Study of Regorafenib and Sildenafil for Advanced Solid Tumors

NCT02466802 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: MCC-13-09812HM20004297NCI-2015-01101
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1 study of sildenafil in combination with regorafenib in patients with progressive advanced solid tumors. A modified 3+3 dose escalation design will be conducted for the dose escalation of the treatment combination: additional patients will be enrolled at the MTD until a total of 12 patients have been treated at the MTD.

Conditions

Solid Tumor

Keywords

Advanced

Outcome Measures

Primary Outcomes (1)

• To determine the recommended phase 2 dose (RP2D) of the combination of regorafenib and of sildenafil when given to patients with advanced solid tumors.

  Patients' treatment dosing level, dose modification, DLTs, and evaluability for DLTs will be listed and summarized by basic descriptive statistics (such as frequency and proportion). The MTD/RP2D will be found based on the Definitions of Dose-Limiting Toxicity, Maximum Tolerated Dose, and Recommended Phase 2 Dose. RP2D for the combination of regorafenib and sildenafil that is less than or the same as the MTD.

  28 days

Secondary Outcomes (4)

• To evaluate the safety and toxicity of the regorafenib and sildenafil combination

  Up to 30 days after completion of study treatment

• To explore the antitumor effects of the regorafenib and sildenafil combination

  Up to 30 days after completion of study treatment

• To determine the pre-treatment expression of phosphodiesterase type 5 (PDE5) in tumor samples

  12- 24 months

• To evaluate the impact of sildenafil on the pharmacokinetics of regorafenib

  12-24 months

Other Outcomes (4)

• To explore the PD relationships between regorafenib and tumor response

  12-24 months

• To assess the feasibility of isolating, enumerating, and analyzing CTCs to characterize cGMP within tumor cells

  Up to 30 days after completion of study treatment

• To assess the bioactivity of sildenafil in plasma

  12-24 months

Study Arms (1)

A: regorafenib and sildenafil citrate

EXPERIMENTAL

Patients receive regorafenib and sildenafil citrate by mouth every day (PO QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Regorafenib; Drug: Sildenafil Citrate

Interventions

Regorafenib DRUG

Combination of regorafenib and of sildenafil when given to patients with advanced solid tumors. Regorafenib Administration and Treatment Schedule. Regorafenib will be taken orally once daily for the first 21 days of each 28-day cycle. Regorafenib will not be taken on the last 7 days of each cycle. Patients will be instructed as follows: Take regorafenib once daily with a low fat meal that contains less than 30% fat. Take the regorafenib tablets at about the same time each day. Swallow the tablets whole.

Also known as: Stivarga, 755037-03-7, BAY 73-4506

A: regorafenib and sildenafil citrate

Sildenafil Citrate DRUG

Combination of regorafenib and of sildenafil when given to patients with advanced solid tumors.Sildenafil Administration and Treatment Schedule. Sildenafil will be taken orally once daily at the same time the regorafenib dose is taken for the first 21 days of each 28-day cycle. Sildenafil will not be taken on the last 7 days of each cycle.

Also known as: Viagra, SILDENAFIL, Revatio, 171599-83-0

A: regorafenib and sildenafil citrate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced solid tumor that has progressed during or after treatment with approved therapies or for which there is no standard effective therapy available
• Note: patients with solid tumors for which regorafenib would be considered a standard treatment are eligible as long as regorafenib has not been previously administered
• Measurable or evaluable disease by RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophil count (ANC) \>= 1500/mm\^3
• Platelets \>= 100,000/mm\^3
• Hemoglobin \> 9 g/dL (untransfused)
• Creatinine =\< 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance \>= 60 mL/min
• Proteinuria =\< grade 1 (ie, =\< 1+ \[30 mg/dL\] using a random urine sample or \< 1.0 gm using a 24-hour sample)
• Note: if urine sample indicates \>= grade 2 proteinuria (ie, 2+ \[100 mg/dL\]), a 24-hour urine sample must be collected and tested; urine protein in the 24-hour sample must be \< 1.0 gm/24 hours • Total bilirubin =\< 1.5 x ULN for the laboratory
• Exception: if a patient has documented Gilbert's syndrome and a total bilirubin is \> 1.5 x ULN, the total bilirubin requirement may be waived provided the direct bilirubin is within normal limits (WNL) for the laboratory
• Aspartate aminotransferase (AST) =\< 2.5 x ULN for the laboratory
• Alanine aminotransferase (ALT) =\< 2.5 x ULN for the laboratory
• Alkaline phosphatase =\< 2.5 x ULN for the laboratory (=\< 5 x ULN for patients with cancer involving the liver and/or bone)
• Non-hematologic toxicities from previous cancer therapies resolved to =\< grade 1

You may not qualify if:

• Meningeal metastases or brain metastases that are symptomatic or untreated \* Note: patients who are asymptomatic and have had post-treatment imaging that indicates stable brain disease are eligible; (patients with meningeal metastasis are not eligible even if stable following treatment); also, note that brain imaging is required within 8 weeks prior to initiation of study therapy
• Any investigational agent within 4 weeks prior to initiating study treatment
• Previous therapy with regorafenib
• If sorafenib was previously administered, intolerance to sorafenib
• Inability to swallow medication
• Known or suspected malabsorption condition or obstruction
• Contraindications to sildenafil including:
• Known retinitis pigmentosa
• History of priapism related to PDE5 inhibitors (eg, sildenafil, vardenafil, tadalafil)
• Presence of nonmalignant hematologic disorders, such as sickle cell disease, that may increase the risk of priapism
• Contraindication to antiangiogenic agents, including:
• Serious non-healing wound, non-healing ulcer, or bone fracture
• Major surgical procedure or significant traumatic injury within 4 weeks prior to initiating study treatment
• Pulmonary hemorrhage/bleeding event \>= grade 2 within 12 weeks prior to initiating study treatment
• Any other hemorrhage/bleeding event \>= grade 3 within 12 weeks prior to initiating study treatment

Sponsors & Collaborators

• Virginia Commonwealth University: lead
• Bayer: collaborator

Study Sites (1)

Virginia Commonwealth University/Massey Cancer Center

Richmond, Virginia, 23298, United States

Location

Related Publications (2)

• Poklepovic AS, Gordon SW, Kothadia S, McGuire WP, Thacker LR, Deng X, Tombes MB, Shrader E, Hudson D, Bandyopadhyay D, Ryan AA, Kmieciak M, Smith S, Dent P. A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors. Anticancer Drugs. 2024 Jun 1;35(5):450-458. doi: 10.1097/CAD.0000000000001584. Epub 2024 Mar 8.

  PMID: 38452059 DERIVED

• Booth L, Roberts JL, Rais R, Cutler RE Jr, Diala I, Lalani AS, Hancock JF, Poklepovic A, Dent P. Neratinib augments the lethality of [regorafenib + sildenafil]. J Cell Physiol. 2019 Apr;234(4):4874-4887. doi: 10.1002/jcp.27276. Epub 2018 Sep 10.

  PMID: 30203445 DERIVED

MeSH Terms

Interventions

regorafenib; Sildenafil Citrate

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Andrew S. Poklepovic, MD

  Massey Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 4, 2015
• First Posted: June 9, 2015
• Study Start: July 1, 2015
• Primary Completion: January 28, 2019
• Study Completion: January 28, 2019
• Last Updated: February 20, 2020

Record last verified: 2020-02

Locations

US (1)