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Safety, Tolerability and Pharmacokinetics of Quisinostat, a Histone Deacetylase Inhibitor, in Combination With Chemotherapy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02728492
Recruitment Status : Completed
First Posted : April 5, 2016
Last Update Posted : May 3, 2016
Sponsor:
Collaborator:
Janssen Pharmaceutica N.V., Belgium
Information provided by (Responsible Party):
NewVac LLC

Brief Summary:
Quisinostat besides its own efficacy, which can potentially lead to better results of polychemotherapy and increase the mean time to progression, it may be demonstrated that Quisinostat leads to sustained tumor sensitivity to platinum drugs. In this study safety and tolerability of multiple administrations of Quisinostat in doses ranging from 8 mg to 12 mg combined with standard backbone chemotherapy in patients with non-small cell lung cancer (second line) and ovarian cancer (second and subsequent lines) will be investigated.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Epithelial Ovarian Cancer Drug: Quisinostat Drug: Paclitaxel Drug: Carboplatin Drug: Gemcitabine Drug: Cisplatin Phase 1

Detailed Description:

It was proven that Quisinostat increases HDAC1-inhibited E-cadherin expression (at the low concentrations of 30 nM) which increases susceptibility to epidermal growth factor inhibitors in case of non-small-cell lung cancer and stops proliferation of paclitaxel-resistant cells. Thus, besides its own efficacy, which can potentially lead to better results of polychemotherapy and increase the mean time to progression, it may be demonstrated that Quisinostat leads to sustained tumor sensitivity to platinum drugs and possibly to resensitiztion in case of acquired or primary resistance.

The main objective of the study is to evaluate the safety and tolerability of Quisinostat in multiple ascending doses and establish its maximum tolerated dose (MTD), administered in combination with standard backbone chemotherapy, as follows: Gemcitabine + Cisplatin in patients with non-small-cell lung cancer (second line) and Paclitaxel + Carboplatin in patients with non-small-cell lung cancer (second line) and in patients with ovarian cancer (second and subsequent lines). MTD is defined as maximum dose at which DLT occurs in no more than 1 patient of 6.

Secondary objectives are:

• Study of pharmacokinetics (PK) of multiple dosing of Quisinostat administered in combination with chemotherapy, as follows: Gemcitabine + Cisplatin in patients with non-small-cell lung cancer (second line) and Paclitaxel + Carboplatin in patients with non-small-cell lung cancer (second line) and in patients with ovarian cancer (second and subsequent lines) Preliminary estimation of possible effect of the drug, added to chemotherapy, on tumor growth.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label Multicenter Multiple Ascending Dose Study to Evaluate Safety, Tolerability and Pharmacokinetics of Quisinostat, a Histone Deacetylase Inhibitor, in Combination With Gemcitabine + Cisplatin Chemotherapy (Second Line for Patients With Non-small Cell Lung Cancer) or Paclitaxel + Carboplatin Chemotherapy (Second Line for Patients With Non-small-cell Lung Cancer, Second and Subsequent Lines for Patients With Epithelial Ovarian Cancer)
Study Start Date : August 2013
Actual Primary Completion Date : December 2015
Actual Study Completion Date : January 2016


Arm Intervention/treatment
Experimental: Quisinostat 8 mg & Paclitaxel & Carboplatin
Quisinostat 8 mg capsule every other day and Paclitaxel 175 mg/m2 on Day 7 of every 3-weeks course and Carboplatin (mg/ml х min) х [GFR (ml/min) + 25] on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Paclitaxel
Drug: Carboplatin
Experimental: Quisinostat 10 mg & Paclitaxel & Carboplatin
Quisinostat 10 mg capsule every other day and Paclitaxel 175 mg/m2 on Day 7 of every 3-weeks course and Carboplatin (mg/ml х min) х [GFR (ml/min) + 25] on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Paclitaxel
Drug: Carboplatin
Experimental: Quisinostat 12 mg & Paclitaxel & Carboplatin
Quisinostat 12 mg capsule every other day and Paclitaxel 175 mg/m2 on Day 7 of every 3-weeks course and Carboplatin (mg/ml х min) х [GFR (ml/min) + 25] on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Paclitaxel
Drug: Carboplatin
Experimental: Quisinostat 8 mg & Gemcitabine 1000 mg/m2 & Cisplatin
Quisinostat 8 mg capsule every other day and Gemcitabine 1000 mg/m2 on Day 7 and on Day 14 of every 3-weeks course and Cisplatin 75 mg/m2 on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Gemcitabine
Drug: Cisplatin
Experimental: Quisinostat 10 mg & Gemcitabine 1000 mg/m2 & Cisplatin
Quisinostat 10 mg capsule every other day and Gemcitabine 1000 mg/m2 on Day 7 and on Day 14 of every 3-weeks course and Cisplatin 75 mg/m2 on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Gemcitabine
Drug: Cisplatin
Experimental: Quisinostat 12 mg & Gemcitabine 1000 mg/m2 & Cisplatin
Quisinostat 12 mg capsule every other day and Gemcitabine 1000 mg/m2 on Day 7 and on Day 14 of every 3-weeks course and Cisplatin 75 mg/m2 on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Gemcitabine
Drug: Cisplatin
Experimental: Quisinostat 12 mg & Gemcitabine 1250 mg/m2 & Cisplatin
Quisinostat 12 mg capsule every other day and Gemcitabine 1250 mg/m2 on Day 7 and on Day 14 of every 3-weeks course and Cisplatin 75 mg/m2 on Day 7 of every 3-weeks course up to 6 cycles
Drug: Quisinostat
Other Name: JNJ-26481585

Drug: Gemcitabine
Drug: Cisplatin



Primary Outcome Measures :
  1. safety and tolerability of Quisinostat based on number of patients with treatment -related AEs assessed by CTCAE v4.0, number of patients with abnormal laboratory values and instrumental tests (ECG) that are related to treatment [ Time Frame: 22 weeks ]

Other Outcome Measures:
  1. Peak Plasma Concentration (Cmax) of Quisinostat [ Time Frame: Day 1, Day 7 ]
  2. Area under the Quisinostat plasma concentration versus time curve (AUC) [ Time Frame: Day 1, Day 7 ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

General criteria for the inclusion of patients with non-small cell lung cancer (NSCLC) and ovarian cancer (OC):

  1. Signed patient's information sheet and informed consent form to participate in the study
  2. Age 18 and older
  3. The value of left ventricular ejection fraction, as determined by echocardiography data, more than 50%
  4. Patient's ability to carry out visits and study procedures and to comply with the protocol
  5. Requirements to laboratory parameters determined below:

    Complete blood count: Absolute neutrophil count:

    Platelets:

    Haemoglobin: ≥ 1500/mm3 (1.5 x 109 cells/l)

    • 100 000/mm3 (100 x 109 cells/l)
    • 9.0 g/dl

    Liver function: Total bilirubin:

    aspartate aminotransferase (AST) and alanine aminotransferase (ALT): ≤ 1.5-fold of the upper limit of normal (ULN)

    ≤ 2.5--fold of ULN or ≤ 5.0-fold of ULN in case of metastases in liver Kidney function: GRF (by Cockcroft-Gault equation) > 50 ml/min

  6. The expected survival time not less than 6 months
  7. Women and men of childbearing potential (not sterile or in menopause less than 2 years) must be practicing an effective method of birth control starting from the screening period, during the study and 6 months after the last administration of the investigational product. Effective methods include use a condom or diaphragm (barrier method) with spermicide.
  8. Functional status of the patient according to the ECOG 0 - 2 Special criteria for patients with NSCLC
  9. Histologically or cytologically confirmed diagnosis of non-resectable non-small-cell lung cancer
  10. The progression of lung cancer after a maximum of one line of systemic anticancer therapy (adjuvant chemotherapy will be considered first-line therapy if the time from the moment of its completion until disease progression was less than 6 months)
  11. No history of treatment with Gemcitabine if the patient is planned for inclusion in the group of chemotherapy with Cisplatin and Gemcitabine, or Paclitaxel if the patient is planned for inclusion in the group of Carboplatin and Paclitaxel.
  12. Vital capacity of lung by spirometry data is more than 50% of normal at screening

    Special inclusion criteria for patients with ovarian cancer

  13. Histologically confirmed diagnosis of ovarian cancer.
  14. Progression after no more than three modes of anticancer drug therapy for ovarian cancer.

Exclusion Criteria:

  1. Indications for X-ray therapy or chemoradiation therapy at the time of inclusion, regardless of the treated area;
  2. Presence of clinical and/or radiological signs of metastases in the brain and meningeal structures (CNS);
  3. Previous therapy with HDAC inhibitors
  4. Any contraindications to the chemotherapy with Gemcitabine + Cisplatin or Paclitaxel + Carboplatin (in patients with lung cancer); contraindications to chemotherapy according to the standard chemotherapy combination scheme Paclitaxel + Carboplatin (in female patients with ovarian cancer);
  5. Any contraindications to administration of glucocorticosteroids, antihistamine drugs, serotonin 5-HT3 receptor antagonists, aprepitant;
  6. Any contraindications to forced rehydration and/or administration of forced diuresis (in case of lung cancer);
  7. Conditions that require continuous use of oral anticoagulants, or clinically significant changes in blood coagulation parameters at screening (INR > 1.5, aPTT> 1.5 х ULN)
  8. Conditions that require admission of prohibited drugs, or impossibility to replace those with allowed drugs in the study
  9. Current infection or other systemic conditions constituting a contraindication to the intended chemotherapy;
  10. Diseases of the digestive system which may infringe absorption of the investigational product (Crohn's disease, nonspecific ulcerative colitis, irritable bowel syndrome)
  11. Clinically significant cardiovascular diseases including:

    • Myocardial infarction within 12 months before screening
    • Unstable angina within 12 months before screening
    • Congestive heart failure Class III or IV according to the New York Heart Association criteria (NYHA)
    • Clinically significant ventricular arrhythmia including ventricular tachycardia, ventricular fibrillation, history of cardiac arrest, atrioventricular block (Mobitz II or III), use of cardiostimulator
    • QTc interval > 450 ms in men or 470 ms in women (ECG) (calculated according to Fredericia formula), or a diagnosis of long QT syndrome
    • Hypotension (systolic blood pressure < 86 mm Hg or bradycardia with a heart rate of < 50 beats per minute (ECG) except when caused by medications (e.g. beta-blockers).
    • Uncontrolled arterial hypertension (systolic arterial pressure > 170 millimeters of mercury or diastolic blood pressure > 105 millimeters of mercury)
  12. Pregnancy and lactation
  13. Presence of HIV antibodies, Hepatitis В and С antibodies
  14. Drug or alcohol abuse at the moment of screening or in the past which according to the opinion of the Investigator makes the patient unsuitable for participation in the study
  15. Significant allergic reactions in medical history
  16. Participation in other clinical studies or administration of test drugs during 30 days before beginning of the study or persisting side effect of any of the test drugs;
  17. Toxic effects of previous treatments or complications after surgical treatments that did not resolve to grades 1 and/or 0 (according to the CTCAE scale).
  18. Patient not willing to participate in the study or unable to understand or follow the protocol instructions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02728492


Locations
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Russian Federation
Russian Oncological Research Center n.a. N. N. Blokhin RAMS
Moscow, Russian Federation, 115478
State Budgetary Healthcare Institution of Stavropol Territory "Pyatigorsk oncology dispensary"
Pyatigorsk, Russian Federation, 357502
Saint-Peterburg State Budgetary healthcare Institution "City Clinical Oncology Dispensary"
Saint-Petersburg, Russian Federation, 197022
BioEq LLC
Saint-Petersburg, Russian Federation, 197342
State Budget Institution of healthcare "Saint-Petersburg clinical research and practical centre of specialized medical aid (oncology)"
Saint-Petersburg, Russian Federation, 197758
State Healthcare Institution of Yaroslavl region "Regional Clinical oncology hospital"
Yaroslavl, Russian Federation, 150054
Sponsors and Collaborators
NewVac LLC
Janssen Pharmaceutica N.V., Belgium
Investigators
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Principal Investigator: Sergey Tjulandin, Prof Russian Oncological Research Center n.a. N. N. Blokhin RAMS
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Responsible Party: NewVac LLC
ClinicalTrials.gov Identifier: NCT02728492    
Other Study ID Numbers: ONC-13-NSCLC/OVA-7-QUI-1B
First Posted: April 5, 2016    Key Record Dates
Last Update Posted: May 3, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Final results will be published
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gemcitabine
Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators