Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at San Francisco, California
Dates
study started
estimated completion
Principal Investigator
Pamela Munster
Photo of Pamela Munster
Pamela Munster

Description

Summary

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

Official Title

Phase I Study to Evaluate the Tolerability, Efficacy, and Safety of Pazopanib in Combination With PCI-24781 in Patients With Metastatic Solid Tumors

Details

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 progression-free survival (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.

Keywords

Metastatic Solid Tumors metastatic solid sarcoma progression Neoplasms Abexinostat PZP115891, PCI-24781

Eligibility

You can join if…

Open to people ages 18 years and up

  1. Patients must provide written informed consent prior to performance of study-specific procedures or assessments, and must be willing to adhere with treatment and followup.
  2. Age ≥ 18 years
  3. Phase Ia: Patients must have histologically or cytologically documented metastatic solid tumor malignancies. Phase Ib: Patients must have histologically or cytologically confirmed locally advanced, solid tumor malignancies of one of the following tumor types:
  4. Renal cell carcinoma (N = 20 patients) (Cohort A)
  5. Non-anaplastic thyroid carcinoma (N = 20 patients) (Cohort B) Documentation of histology from a primary or metastatic site is allowed.
  6. Soft tissue sarcoma (N = 20 patients) (Cohort C). Patients must have progressed in a prior line of therapy.
  7. Ovarian carcinoma (N = 20 patients) (Cohort D)
  8. Measurable disease by RECIST 1.1
  9. 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 may have had any number of prior treatments, or prior pazopanib.
  10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  11. Resolution of all chemotherapy or radiation-related toxicities to Grade 1 severity or lower except for alopecia
  12. Patient must be at least 4 weeks or five half-lives (whichever is shorter) from last standard or experimental therapy, except Patients who have received prior pazopanib are eligible but must not have received it in the last two weeks.
  13. Patients must be at least 28 days from last radiation therapy dose, Peptide Receptor Radionuclide Therapy (PRRT), surgery, or tumor embolization prior to the first dose of pazopanib/PCI-24781
  14. . A female is eligible to enter and participate in this study if she is of:
  15. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
  16. A hysterectomy
  17. A bilateral oophorectomy (ovariectomy)
  18. A bilateral tubal ligation
  19. 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
  20. 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. Novartis Pharmaceuticals acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follow:
  21. 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
  22. Oral contraceptive, either combined or progestogen alone
  23. Injectable progestogen
  24. Estrogenic vaginal ring
  25. Percutaneous contraceptive patches
  26. Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year
  27. 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
  28. Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
  29. 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.
  30. . Adequate organ system function as defined below
  31. Absolute neutrophil count (ANC) 1.5 X 109/L
  32. Hemoglobin 9 g/dL (5.6 mmol/L)
  33. Platelets 100 X 109/L
  34. Prothrombin time (PT) or international normalized ratio (INR) 1.2 X upper limit of normal (ULN)
  35. Activated partial thromboplastin time (aPTT) 1.2 X ULN
  36. Total bilirubin 1.5 X ULN
  37. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN
  38. Serum creatinine <1.5 x ULN Or, if >1.5 mg/dL: Calculated creatinine clearance 50 mL/min Urine Protein to Creatinine Ratio (UPC) e <1
  39. . Subjects may not have had a transfusion within 7 days of screening assessment.
  40. . Subjects receiving anticoagulant therapy are eligible if their INR is within the recommended range for the desired level of anticoagulation.
  41. . Patients with increased bilirubin due to Gilberts disease will not be excluded, if increased bilirubin is the only protocol

You CAN'T join if...

met.

  1. . Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.
  2. . If UPC ≥1, then a 24-hour urine protein must be assessed. Subjects must have a 24-hour urine protein value <1 g to be eligible.

5.1.2 Exclusion Criteria

  1. Patients with other primary malignancies receiving active treatment at the time of study entry, other than carcinoma in situ of the cervix, non-melanoma skin cancer, nonmuscle invasive bladder cancer.
  2. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases.
  3. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
  4. Active peptic ulcer disease
  5. Known intraluminal metastatic lesion/s with risk of bleeding
  6. Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
  7. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
  8. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
  9. Malabsorption syndrome
  10. Major resection of the stomach or small bowel.
  11. Presence of known active hepatitis C viral (HCV) or active hepatitis B viral (HBV) infection, history of human immunodeficiency virus (HIV), or other uncontrolled systemic infection
  12. Corrected QT interval (QTc) > 480 msecs using Bazett's formula
  13. Concurrent use of medications that are known to prolong or cause QT prolongation
  14. History of any one or more of the following cardiovascular conditions within the past 6 months:
  15. Cardiac angioplasty or stenting
  16. Myocardial infarction
  17. Unstable angina
  18. Coronary artery bypass graft surgery
  19. Symptomatic peripheral vascular disease
  20. Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA), see Appendix A
  21. . Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥160 mmHg or diastolic blood pressure (DBP) of ≥ 100 (mmHg].

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) Systolic Blood Pressure/Diastolic Blood Pressure values from each blood pressure assessment must be <160/100 mmHg in order for a subject to be eligible for the study.

  1. . History of cerebrovascular accident, including transient ischemic attack (TIA)
  2. . 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
  3. . 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)
  4. . Evidence of active bleeding or bleeding diathesis
  5. . 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 with study procedures
  6. . Unable or unwilling to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is shorter) prior to the first dose of study drug and for the duration of the study

Location

  • University of California, San Francisco accepting new patients
    San Francisco California 94143 United States

Lead Scientist at UCSF

  • Pamela Munster
    Professor, Medicine. Authored (or co-authored) 123 research publications.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Pamela Munster
ID
NCT01543763
Phase
Phase 1
Study Type
Interventional
Last Updated