Patient case: 62-year-old female with mucosal melanoma; genetic feature: KIT (L576P), KIT amplification

Clinical trial: Phase I Tolerability, Efficacy, and Safety Study of Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors

Summary: This is a open-label non-randomized, dose escalation and expansion Phase Ia/b study to determine the safety, tolerability and maximum tolerated dose (MTD) of pazopanib in combination with PCI-24781 in patients with advanced solid tumors.

Detailed description: Study rationale/purpose
  Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor44 of VEGFR-1, -2, -3, PDGFR-α and -β and c-kit approved for metastatic renal cell carcinoma based on phase III data showing a significant prolongation of PFS (5 mos in pretreated patients and 8.3 mos in treatment-naïve patients). In addition recent data was presented this year, but is not yet published, with treatment-refractory sarcoma patients that showed a PFS was significantly prolonged from a median of 20 vs. 7 weeks. As can occur with all antiangiogenic agents, resistance to pazopanib may develop. Epigenetic modification with HDAC inhibitors may overcome drug resistance by causing an increase in accessibility of DNA to chemotherapeutic agents and may therefore significantly potentiate their cytotoxicity. Combination trials with chemotherapy agents are ongoing (clinicaltrials.gov.) To our knowledge, a combination trial of HDACi with anti-angiogenesis agents has not yet been performed and represents an unmet medical need.
  PCI-24781 is a pan HDAC inhibitor. In cell lines tested, up-regulation and down-regulation of genes known to result in changes with signal transduction, oxidation, metabolic changes, apoptosis, proliferation, differentiation and angiogenesis were seen. In addition, ongoing single agent and combination trials have shown the drug to be effective and well-tolerated.
  Hypothesis: Combining an antiangiogenic agent, such as pazopanib, with an epigenetic modifier, such as histone deacetylase inhibitor (HDACi) PCI-24781, can increase the efficacy of pazopanib as well as overcome development of resistance to pazopanib.

Eligibility: Inclusion Criteria:
  -  Patients must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to adhere with treatment and follow-up.
  -  Age ≥ 18 years
  -  Phase Ia: Patients must have histologically or cytologically documented metastatic solid tumor malignancies.
  Phase Ib: Patients must have histologically or cytologically confirmed locally advanced, unresectable or metastatic sarcoma or renal cell carcinoma, any histologic subtype.
  -  Measurable disease by RECIST 1.1
  -  Phase Ia: Patients may have de novo metastatic disease, or documented progression despite any number of prior therapies. Patients must have no curative or other effective therapeutic options available.
  Phase Ib: Patients with sarcoma and RCC may have had any number of prior treatments, including 0, or prior pazopanib. Patients with sarcoma must be ineligible for chemotherapy or must have received at least one standard chemotherapy regimen in the metastatic setting.
  -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  -  Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower except for alopecia
  -  Patient must be at least 2 weeks or five half-lives (whichever is longer) from last standard or experimental therapy, exceptions listed below
  -  radiation therapy, surgery or tumor embolization more than 28 days prior to the first dose of Pazopanib/PCI-24781
  -  patients who have received prior pazopanib are eligible but must not have received it in the last two weeks
  -  A female is eligible to enter and participate in this study if she is of:
  -  Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
  -  A hysterectomy
  -  A bilateral oophorectomy (ovariectomy)
  -  A bilateral tubal ligation
  -  Is post-menopausal Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
  Subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT
  -  Childbearing potential, including any female who has had a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception. GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:
  -  Complete abstinence from sexual intercourse for 14 days before exposure to investigational product, through the dosing period, and for at least 21 days after the last dose of investigational product
  -  Oral contraceptive, either combined or progestogen alone
  -  Injectable progestogen
  -  Estrogenic vaginal ring
  -  Percutaneous contraceptive patches
  -  Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year
  -  Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject
  -  Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
  -  Adequate organ system function
  Exclusion Criteria:
  -  Patients with other untreated, current primary malignancies, other than carcinoma in situ of the cervix or non-melanoma skin cancer
  -  History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases.
  -  Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
  Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of bleeding Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment
  -Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: Malabsorption syndrome Major resection of the stomach or small bowel.
  -  Presence of active HCV or HBV infection, history of HIV, or other uncontrolled systemic infection
  -  Corrected QT interval (QTc) > 480 msecs using Friedrichs formula
  -  Use of medications that are known to prolong cause QT prolongation
  -  History of any one or more of the following cardiovascular conditions within the past 6 months:
  -  Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery bypass graft surgery Symptomatic peripheral vascular disease Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
  -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].
  Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. BP must be re-assessed on two occasions that are separated by a minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP/DBP values from each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the study.
  -  History of cerebrovascular accident, including transient ischemic attack (TIA)
  -  History of pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months Note: Patients with recent DVT who have been treated with therapeutic anticoagulation including Coumadin or any low molecular weight heparin for at least 6 weeks are eligible
  -  Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major)
  -  Evidence of active bleeding or bleeding diathesis
  -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures
  -  Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study

Relevance to patient case: not relevant