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

  • STATUS
    Recruiting
  • End date
    Jan 1, 2025
  • participants needed
    120
  • sponsor
    Pamela Munster
Updated on 26 January 2021

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.

Description

Study rationale/purpose

Pazopanib is a potent, multi-targeted tyrosine kinase inhibitor44 of VEGFR-1, -2, -3, PDGFRand - 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-nave 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.

Details
Condition Metastatic Solid Tumors
Treatment PZP115891, PCI-24781
Clinical Study IdentifierNCT01543763
SponsorPamela Munster
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Metastatic Solid Tumors?
Do you have any of these conditions: Do you have Metastatic Solid Tumors??
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
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, solid tumor malignancies of one of the following tumor
types
Renal cell carcinoma (N = 20 patients) (Cohort A)
Non-anaplastic thyroid carcinoma (N = 20 patients) (Cohort B) Documentation of histology from a primary or metastatic site is allowed
Soft tissue sarcoma (N = 20 patients) (Cohort C). Patients must have progressed in a prior line of therapy
Ovarian carcinoma (N = 20 patients) (Cohort D)
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 may have had any number of prior treatments, or prior pazopanib
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 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
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
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 milli-international units per millilitre (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. 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
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 as defined below
Absolute neutrophil count (ANC) 1.5 X 109/L
Hemoglobin 9 g/dL (5.6 mmol/L)
Platelets 100 X 109/L
Prothrombin time (PT) or international normalized ratio (INR) 1.2 X upper limit of normal (ULN)
Activated partial thromboplastin time (aPTT) 1.2 X ULN
Total bilirubin 1.5 X ULN
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN
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
Subjects may not have had a transfusion within 7 days of screening assessment
Subjects receiving anticoagulant therapy are eligible if their INR is within the recommended range for the desired level of anticoagulation
Patients with increased bilirubin due to Gilberts disease will not be excluded, if increased bilirubin is the only protocol exclusion criteria met
Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted
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

Exclusion Criteria

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
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 known active hepatitis C viral (HCV) or active hepatitis B viral (HBV) infection, history of human immunodeficiency virus (HIV), or other uncontrolled systemic infection
Corrected QT interval (QTc) > 480 msecs using Bazett's formula
Concurrent use of medications that are known to prolong or 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), see Appendix A
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
\. 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 with 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 shorter) prior to the
first dose of study drug and for the duration of the study
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