MC# 20-28 - A Multi-Center, Open-Label, Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Surufatinib (HMPL-012), Previously Named Sulfatinib in Advanced Solid Tumors

  • Agent(s): Surufatinib (HMPL-012)
  • Disease Type(s): Leiomyosarcoma, Undifferentiated Pleomorphic Sarcoma, Synovial Sarcoma, Epithelioid Sarcoma, Angiosarcoma, Pigmented Villonodular Synovitis
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): VEGFR1, VEGFR2, VEGFR3, FGFR1

Mechanism of Action

Surufatinib is a small molecule inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and the fibroblast growth factor receptor type 1 (FGFR1) that binds to and inhibits VEGFRs and FGFR1 thereby inhibiting VEGFR- and FGFR1-mediated signal transduction pathways.  This leads to a reduction of angiogenesis and tumor cell proliferation in VEGFR/FGFR1-overexpressing tumor cells.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of surufatinib can be given with an acceptable level of side effects
  • The effects of surufatinib (good and bad)
  • How much of surufatinib is absorbed into the blood and how fast it is removed
Inclusion Criteria
  1. Fully understand the study and voluntarily sign the informed consent form;
  2. At least 18 years old;
  3. Dose escalation phase: Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type, that has progressed on available standard systemic therapy, and for which no effective therapy or standard of care exists;
  4. Dose expansion phase: Histologically or cytologically documented, locally advanced or metastatic BTC that has progressed on standard first line chemotherapy (Arm A), low- to-intermediate grade (G1 or G2), well differentiated, unresectable or metastatic pNET that has progressed on everolimus, sunitinib, or both (Arm B), low-to-intermediate grade (G1 or G2), well differentiated, unresectable or metastatic EP-NET that has progressed on everolimus (Arm C), and advanced STS (of the subtypes listed below) that has progressed on at least one line of standard therapy or refused standard frontline cytotoxic chemotherapy will be evaluated for enrollment.

NET expansion patients must also meet the following criteria:

  • Gastroenteropancreatic NETs (GEP-NETs) or NETs of origins other than the lung or thymus (including unknown origins), with a mitotic rate of ≤ 20/10 high powered field (HPF) and/or a Ki-67 proliferative index of ≤ 20%; if the mitotic rate and Ki-67 index indicated different grades, the higher grade is used to assign classification; or
  • NETs of the lung or thymus with a mitotic rate of ≤ 10/10 HPF;

STS subtype eligible to be enrolled:

  • Leiomyosarcoma (LMS)
  • Pigmented villonodular synovitis (PVNS)
  • Angiosarcoma
  • Epitheloid sarcoma
  • Undifferentiated pleomorphic sarcoma (UPS)
  1. Patients taking a somatostatin analogue (SSA) to control symptoms of functioning pNET or EP-NET will be permitted to enroll in the study provided that they have been on a stable SSA regimen for at least 2 months before enrollment and will continue on this regimen during the study;
  2. Patients taking SSAs in the absence of secretory symptoms must also have been treated with everolimus (pNET or EP-NET) or sunitinib (pNET) in order to be eligible for this study.  Since disease progression is a requirement for enrollment in the dose expansion phase, in such cases both the targeted therapy (everolimus and sunitinib) and the SSA must be discontinued at least 4 weeks before the first dose of study drug.
  3. Patients must have measurable disease (according to RECIST v. 1.1);
  4. Patients must have radiological documentation of progression of disease in the last 12 months prior to the initiation of study drug;
  5. ECOG performance status of 0 or 1;
  6. Expected survival of more than 12 weeks;
  7. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and partner) to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug.  Such methods include: oral hormonal contraception (combined estrogen/progestogen, or progestogen-only), associated with inhibition of ovulation together with another additional barrier method (e.g., diaphragm, always containing a spermicide), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), or sexual abstinence.  Oral contraception should always be combined with an additional contraceptive method (i.e., barrier method) because of a potential interaction with the study drug.  The same rules are valid for male patients involved in this clinical trial if they have a partner of childbearing potential. Male patients must always use a condom.  A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (ie, ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of the ovaries and/or uterus).
Exclusion Criteria
  1. Patients with high-grade (G3) neurodendocrine tumor, even if it is well differentiated;
  2. Absolute neutrophil count (ANC) of < 1.5 × 109/L, or platelet count of <100 × 109/L, or hemoglobin <9 g/dL;
  3. Serum total bilirubin >1.5 times the upper limit of normal (× ULN);
  4. ALT or AST >1.5 × ULN without hepatic metastases or ALT or AST >3 × ULN with hepatic metastases;
  5. Serum potassium, calcium, or magnesium levels out of normal laboratory range, and clinically significant in the investigator’s judgment;
  6. Creatinine clearance <60 mL/min on the basis of either 24-hour urine collection or the glomerular filtration rate estimated by Cockcroft-Gault equation: [(140 - age)  x (weight in kg) × 0.85 if female] ÷ [72 × (serum creatinine in mg/dL)]
  7. Urine protein ≥2+; patients discovered to have ≥1+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein in 24-hour urine;
  8. Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90mmHg;
  9. International Normalized Ratio (INR) >1.5 or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intending to receive anti-coagulants for therapeutic purposes.;
  10. Risk of or active hemorrhage; history of: active gastric/duodenal ulcer or ulcerative colitis; active hemorrhage of an unresected gastrointestinal tumor; history of gastrointestinal perforation or fistulas; or any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation within 6 months prior to first dose of study drug;
  11. History of severe hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to first dose of study drug;
  12. History of thromboembolic event (including deep vein thrombosis [DVT], pulmonary embolism [PE], stroke and/or transient ischemic attack [TIA]) within 6 months prior to the first dose of study drug;
  13. Patients with squamous non-small cell lung cancer (NSCLC);
  14. Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment or left ventricular ejection fraction (LVEF) <50%;
  15. Mean corrected QT interval by Fridericia’s formula (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in a first-degree relative;
  16. Concomitant use of any medication known to cause QT prolongation or torsades de pointes;
  17. Systemic anti-neoplastic therapies within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
  18. Administration of SSAs in the absence of secretory symptoms must be discontinued at least 4 weeks before the first dose of study drug;
  19. Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
  20. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the first dose of study drug;
  21. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before the first dose of study drug (3 weeks for St John’s Wort).
  22. Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first dose of study drug;
  23. Surgery or invasive procedure (ie, procedure that include a biopsy), or unhealed surgical incision, within 60 days prior to the first dose of study drug;
  24. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 (except for alopecia);
  25. Known human immunodeficiency virus (HIV) infection;
  26. Known clinically significant history of liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis.  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured.  Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load;
  27. Evidence of ongoing or active infection requiring intravenous antibiotics;
  28. Women who are pregnant or lactating;
  29. Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment will be excluded;
  30. Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
  31. Received investigational treatment in another clinical study within 4 weeks prior to the initiation of investigational treatment;
  32. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition that investigators suspect may prohibit use of the investigational product (ie, hypersensitivity to excipients of the study drug), affect interpretation of study results, or put the patient at high risk

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03779113

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Re: MC# 20-28