies compatible with HCC.
• Age 18 years and above
• ECOG performance status of 0 or 1
• Not a candidate for curative treatments (i.e., resection, transplantation)
• Child-Pugh class A or B7 liver function
• Measurable disease as defined by RECIST 1.1
• Patients who received prior local therapy (e.g., TACE) are eligible.
• Documented virology status of hepatitis, as confirmed by screening HBsAg, anti-HBc, and/or anti-HCV
• Life expectancy> 3 months
• For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use two adequate methods of contraception. For men: agreement to use a barrier method of contraception during the treatment period
• Hematologic, Biochemical, and Organ Function within 7 days prior to Cycle 1 Day 1: Granulocyte count > 1500/mm3, Platelet count > 75,000/ mm3, Hemoglobin > 8 g/dL; Total bilirubin < 2.0; Albumin > 2.8g/dl; AST (SGOT) and ALT (SGPT) < 5 x ULN; Serum creatinine< 1.5 x ULN
• Cohort 1 (with sorafenib): No previous systemic therapy including sorafenib or chemotherapy treatment. Previous TACE and local treatments are permitted.
• Cohort 2 (on progression of sorafenib): Patients who have received prior sorafenib therapy for at least 4 weeks and has confirmation of disease progression on CT/MRI. Prior surgery or local therapy within 4 weeks prior to Cycle 1 Day 1, with the exception of palliative radiation therapy to the bone

Exclusion Criteria:

• Patients receiving prior therapy with 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 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 or untreated diabetic retinopathy (stable retinopathy is allowed).
• Patients may not be receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to HCQ.
• Patients requiring the use of enzyme-inducing anti-epileptic medication (phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine) are not eligible for entry into the study.
• 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
• QTc > 500 milliseconds (ms) at baseline.
• 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 sorafenib 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 sorafenib, 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.

Contacts and Locations

Contacts

Contact: Epp Goodwin; 210-450-5798; ctrcreferral@uthscsa.edu

Contact: Sukeshi Patel Arora, MD; 210-450-1015; aroras@uthscsa.edu

Locations

United States, Texas

University of Texas Health Cancer Center; Recruiting

San Antonio, Texas, United States, 78229

Contact: Epp Goodwin 210-450-5798 goodwine@uthscsa.edu

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

Investigators

• Principal Investigator: Sukeshi Patel Arora, MD; Cancer Therapy & Research Center University of Texas Health Science Center San Antonio

More Information

• Responsible Party: Sukeshi Patel, Principal Investigator, The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT03037437
• Other Study ID Numbers: CTMS 16-0076; HSC20160515H ( Other Identifier: University of Texas Health Science Center- San Antonio )
• First Posted: January 31, 2017
• Last Update Posted: September 19, 2022
• Last Verified: September 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sukeshi Patel, The University of Texas Health Science Center at San Antonio:

Hepatocellular Cancer; Sorafenib; Hydroxychloroquine

Additional relevant MeSH terms:

Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Liver Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Carcinoma, Hepatocellular; Digestive System Diseases; Adenocarcinoma; Carcinoma; Hydroxychloroquine; Sorafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Antirheumatic Agents