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Phase I Study of Weekly Topotecan in Combination With Sorafenib in Treatment of Relapsed Small Cell Lung Cancer

2015년 12월 15일 업데이트: HealthPartners Institute
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population

연구 개요

상태

완전한

정황

개입 / 치료

상세 설명

Small cell lung cancer (SCLC) comprises approximately 15 percent of all lung cancers in the United States. It is highly correlated with tobacco use and occurs almost exclusively in smokers. SCLC is a particularly virulent malignancy characterized by rapid growth and a tendency to metastasize early in the disease course. In first line treatment, SCLC has a high response rate to cytotoxic chemotherapy. Unfortunately, the disease develops drug resistance in almost all cases resulting in recurrence. In second line treatment, the likelihood of response to treatment is considerably less. Multiple agents have been used in this setting with response rates typically around 25% and median survival of less than 6 months1-3. There is clearly a great need for more effective treatments in this disease.

Topotecan is a semi-synthetic, water soluble derivative of camptothecin, a cytotoxic alkaloid extracted from plants of the genus Camptotheca. Its mechanism of action is inhibition of topoisomerase I, an enzyme necessary to relieve torsional strain of DNA which is necessary to carry out replication. This results in DNA double-strand breaks and ultimately cell death. Topotecan has demonstrated activity in a number of malignancies and is currently indicated for the treatment of ovarian cancer, cervical cancer and recurrent small cell lung cancer.

Topotecan has demonstrated single agent activity in recurrent small cell lung cancer in a number of trials. Reported response rates range from 2 to 31%3-7. A phase III trial compared topotecan to CAV (cyclophosphamide, doxorubicin and vincristine) in treatment of recurrent SCLC5. Response rate, survival and time to progression were similar in both groups. The topotecan group demonstrated significant improvement in symptoms including anorexia, fatigue and dyspnea. This led to FDA approval of topotecan for treatment of recurrent SCLC.

The dose limiting toxicity of topotecan is hematologic. The approved schedule of administration is 1.5mg/m2 daily x 5 every 21 days. A modified schedule of weekly administration at 4mg/m2 has been shown to have similar efficacy with less toxicity8 and has been widely adopted in clinical practice.

Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. It has several biochemically important mechanisms including inhibition of Raf-1 and B-Raf which are pivotal components of the Ras/Raf/Mek/Erk signaling pathway. It also has inhibitory activity against the tyrosine kinases for VEGF and PDGFR as well as Flt-3 and c-kit.

Sorafenib has been safely combined with full dose cytotoxic chemotherapy in several Phase I trials9-11. There is no data on the combination of topotecan and sorafenib to date. Sorafenib is metabolized in the liver undergoing oxidation via CYP3A4 and glucuronidation via UGT1A9. There is no evidence that topotecan affects activity of the cytochrome P450 pathways suggesting low likelihood of a drug-drug interaction. There are no significant overlapping toxicities making this an ideal drug combination to investigate.

연구 유형

중재적

등록 (실제)

16

단계

  • 1단계

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 장소

  • 미국
    • Minnesota
      • St. Louis Park, Minnesota, 미국, 55416
        • Park Nicollet Institute

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

  • 어린이
  • 성인
  • 고령자

건강한 자원 봉사자를 받아들입니다

아니

연구 대상 성별

모두

설명

Inclusion Criteria:

  • Patients must have histologically proven small cell carcinoma of bronchogenic origin.
  • Must have received one course of systemic chemotherapy which included cisplatin or carboplatin. Chemotherapy administered during radiation is allowable.
  • Must have radiographically documented disease recurrence or progression by CT scan or bone scan. CNS only recurrence is not sufficient. Measurable disease per RECIST criteria is not required.
  • ECOG Performance status of 0 to 2

  • Adequate organ function within 14 days of study enrollment as defined by the following:

    • Absolute neutrophil count ≥ 1500/mm3
    • Platelet count ≥ 100,000/mm3
    • Hemoglobin ≥ 9 gm/dL
    • Creatinine ≤ 1.5 mg/dL
    • Bilirubin < 1.5 times upper limit of normal (x UNL)
    • Alkaline phosphatase, aspartate transaminase and alanine transaminase < 3 x ULN (may be <5 x ULN if hepatic metastases)
  • Women of childbearing potential and sexually active males must use an effective method of contraception during the study and for 3 months after the last dose of study drug.
  • Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment.
  • Treated brain metastases that are stable for a minimum of 4 weeks following surgery or radiation and off therapeutic glucocorticoids are allowed.
  • INR<1.5 or a PT/PTT within normal limits. Patients receiving anti- coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
  • Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

  • Pregnant or breast feeding.
  • Myocardial infarction or cerebrovascular accident within 6 months.
  • Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management.
  • History of other active invasive malignancy (except for basal cell or squamous cell skin cancer) within 12 months.
  • Major surgery within 4 weeks.
  • Chemotherapy within 4 weeks.
  • Cardiac disease: Congestive heart failure > NYHA Class II, unstable or new-onset angina within prior 3 months.
  • History of bleeding diathesis or coagulopathy.
  • Active clinically serious infection > CTCAE Grade 2.
  • Ventricular arrhythmias requiring anti-arrhythmic therapy.
  • Serious non-healing wound, ulcer or fracture.
  • Any hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks of study enrollment.
  • Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.
  • Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
  • Known human immunodeficiency virus (HIV) or chronic hepatitis B or C infection.
  • Any condition that impairs patient's ability to swallow whole pills.
  • Any gastrointestinal malabsorption syndrome
  • Use of St. John's wort or rifampin.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 치료
  • 할당: 무작위화되지 않음
  • 중재 모델: 단일 그룹 할당
  • 마스킹: 없음(오픈 라벨)

무기와 개입

참가자 그룹 / 팔
개입 / 치료
실험적: 1
Weekly Topetecan in combination with Sorafenib
의약품: Topotecan
4 mg/m2 IV on day 1, 8, 15. Repeat every 28 days.
다른 이름들:
  • 하이캄틴
의약품: Sorafenib
Dose escalation study at 3 dose levels: 200 mg po daily, 200 mg po bid, 400 mg po bid.
다른 이름들:
  • 넥사바

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
기간
The primary objective of this study is to determine the maximum tolerated dose of sorafenib up to the full active dose when combined with standard weekly dosing of topotecan in patients with recurrent small cell lung cancer and to
기간: 2 years
2 years
characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
기간: 2 years
2 years

2차 결과 측정

결과 측정
기간
To evaluate the objective response rate (CR, PR or stable disease)
기간: 2 years
2 years
To measure time-to-event efficacy looking at the following variables:
기간: 2 years
2 years
o Time to disease progression
기간: 2 years
2 years
o Overall survival
기간: 2 years
2 years

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

스폰서

HealthPartners Institute

수사관

  • 수석 연구원: Joseph Leach, MD, HealthPartners Institute

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작

2007년 4월 1일

기본 완료 (실제)

2009년 12월 1일

연구 완료 (실제)

2010년 3월 1일

연구 등록 날짜

최초 제출

2007년 4월 24일

QC 기준을 충족하는 최초 제출

2007년 4월 25일

처음 게시됨 (추정)

2007년 4월 27일

연구 기록 업데이트

마지막 업데이트 게시됨 (추정)

2015년 12월 16일

QC 기준을 충족하는 마지막 업데이트 제출

2015년 12월 15일

마지막으로 확인됨

2007년 4월 1일

추가 정보

이 연구와 관련된 용어

키워드

추가 관련 MeSH 약관

기타 연구 ID 번호

  • 3557-07-C

이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .

폐암에 대한 임상 시험

Topotecan에 대한 임상 시험

유사한 임상시험 검색

스폰서 및 공동 작업자

건강 상태

약물 개입

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약물 개입

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위치

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