NCT02795819

Study of the Pan-DAC Inhibitor AR-42 and Pazopanib in Advanced Sarcoma and Kidney Cancer

Terminated Phase 1 Results posted Last updated 24 October 2019

What this trial tests

Phase 1 trial testing AR-42 in Renal Cell Carcinoma in 6 participants. Terminated before completion.

Timeline

8 July 2016

Primary endpoint
24 November 2016

14 March 2019

Quick facts

Lead sponsor	Virginia Commonwealth University
Phase	Phase 1
Status	Terminated
Study type	INTERVENTIONAL
Allocation	non randomized
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	6
Start date	8 July 2016
Primary completion	24 November 2016
Estimated completion	14 March 2019
Sites	1 location across United States

Drugs / interventions tested

• AR-42 — full drug profile →
• Pazopanib — full drug profile →

Conditions studied

• Renal Cell Carcinoma — all drugs for Renal Cell Carcinoma →
• Soft Tissue Sarcoma — all drugs for Soft Tissue Sarcoma →
• Metastatic Disease — all drugs for Metastatic Disease →

Sponsor

Virginia Commonwealth University

Who can join

18 and older, any sex, with Renal Cell Carcinoma or Soft Tissue Sarcoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

The Recommended Phase 2 Doses (RP2Ds) of AR-42 and Pazopanib When Given in Combination. Primary · 1 month

To determine the recommended phase 2 doses (RP2Ds) for AR-42 and pazopanib that are the same as or less than the maximum tolerated doses (MTDs). The dose-limiting toxicity (DLT) evaluation period will be the first treatment cycle. Patients must have taken a minimum of 6 AR-42 doses and a minimum of 21 pazopanib doses during cycle 1 to be considered evaluable for DLT, if DLT has not been observed at the delivered dose. Patients' treatment dose level, dose modification, evaluability for DLT, and DLTs will be listed and summarized by basic descriptive statistics such as frequency and proportion.

Group	Value	95% CI
Cohort Minus 1 (-1)	0
Cohort 1	2
Cohort 2	0
Cohort 3A	0
Cohort 3B	0
Cohort 4A	0
Cohort 4B	0

Number of Participants With Adverse Events That Were Related to Treatment, AR-42 and Pazopanib Combination. Secondary · 5 months

The safety and toxicity of AR-42 and pazopanib when given in combination. Adverse Events (AEs) were characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) to determine the safety and toxicity of the combination of AR-42 and pazopanib. All AEs regardless of grade were recorded from the beginning of the study procedures through 30 days following the end of study treatment.

Group	Value	95% CI
Cohort Minus 1 (-1)	0
Cohort 1	6
Cohort 2	0
Cohort 3A	0
Cohort 3B	0
Cohort 4A	0
Cohort 4B	0

The Antitumor Effects of the AR-42 and Pazopanib Treatment Regimen in Patients With Advanced Renal Cell Carcinoma (RCC) or Soft Tissue Sarcoma (STS). Secondary · 5 months

Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that i

Group	Value	95% CI
Cohort Minus 1 (-1)	0
Cohort 1	1
Cohort 2	0
Cohort 3A	0
Cohort 3B	0
Cohort 4A	0
Cohort 4B	0
Cohort Minus 1 (-1)	0
Cohort 1	2
Cohort 2	0
Cohort 3A	0
Cohort 3B	0
Cohort 4A	0
Cohort 4B	0
Cohort Minus 1 (-1)	0
Cohort 1	1
Cohort 2	0
Cohort 3A	0
Cohort 3B	0
Cohort 4A	0
Cohort 4B	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse event data was collected from Cycle 1 Day 1 to Off-Study Visit for each patient. All trial patients were enrolled on Cohort 1.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1

Serious: 2/6 (33%)

Deaths: 1/6

Serious adverse events (37 terms)

Reaction	System	Cohort 1
Anemia	Blood and lymphatic system disorders	—
Disseminated Intravascular Coagulation	Blood and lymphatic system disorders	—
Cardiac Arrest	Cardiac disorders	—
Sinus Tachycardia	Cardiac disorders	—
Ventricular Tachycardia	Cardiac disorders	—
Abdominal Pain	Gastrointestinal disorders	—
Mucositis Oral	Gastrointestinal disorders	—
Nausea	Gastrointestinal disorders	—
Fatigue	General disorders	—
General Disorders administration site conditions - Other, specify	General disorders	—
Multi Organ Failure	General disorders	—
Sepsis	Infections and infestations	—
Upper Respiratory Infection	Infections and infestations	—
Urinary Tract Infection	Infections and infestations	—
Alanine aminotransferase increased	Investigations	—
Creatinine increased	Investigations	—
Fibrinogen decreased	Investigations	—
Urine output decreased	Investigations	—
Anorexia	Metabolism and nutrition disorders	—
Dehydration	Metabolism and nutrition disorders	—
Hypoalbuminemia	Metabolism and nutrition disorders	—
Hypoglycemia	Metabolism and nutrition disorders	—
Arthritis	Musculoskeletal and connective tissue disorders	—
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	—
Encephalopathy	Nervous system disorders	—

Other adverse events (104 terms — click to expand)

Reaction	System	Cohort 1
Lymphocyte count decreased	Investigations	—
Neutrophil count decreased	Investigations	—
White blood cell decreased	Investigations	—
Anorexia	Metabolism and nutrition disorders	—
Nausea	Metabolism and nutrition disorders	—
Abdominal pain	Gastrointestinal disorders	—
Bloating	Gastrointestinal disorders	—
Malaise	General disorders	—
Pain	General disorders	—
Alanine aminotransferase increased	Investigations	—
Platelet count decreased	Investigations	—
Musculoskeletal and connective tissue disorder - Other, specify	Musculoskeletal and connective tissue disorders	—
Headache	Nervous system disorders	—
Anemia	Blood and lymphatic system disorders	—
Sinus tachycardia	Cardiac disorders	—
Dry mouth	Gastrointestinal disorders	—
Mucositis oral	Gastrointestinal disorders	—
Vomiting	Gastrointestinal disorders	—
Fatigue	General disorders	—
Fever	General disorders	—
Alkaline phosphatase increased	Investigations	—
Aspartate aminotransferase increased	Investigations	—
Weight loss	Investigations	—
Hypermagnesemia	Metabolism and nutrition disorders	—
Hypocalcemia	Metabolism and nutrition disorders	—
Hypokalemia	Metabolism and nutrition disorders	—
Hyponatremia	Metabolism and nutrition disorders	—
Arthralgia	Musculoskeletal and connective tissue disorders	—
Insomnia	Psychiatric disorders	—
Hematuria	Renal and urinary disorders	—
Proteinuria	Renal and urinary disorders	—
Skin and subcutaneous tissue disorders - Other, specify	Skin and subcutaneous tissue disorders	—
Hypertension	Vascular disorders	—
Diarrhea	Gastrointestinal disorders	—
Flatulence	Gastrointestinal disorders	—
Gastroesophageal reflux disease	Gastrointestinal disorders	—
Chills	General disorders	—
General disorders and administration site conditions - Other, specify	General disorders	—
Activated partial thromboplastin time prolonged	Investigations	—
Blood bilirubin increased	Investigations	—

Most-reported serious reactions: Anemia, Disseminated Intravascular Coagulation, Cardiac Arrest, Sinus Tachycardia, Ventricular Tachycardia, Abdominal Pain, Mucositis Oral, Nausea.

Data from ClinicalTrials.gov NCT02795819 adverse events section.

Sponsor's own description

This phase 1 study was developed to identify recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib when given in combination for subsequent clinical trials and may have potentially identified candidate pharmacodynamic and predictive biomarkers.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Molecular Insights into the Mechanism of Necroptosis: The Necrosome As a Potential Therapeutic Target.
   Chen J, Kos R, Garssen J, Redegeld F. · · 2019 · cited 135× · PMID 31766571 · DOI 10.3390/cells8121486
2. Epigenetics-targeted drugs: current paradigms and future challenges.
   Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
3. HDAC inhibitors enhance the immunotherapy response of melanoma cells.
   Booth L, Roberts JL, Poklepovic A, Kirkwood J, et al · · 2017 · cited 109× · PMID 29137331 · DOI 10.18632/oncotarget.17950
4. Histone Deacetylase Inhibitors and Diabetic Kidney Disease.
   Hadden MJ, Advani A. · · 2018 · cited 61× · PMID 30189630 · DOI 10.3390/ijms19092630
5. The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo.
   Booth L, Roberts JL, Sander C, Lee J, et al · · 2017 · cited 48× · PMID 28146421 · DOI 10.18632/oncotarget.14829
6. MicroRNAs Bioinformatics Analyses Identifying HDAC Pathway as a Putative Target for Existing Anti-COVID-19 Therapeutics.
   Teodori L, Sestili P, Madiai V, Coppari S, et al · · 2020 · cited 37× · PMID 33363465 · DOI 10.3389/fphar.2020.582003
7. The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments.
   Angulo JC, Manini C, López JI, Pueyo A, et al · · 2021 · cited 25× · PMID 33922974 · DOI 10.3390/cancers13092071
8. Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor.
   Liva SG, Tseng YC, Dauki AM, Sovic MG, et al · · 2020 · cited 25× · PMID 31930715 · DOI 10.15252/emmm.201809910