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Dose Finding Study Of PF-05212384 With Paclitaxel And Carboplatin In Patients With Advanced Solid Tumor (IOSI-NDU-001)

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ClinicalTrials.gov Identifier: NCT02069158
Recruitment Status : Completed
First Posted : February 24, 2014
Last Update Posted : May 21, 2019
Sponsor:
Information provided by (Responsible Party):
Cristiana Sessa, Oncology Institute of Southern Switzerland

Brief Summary:

This is a phase Ib single arm, open-label, multiple dose, dose escalating, safety, pharmacokinetic and pharmacodynamic study of the combination of PF-05212384 with paclitaxel and carboplatin. The study will be conducted in adult patients with advanced breast, NSCLC, ovarian or endometrial, small cell lung cancer (SCLC) and Head and Neck (HNSCC) cancer for whom there is an indication to the use of paclitaxel and carboplatin.

Successive cohorts of patients will receive escalating doses of PF-05212384 in combination with paclitaxel and carboplatin, starting at a dose level determined to be the 60% of single agent MTD.

The study will consist of two parts: the dose finding part (Part 1) and the expansion part (Part 2).

During Part 1 patients with breast, NSCLC, ovary and endometrial, small cell lung cancer (SCLC) and Head and Neck (HNSCC) cancer will be enrolled.

During Part 2, only patients with ovarian cancer will be enrolled. In Part 1, a 3+3 design is employed. Once the MTD of the combination is defined in Part 1, Part 2 is performed for a better definition of the safety profile, of the potential antitumor activity and of the pharmacodynamic effects of the combination; it will be conducted in at least 12 patients with ovarian cancer.

Approximately 40 patients are expected to be enrolled in the study overall.


Condition or disease Intervention/treatment Phase
Breast Cancer NSCLC Ovary Cancer Endometrial Cancer Small Cell Lung Cancer (SCLC) Head and Neck (HNSCC) Drug: PF-05212384 Drug: Paclitaxel Drug: Carboplatin Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: DOSE FINDING STUDY OF PF-05212384 WITH PACLITAXEL AND CARBOPLATIN IN PATIENTS WITH ADVANCED SOLID TUMOR
Actual Study Start Date : April 2014
Actual Primary Completion Date : May 2019
Actual Study Completion Date : May 2019


Arm Intervention/treatment
Experimental: PF-05212384, Carboplatin, Paclitaxel
starting dose of PF-05212384: 95 mg iv weekly Dose of Carboplatin: 5 AUC every 28 days Dose of Paclitaxel: 80 mg/m2 on days 1, 8 and 15
Drug: PF-05212384
iv administrartion

Drug: Paclitaxel
iv administration
Other Name: Taxol

Drug: Carboplatin
iv administration
Other Name: no applicable




Primary Outcome Measures :
  1. dose limiting toxicity (DLT) [ Time Frame: 28 days after the first administration ]
    Assessment of the dose limiting toxicities (DLT) during first cycle

  2. Adverse Events [ Time Frame: minimum 8 weeks ]
    Adverse Event characterized by type, frequency and severity (as graded by NCICTCAE v. 4.03) during the treatment until progessive disease

  3. laboratory Adverse Events [ Time Frame: minimum 8 weeks ]
    Laboratory abnormalities characterized by type, frequency and severity (as graded by NCICTCAE v. 4.03) during all treatment until progressive disease


Secondary Outcome Measures :
  1. Pharmacokintecs of PF-05212384 [ Time Frame: Cycle 1 day 1 and Cycle 2 day 1 ]
    Evaluation of the pharmacokinetic of PF-05212384 single agent or in combination with paclitaxel and carboplatin

  2. Tumor response [ Time Frame: every 8 weeks ]
    Objective tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST), RR, TTP

  3. biomarkers of pathway inhibition [ Time Frame: Day 1 of each cycle ]
    Serum glucose, and other circulating biomarkers of pathway inhibition (pS6K1)

  4. Pharmacodynamic [ Time Frame: Just before the treatment starts and cycle 1 day 22 ]
    Evaluation of the pharmacodynamic of biomarkers in tumor tissues (archived and fresh tumor biopsy)

  5. Gene expression [ Time Frame: Just before the treatment starts ]
    Gene expression in biopsied tumor tissues (fresh or archived) relating to PI3K and MAPK signaling



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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:

  • Age >18 years.
  • Histological or cytological diagnosis of advanced/metastatic breast, NSCLC, ovarian and endometrial, small cell lung cancer (SCLC) and Head and Neck (HNSCC) cancer for which there is an indication to the use of paclitaxel and carboplatin.
  • For patients enrolled to Part 1, lesions may be measurable or non measurable; for patients enrolled to Part 2, at least one measurable lesion is requested.
  • All patients must provide an archived or fresh tumor sample; paired fresh tumor biopsies are mandatory for patients enrolled to Part 2 (at baseline and on Day 22 of Cycle 1).
  • ECOG Performance Status must be 0 or 1.
  • Adequate Bone Marrow Function, including:

    1. Absolute Neutrophil Count (ANC) ≥1,500/mm3 (or ≥1.5 x 109/L);
    2. Platelets ≥100,000/mm3 (or ≥100 x 109/L);
    3. Hemoglobin ≥9 g/dL.
  • Adequate renal function, including: serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution.
  • Adequate Liver Function, including:

    1. Total serum bilirubin ≤1.0 mg/dL Aspartate and Alanine Aminotransferase AST & ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is liver involvement secondary to tumor.
    2. Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in case of bone metastasis).
  • Adequate glucose control, including no previous diagnosis of diabetes mellitus and HbA1c <7%.
  • Adequate cardiac function, including: 12 Lead ECG with normal tracing or non clinically significant changes that do not require medical intervention.
  • Resolved acute effects of any prior therapy to baseline severity or Grade

    • 1 CTCAE except for AEs not constituting a safety risk by Investigator judgment.
  • Serum/urine pregnancy test (for females of childbearing potential) negative at screening and at baseline.
  • Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Male patients must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the principal Investigator or a designated associate.
  • Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
  • Written informed consent.

Exclusion Criteria:

  • More than 2 prior lines of chemotherapy for advanced disease for Part 1, more than 1 prior line of chemotherapy for advanced disease for Part 2.
  • Resistance to platinum agents (progression during the treatment or within 3 month from the stop of the treatment).
  • Prior treatment with weekly paclitaxel with tumor progression.
  • Pre-existing neuropathy ≥ G2.
  • Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
  • Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), biological or investigational agents within 4 weeks of the start of the study treatment (6 weeks for mitomycin C or nitrosoureas).
  • Any surgery (not including minor procedures such as lymph node biopsy, needle biopsy, and/or placement of port-a-cath) within 4 weeks of the start of the study treatment or not fully recovered from any side effects of previous procedures.
  • For patients enrolling to Part 2, prior therapy with an agent that is known or proposed to be active by action on PI3K and/or mTOR completed within the last 6 months.
  • Uncontrolled or significant cardiovascular disease:
  • A myocardial infarction within 12 months.
  • Uncontrolled angina within 6 months.
  • Congestive heart failure within 6 months.
  • Diagnosed or suspected congenital long QT syndrome.
  • Any history of ventricular arrhythmias (such as ventricular tachycardia, ventricular Fibrillation, or Torsades de pointes).
  • Any history of second or third degree heart block (may be eligible if currently have a pacemaker).
  • Heart rate <50/minute on pre entry electrocardiogram.
  • Uncontrolled hypertension.
  • Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors. Because inhibition of CYP3A4 isoenzymes may increase PF- 05212384 exposure leading to a potential increases in toxicities, the use of known strong inhibitors (strong CYP3A4 Inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, erythromycin, clarithromycin, telithromycin, verapamil, indinavir, saquinavir, ritonavir, nelfinavir, nefazodone, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine, troleandomycin, mibefradil, conivaptan) are not permitted from 10 days prior to the first dose of study drug until discontinuation. Concurrent administration of herbal preparations and current or anticipated need for food or drugs that are known substrates of UGT1A9 (eg, propofol, acetaminophen, and propranolol), of which PF-05212384 is a strong inhibitor, is not permitted from 10 days prior to the first dose of study drug until discontinuation.
  • Current or anticipated need for food or drugs that are known potent CYP3A4 inducers. PF-05212384 metabolism may be induced when taking strong CYP3A4 inducers (eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St. John's Wort) resulting in reduced plasma concentrations. Therefore co administration of study drug in combination with these and other strong CYP3A4 inducers is not permitted from 10 days prior to the first dose of study drug until study treatment discontinuation.
  • Breast feeding or intercurrent pregnancy; no use of highly effective contraception or not agreeing to continue highly effective contraception for 90 days after last dose of investigational product.
  • Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of the protocol.

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): NCT02069158


Locations
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Switzerland
Oncology Institute of Southern Switzerland (IOSI)
Bellinzona, TI, Switzerland, 6500
Sponsors and Collaborators
Cristiana Sessa
Investigators
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Principal Investigator: Anastasios Stathis, Prof. IOSI Sponsor Unit

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Responsible Party: Cristiana Sessa, Prof., Oncology Institute of Southern Switzerland
ClinicalTrials.gov Identifier: NCT02069158     History of Changes
Other Study ID Numbers: IOSI-NDU-001
First Posted: February 24, 2014    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Cristiana Sessa, Oncology Institute of Southern Switzerland:
Advanced solid tumor
Additional relevant MeSH terms:
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Ovarian Neoplasms
Ovarian Diseases
Small Cell Lung Carcinoma
Endometrial Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Uterine Diseases
Genital Diseases, Female
Endocrine Gland Neoplasms
Adnexal Diseases
Endocrine System Diseases
Gonadal Disorders
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Gedatolisib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents