Status and phase
Conditions
Treatments
About
The purpose of this study is to determine the Maximum Tolerated Dose (MTD) of Panobinostat (LBH589) when administered in combination with Carboplatin and Paclitaxel in patients with advanced solid malignancies and to identify the Recommended Dose (RD) for a subsequent Phase II study.
Full description
The combination of Carboplatin (C) and Paclitaxel (PTX) is considered standard treatment in patients with epithelial ovarian cancer and endometrial cancer, in USA and in those in whom anthracyclines are not recommended. In cervical cancer, where very often the renal function is impaired, C represents a convenient substitute of cisplatin in the combination with PTX; in NSCLC the C and PTX regimen is first choice therapy for outpatient treatment first or second line.
LBH is a histone deacetylase (HDAC) inhibitor available also for oral administration.
In combination with platinum agents LBH589 could improve efficacy on DNA by multiple non-exclusive mechanisms (by increasing drug access to chromosomal DNA, interfering with DNA repair, modulating the levels of pro antiapoptotic genes or proliferation/survival genes).
The inclusion of Paclitaxel in the combination of LBH589 and Carboplatin is supported by the results already available with the combination of the HDAC inhibitor Vorinostat (suberoylanilide hydroxamic acid) given orally with carboplatin (AUC 6 mg/ml.h) and paclitaxel (200 mg/m2) in a Phase I study in patients with solid tumors. The regimen proved to be feasible, well tolerated and was associated with promising antitumor activity in patients with NSCLC.
The mechanism of action, and the preliminary preclinical data, suggest that the combination of LBH589, Carboplatin and Paclitaxel could be feasible and worthy of clinical investigation.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Histological/cytological diagnosis of solid tumors in which treatment with Carboplatin and Paclitaxel is indicated, e.g. NSCLC, GY tumors, prostate cancer, unknown primary
Progressive disease (also in terms of tumor markers only, like CA 125 for ovary and PSA for prostate).
Age 18-75 years
Prior chemotherapy of ≤ 1 line for advanced disease
ECOG Performance Status < 2
Life expectancy of at least 3 months
The patient must be able to read, understand and provide written evidence of informed consent
Female patients may not be pregnant or lactating and must be willing to practice contraception. The effects of LBH589 on the developing human fetus are unknown. For this reason, women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation.
Male patients that are not surgically sterile must be practicing a medically acceptable contraceptive regimen while on study treatment
Adequate organ function as defined by the following:
Exclusion criteria
Other chemotherapy treatment < 4 weeks prior to enrolment
Hypersensitivity or allergic reactions to platinum compounds or Carboplatin®; hypersensitivity or allergic reactions to Paclitaxel
Radiotherapy involving > 30% of the active bone marrow
Radiotherapy < 4 weeks prior to enrolment
Pre-existing peripheral neuropathy ≥ grade 2
Pre-existing CTCAE hearing loss or tinnitus ≥ grade 2
Symptomatic pleural effusion
Clinically significant third space fluid accumulation (e.g. ascites,..)
Symptomatic brain metastasis or meningeal tumors
Patients who have not recovered (> grade 1) from the following toxicities of previous regimens before enrolment: fatigue, mucositis, nausea/vomiting, diarrhea
Concurrent enrolment, or previous enrolment within 30 days prior to registration in another investigational device or drug trial(s) or is receiving other investigational agent(s)
Human immunodeficiency virus (HIV) infection
History of bone marrow or major organ transplant
Prior high dose treatment with PBSC support
Impaired cardiac function, including any one of the followings:
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, malabsorption syndrome, or small bowel resection)
Acute or chronic liver or renal disease
Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease) that could cause unacceptable safety risks or compromise compliance with the protocol
Concomitant use of CYP3A4/5 inhibitors or inducers where the treatment can not be discontinued or switched to a different medication prior to starting study drug (medications listed in Appendix 3). The medications listed in Appendix 3 have a relative risk of prolonging the QT interval or inducing Torsades de Pointes, but do not represent an exclusion criteria
Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF) ≤ 2 weeks prior to starting study drug.
Treatment with therapeutic doses of sodium warfarin (Coumarin ). Low doses of Coumarin (e.g., ≤ 2 mg/day) for line patency is allowable
Patients who have received biologic therapy (excluding antiangiogenics) or immunotherapy ≤ 2 weeks prior to starting study treatment or who have not recovered from side effects of such therapy
Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Unable or unwilling to comply with all study procedures
Current history of alcohol or drug abuse
Primary purpose
Allocation
Interventional model
Masking
36 participants in 1 patient group
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal