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Ribociclib and Gemcitabine Hydrochloride in Treating Patients With Advanced Solid Tumors or Lymphoma

2022年7月20日 更新者:Roswell Park Cancer Institute

A Phase I Study of CDK4/6 Inhibitor LEE011 Combined With Gemcitabine in Patients With Advanced Solid Tumors or Lymphoma

This phase I trial studies the side effects and best dose of ribociclib and gemcitabine hydrochloride in treating patients with solid tumors or lymphoma that have spread to other places in the body and usually cannot be cured or controlled with treatment. Ribociclib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib together with gemcitabine hydrochloride may work better in treating patients with solid tumors or lymphoma.

調査の概要

詳細な説明

PRIMARY OBJECTIVES:

I. To describe the dose-limiting toxicities and identify the maximum tolerated dose (MTD) and recommended Phase II dose of the combination of LEE011 (ribociclib) and gemcitabine (gemcitabine hydrochloride) in patients with advanced solid tumors or lymphoma.

SECONDARY OBJECTIVES:

I. To describe the safety and tolerability of the combination of LEE011 and gemcitabine.

II. To describe the pharmacokinetic (PK) of LEE011 in combination with gemcitabine.

III. To describe preliminary evidence of efficacy of the combination of LEE011 and gemcitabine.

IV. To evaluate the correlation of cyclin-dependent kinase (CDK) amplification (testing by fluorescence in situ hybridization [FISH]), retinoblastoma (RB) and P16 expression (by immunohistochemistry) in archived and biopsied tumor tissue with treatment response.

OUTLINE: This is a dose-escalation study.

Patients receive ribociclib orally (PO) on days 1-14 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

研究の種類

介入

入学 (実際)

10

段階

  • フェーズ 1

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

    • New York
      • Buffalo、New York、アメリカ、14263
        • Roswell Park Cancer Institute

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年歳以上 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

Inclusion Criteria:

  • Patients must have advanced/metastatic solid malignancy or lymphoma for which no standard treatment option exists that will confer clinical benefit
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Patients enrolled in the dose expansion phase must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for solid tumors or measurable nodal disease at baseline as defined by Cheson criteria for lymphoma
  • Written informed consent must be obtained prior to any screening procedures and according to local guidelines
  • Life expectancy of >= 12 weeks
  • Absolute neutrophil count >= 1.5 × 10^9/L
  • Platelets >= 100 × 10^9/L
  • Hemoglobin >= 9 g/dL
  • Potassium above lower limit normal range for the institution; supplementation may be given before the first dose of study medication
  • Total calcium (corrected for serum albumin if albumin abnormal) above lower limit normal range for the institution; supplementation may be given before the first dose of study medication
  • Magnesium above lower limit normal range for the institution; supplementation may be given before the first dose of study medication
  • Sodium above lower limit normal range for the institution; supplementation may be given before the first dose of study medication
  • Phosphorus above lower limit normal range for the institution; supplementation may be given before the first dose of study medication
  • International normalized ratio (INR) =< 1.5
  • Serum creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min (calculated by Cockcroft Gault equation)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 upper limit of normal (ULN) or =< 5 x ULN if liver metastases are present
  • Total bilirubin =< ULN; or total bilirubin =< 3.0 x ULN with direct bilirubin =< 1.5 ULN n patients with well documented Gilbert's syndrome
  • Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to the start of study drug
  • Must be able to swallow ribociclib capsules

Exclusion Criteria:

  • Previous anti-cancer chemotherapy, immunotherapy or investigational agents < 4 weeks prior to the first day of study defined treatment
  • Patient who has received radiotherapy =< 4 weeks or limited field radiation for palliation =< 2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom >= 25% of the bone marrow was irradiated
  • Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery)
  • Active clinically serious infections or other serious uncontrolled medical conditions
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Patient has baseline neuropathy of > grade 2
  • Patient has known hypersensitivity to any of the excipients of ribociclib
  • Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
  • Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:

    • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
    • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases
  • Clinically significant, uncontrolled heart disease and/ or a history of cardiac dysfunction including any of the following:

    • History of unstable angina pectoris, symptomatic pericarditis, myocardial infarction, coronary artery bypass grafting or coronary angioplasty within 12 months prior to study entry
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Documented cardiomyopathy
    • Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
    • History of clinically significant ventricular arrhythmia and/or conduction delays within 12 months of screening
    • Systolic blood pressure > 160 mmHg or < 90 mmHg
    • Congenital long QT syndrome or family history of long QT syndrome
    • Bradycardia (heart rate < 50 at rest) by electrocardiogram (ECG) or pulse at screening.
  • On screening, inability to determine the Fridericia corrected QT interval (QTcF) interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 450 msec (using Fridericia's correction); all as determined by screening ECG (mean of triplicate ECGs)
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial, or viral infections etc.)
  • Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug (for details):

    • Known strong inducers or inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4/5 (CYP3A4/5) including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
    • Those have a narrow therapeutic window and are predominantly metabolized through CYP3A4
    • Those have a known strong risk to prolong the QT interval or induce Torsades de Pointes
    • Herbal preparations
  • Patient is currently receiving or has received systemic corticosteroids (=< 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment)

    • The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
  • Patient has a history of non-compliance to medical regimen or inability to grant consent
  • Patient is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed
  • Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
  • Patient has not recovered from all toxicities related to prior anticancer therapies to grade 1 per National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (exception to this criterion: patients with any grade of alopecia are allowed to enter the study)
  • Patient with a Child-Pugh score B or C (for cirrhosis patients only)
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation; highly effective contraception methods include:

    • Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening); for female patients on the study, the vasectomized male partner should be the sole partner for that patient
    • Combination of any of the 2 following (a+b or a+c or b+c)

      • a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
      • b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
      • c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository

        • In case of use of oral contraception, women should have been stable on the same pill before taking study treatment
        • Note: oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception
        • Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential
  • Sexually active males unless they use a condom during intercourse while taking the drug and for 21 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか?

デザインの詳細

  • 主な目的:処理
  • 割り当て:なし
  • 介入モデル:単一グループの割り当て
  • マスキング:なし(オープンラベル)

武器と介入

参加者グループ / アーム
介入・治療
実験的:Treatment (ribociclib, gemcitabine hydrochloride)
Patients receive ribociclib PO on days 1-14 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
相関研究
相関研究
与えられた IV
他の名前:
  • ジェムザール
  • dFdCyd
  • ジフルオロデオキシシチジン塩酸塩
  • LY-188011
与えられたPO
他の名前:
  • LEE011
  • LEE-011

この研究は何を測定していますか?

主要な結果の測定

結果測定
メジャーの説明
時間枠
MTD of ribociclib and gemcitabine hydrochloride, defined as the maximum dose level at which =< 1/6 patients have dose limiting toxicities
時間枠:21 days
The frequency of toxicities will be tabulated for the dose estimated to be the MTD.
21 days
Recommended Phase II dose of ribociclib and gemcitabine hydrochloride, using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0)
時間枠:21 days
21 days

二次結果の測定

結果測定
メジャーの説明
時間枠
CDK2/4/6, cyclin D1 and cyclin D3 amplification and RB, P16 expression in tumor tissue
時間枠:Baseline
Will be correlated with treatment response.
Baseline
Disease free survival
時間枠:Up to 30 days after last dose of study drug
Up to 30 days after last dose of study drug
Incidence of adverse events (AEs) of ribociclib and gemcitabine hydrochloride, using the NCI CTCAE v4.0
時間枠:Up to 30 days after last dose of study drug
AEs will be coded and evaluated for severity using NCI-CTCAE, version 4.0 and will be summarized by system organ class and preferred term. The frequency of toxicities will be tabulated by grade across all dose levels and cycles.
Up to 30 days after last dose of study drug
Objective response rate (ORR), calculated as the number of patients with a confirmed complete response (CR) or partial response (PR) divided by the total number of patients, using the RECIST 1.1
時間枠:Up to 30 days after last dose of study drug
Tumor response will be summarized for the evaluable patient population, and the 95% confidence interval for ORR (CR+PR) will be presented. Objective tumor response will be tabulated overall (and by dose level if appropriate).
Up to 30 days after last dose of study drug
Overall survival
時間枠:From the start of treatment until death for any reason, assessed up to 30 days after last dose of study drug
From the start of treatment until death for any reason, assessed up to 30 days after last dose of study drug
PK interactions, including maximum plasma concentration, maximum concentration (Cmax), clearance (CL), half-life, area under the curve (AUC) from 0 to infinity, and AUC from 0 to the last measurable time point (recommended Phase II dose cohort)
時間枠:Pre-dose, 0.5, 1, 2, 4, 6, and 8 hours post-dose on days 1 and 8 of course 1, and pre-dose on day 14 of course 1
Pre-dose, 0.5, 1, 2, 4, 6, and 8 hours post-dose on days 1 and 8 of course 1, and pre-dose on day 14 of course 1
PK/pharmacodynamic parameters of the combination of ribociclib and gemcitabine hydrochloride
時間枠:Up to 30 days after last dose of study drug
A population pharmacokinetic model will be developed utilizing the pharmacokinetic time points collected, and then used to estimate individual AUCs or CL of ribociclib in combination with gemcitabine. The effect of the combination on pharmacokinetic of each drug will be evaluated by the model, along with other participant factors that may explain the inter-participant variability in pharmacokinetics, AUC, as well as the observed Cmax, will then be tested for association changes in responses.
Up to 30 days after last dose of study drug

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

協力者

捜査官

  • 主任研究者:Opyrchal Mateusz、Roswell Park Cancer Institute

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始

2015年5月1日

一次修了 (実際)

2016年4月1日

研究の完了 (実際)

2016年6月1日

試験登録日

最初に提出

2015年4月8日

QC基準を満たした最初の提出物

2015年4月10日

最初の投稿 (見積もり)

2015年4月13日

学習記録の更新

投稿された最後の更新 (実際)

2022年7月25日

QC基準を満たした最後の更新が送信されました

2022年7月20日

最終確認日

2022年7月1日

詳しくは

本研究に関する用語

その他の研究ID番号

  • I 262914 (その他の識別子:Roswell Park Cancer Institute)
  • NCI-2015-00280 (レジストリ識別子:CTRP (Clinical Trial Reporting Program))

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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