Clinical trial NCT02466802: Study of Regorafenib and Sildenafil for Advanced Solid Tumors
Official title: Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Keywords: Advanced
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2015-06-09
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: To determine the recommended phase 2 dose (RP2D) of the combination of regorafenib and of sildenafil when given to patients with advanced solid tumors.
timeFrame: 28 days
Secondary outcomes:
measure: To evaluate the safety and toxicity of the regorafenib and sildenafil combination
timeFrame: Up to 30 days after completion of study treatment
measure: To explore the antitumor effects of the regorafenib and sildenafil combination
timeFrame: Up to 30 days after completion of study treatment
measure: To determine the pre-treatment expression of phosphodiesterase type 5 (PDE5) in tumor samples
timeFrame: 12- 24 months
measure: To evaluate the impact of sildenafil on the pharmacokinetics of regorafenib
timeFrame: 12-24 months
Other outcomes:
measure: To explore the PD relationships between regorafenib and tumor response
timeFrame: 12-24 months
measure: To assess the feasibility of isolating, enumerating, and analyzing CTCs to characterize cGMP within tumor cells
timeFrame: Up to 30 days after completion of study treatment
measure: To assess the bioactivity of sildenafil in plasma
timeFrame: 12-24 months
measure: To assess the cytokine/growth factor levels in plasma
timeFrame: Up to day 21 of course 1
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
Study officials:
affiliation: Massey Cancer Center
name: Andrew S. Poklepovic, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.