LBH589 Oral in Combination With Carboplatin and Paclitaxel in Advanced Solid Tumors

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2011 by Southern Europe New Drug Organization.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Southern Europe New Drug Organization
ClinicalTrials.gov Identifier:
NCT01159418
First received: July 8, 2010
Last updated: September 12, 2011
Last verified: September 2011
  Purpose

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.


Condition Intervention Phase
Advanced Solid Tumors
Drug: Panobinostat (LBH589), Carboplatin and Paclitaxel
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase IB Study of the Histone Deacetylase Inhibitor Panobinostat (LBH589) Given Orally in Combination With Carboplatin and Paclitaxel in Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Southern Europe New Drug Organization:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) Recommended Dose (RD) [ Time Frame: 3 weeks after the first drug administration (1 Cycle) ] [ Designated as safety issue: Yes ]
    Number of Dose-Limiting Tocixities (DLTs)


Secondary Outcome Measures:
  • Hints of antitumor activity [ Time Frame: from first drug administration until tumor progression (every 6 weeks) ] [ Designated as safety issue: No ]
    objective tumor responses based on RECIST criteria

  • Biomarkers of HDAC [ Time Frame: Cycle 1 on day 1, 4, 8, 15 and Cycle 2 on day 1, 8. ] [ Designated as safety issue: No ]
    acetylation of histones, H3, H4 and tubulin in PBMC

  • Safety and tolerability [ Time Frame: 4 weeks after last drug administration ] [ Designated as safety issue: Yes ]
    AE types and frequency monitored by laboratory and instrumental assessments, and physical examination


Estimated Enrollment: 36
Study Start Date: June 2008
Estimated Study Completion Date: March 2012
Estimated Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Panobinostat (LBH589), Carboplatin and Paclitaxel Drug: Panobinostat (LBH589), Carboplatin and Paclitaxel
  1. Panobinostat (LBH589) p.o. on days 1,4,8 and 11 of each cycle (20mg-45mg).Carboplatin i.v.on day 1 at a total dose corresponding to a AUC of 5 µg/ml.h. Paclitaxel as 3 hour infusion on day 1 (135 mg/m2).
  2. Panobinostat (LBH589) p.o. on days 1, 4, 15 and 18 of each cycle (20mg-30mg).Carboplatin i.v. on day 8 at a total dose corresponding to a AUC of 5 µg/ml.h.Paclitaxel as a 3 hour infusion on day 8 (135mg/m2-175mg/m2).
  3. Once the MTD is achieved:Panobinostat (LBH589) p.o. on days 1 and 4 of each cycle(20mg-30 mg). Carboplatin i.v. on day 8 at a total dose corresponding to a AUC of 5 µg/ml.h.Paclitaxel as a 3 hour infusion on day 8 (135mg/m2-175 mg/m2).

The treatment will be repeated every three weeks until disease progression.


Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histological/cytological diagnosis of solid tumors in which treatment with Carboplatin and Paclitaxel is indicated, e.g. NSCLC, GY tumors, prostate cancer, unknown primary
  2. Progressive disease (also in terms of tumor markers only, like CA 125 for ovary and PSA for prostate).
  3. Age 18-75 years
  4. Prior chemotherapy of ≤ 1 line for advanced disease
  5. ECOG Performance Status < 2
  6. Life expectancy of at least 3 months
  7. The patient must be able to read, understand and provide written evidence of informed consent
  8. 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.
  9. Male patients that are not surgically sterile must be practicing a medically acceptable contraceptive regimen while on study treatment
  10. Adequate organ function as defined by the following:

    • ANC > 1500/µL
    • Platelets ≥ 100,000/µL
    • Haemoglobin ≥ 10 g/dl
    • Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 60 ml/min
    • Magnesium, potassium and phosphorus ≥ the lower limit of normal or correctable with supplements
    • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 x ULN or ≤ 5.0 x ULN if hepatic involvement is present
    • Serum bilirubin ≤ 1.5 x ULN
    • Alkaline phosphatase (ALP) ≤ 2.5 x ULN or ALP > 2.5 x UNL with liver fraction ≤ 2.5 x ULN

Exclusion Criteria:

  1. Other chemotherapy treatment < 4 weeks prior to enrolment
  2. Hypersensitivity or allergic reactions to platinum compounds or Carboplatin®; hypersensitivity or allergic reactions to Paclitaxel
  3. Radiotherapy involving > 30% of the active bone marrow
  4. Radiotherapy < 4 weeks prior to enrolment
  5. Pre-existing peripheral neuropathy ≥ grade 2
  6. Pre-existing CTCAE hearing loss or tinnitus ≥ grade 2
  7. Symptomatic pleural effusion
  8. Clinically significant third space fluid accumulation (e.g. ascites,..)
  9. Symptomatic brain metastasis or meningeal tumors
  10. Patients who have not recovered (> grade 1) from the following toxicities of previous regimens before enrolment: fatigue, mucositis, nausea/vomiting, diarrhea
  11. 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)
  12. Human immunodeficiency virus (HIV) infection
  13. History of bone marrow or major organ transplant
  14. Prior high dose treatment with PBSC support
  15. Impaired cardiac function, including any one of the followings:

    • Complete Left Bundle Branch Block or obligate use of a cardiac pacemaker or congenital long QT syndrome or history or presence of atrial or ventricular tachyarrhythmias or clinically significant resting bradycardia (< 50 beats per minute) or QTcF > 480 msec on screening ECG or Right Bundle Branch block + left anterior hemiblock (bifascicular block)
    • Angina pectoris or acute MI ≤ 3 months prior to starting study drug
    • Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
  16. 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)
  17. Acute or chronic liver or renal disease
  18. 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
  19. 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
  20. Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF) ≤ 2 weeks prior to starting study drug.
  21. Treatment with therapeutic doses of sodium warfarin (Coumarin ). Low doses of Coumarin (e.g., ≤ 2 mg/day) for line patency is allowable
  22. 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
  23. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  24. Unable or unwilling to comply with all study procedures
  25. Current history of alcohol or drug abuse
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01159418

Locations
Switzerland
Huniversitätsspitals Basel
Basel, Switzerland, 4031
Istituto Oncologico della Svizzera Italiana
Bellinzona, Switzerland, 6500
Mèdecin Adjoint, ME - CePO, CHUV
Lausanne, Switzerland, 1011
Sponsors and Collaborators
Southern Europe New Drug Organization
Novartis
  More Information

No publications provided

Responsible Party: Southern Europe New Drug Organization
ClinicalTrials.gov Identifier: NCT01159418     History of Changes
Other Study ID Numbers: SKSD00702
Study First Received: July 8, 2010
Last Updated: September 12, 2011
Health Authority: Switzerland: Swissmedic

Keywords provided by Southern Europe New Drug Organization:
solid tumors
Panobinostat
histone deacetylase inhibitors

Additional relevant MeSH terms:
Neoplasms
Panobinostat
Carboplatin
Paclitaxel
Histone Deacetylase Inhibitors
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 27, 2014