Study of Regorafenib and Sildenafil for Advanced Solid Tumors

Virginia Commonwealth University (VCU)

Status and phase: Completed; Phase 1

Conditions: Solid Tumor

Treatments: Drug: Regorafenib; Drug: Sildenafil Citrate

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02466802

NCI-2015-01101 (Registry Identifier)

HM20004297 (Other Identifier)

MCC-13-09812

Details and patient eligibility

About

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.

Full description

This study is a single-arm, open-label, phase 1 trial to determine the RP2D of the combination of regorafenib and sildenafil. Both study medications will be taken orally on days 1-21 of each 28-day cycle.

Using a modified 3+3 dose escalation design, 3-6 patients with an advanced solid tumor will be enrolled at each dose level. Additional patients will be enrolled at the MTD until a total of 12 patients have been treated at the MTD.

Eligible patients will have received available standard treatments. Patients with solid tumors for which regorafenib would be considered a standard treatment are eligible as long as regorafenib has not been previously administered.

Blood samples will be collected for correlative studies including PK, PD, and CTCs. Tumor samples archived from a previous biopsy or surgery will also be collected for correlative studies.

Enrollment: 32 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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
  • International normalized ratio (INR) is =< 1.5
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN for the laboratory
  • Left ventricular ejection fraction (LVEF) assessed by echocardiogram within 3 months prior to initiation of study treatment indicates an LVEF of >= 50%
  • A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of age and has not had a hysterectomy, must have a documented negative serum pregnancy test within 7 days prior to initiating study treatment
  • A WCBP and a male patient with a partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of study treatment and for 2 months following completion of study treatment
  • Ability to understand and willingness to sign the consent form written in English

• Note: the consent form must be signed prior to the conduct of any trial-specific procedure

Exclusion criteria

• 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

• History of organ allograft including corneal transplant

• Any documented history of thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or pulmonary embolism within 6 months prior to initiating study treatment

  * Note: patients with a tumor-associated thrombus of locally-involved vessels should not be excluded from participating in the study

• Evidence of bleeding diathesis or coagulopathy

• Resting systolic blood pressure (BP) < 100 mmHg

• Hypertension defined as systolic BP >= 140 mmHg or diastolic BP >= 90 mmHg despite optimal medical management

• Active or clinically significant cardiac disease including any of the following:

  • Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment
  • Myocardial infarction within 6 months prior to initiating study treatment
  • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
  • New York Heart Association (NYHA) class III or IV congestive heart failure

• Seizure disorder requiring medication

• Serious (ie, >= grade 3) uncontrolled infection

• Known human immunodeficiency virus (HIV) seropositivity

  * Note: HIV testing is not required

• Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy

• Pleural effusion or ascites that causes respiratory compromise (ie, >= grade 2 dyspnea)

• Untreated or metastatic pheochromocytoma

• Planned ongoing treatment with other drugs thought to potentially have adverse interactions with either of the medications included in the study treatment, for example:

  • Alpha 1-blockers

  • Vasodilators, such as nitrates

  • Other PDE5 inhibitors, eg, vardenafil, tadalafil

  • Therapeutic anticoagulation with vitamin K antagonists (eg, warfarin), heparins and heparinoids, or direct thrombin inhibitors (DTIs) ** Note: prophylactic low-dose anticoagulation to maintain vascular access devices or low-dose daily aspirin for cardiac health is permitted

  • Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, roflumilast, pimecrolimus

    ** Note: administration of steroids as part of symptom management or for other supportive care purposes is permitted

  • STRONG cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and/or STRONG CYP3A4 inducers ** Note: if such medications have been used, patients must have discontinued these agents >= 2 weeks prior to initiating study treatment

• Pregnancy or breastfeeding

• Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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32 participants in 1 patient group

A: regorafenib and sildenafil citrate

Experimental group

Description:

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.

Treatment:

Drug: Sildenafil Citrate

Drug: Regorafenib