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

15 dicembre 2015 aggiornato da: 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

Panoramica dello studio

Stato

Completato

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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.

Tipo di studio

Interventistico

Iscrizione (Effettivo)

16

Fase

  • Fase 1

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Stati Uniti
    • Minnesota
      • St. Louis Park, Minnesota, Stati Uniti, 55416
        • Park Nicollet Institute

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

  • Bambino
  • Adulto
  • Adulto più anziano

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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.

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Non randomizzato
  • Modello interventistico: Assegnazione di gruppo singolo
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: 1
Weekly Topetecan in combination with Sorafenib
Droga: Topotecan
4 mg/m2 IV on day 1, 8, 15. Repeat every 28 days.
Altri nomi:
  • Hycamtin
Droga: Sorafenib
Dose escalation study at 3 dose levels: 200 mg po daily, 200 mg po bid, 400 mg po bid.
Altri nomi:
  • Nexavar

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Lasso di tempo
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
Lasso di tempo: 2 years
2 years
characterize the toxicities associated with the combination of topotecan and sorafenib in this patient population
Lasso di tempo: 2 years
2 years

Misure di risultato secondarie

Misura del risultato
Lasso di tempo
To evaluate the objective response rate (CR, PR or stable disease)
Lasso di tempo: 2 years
2 years
To measure time-to-event efficacy looking at the following variables:
Lasso di tempo: 2 years
2 years
o Time to disease progression
Lasso di tempo: 2 years
2 years
o Overall survival
Lasso di tempo: 2 years
2 years

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

HealthPartners Institute

Investigatori

  • Investigatore principale: Joseph Leach, MD, HealthPartners Institute

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio

1 aprile 2007

Completamento primario (Effettivo)

1 dicembre 2009

Completamento dello studio (Effettivo)

1 marzo 2010

Date di iscrizione allo studio

Primo inviato

24 aprile 2007

Primo inviato che soddisfa i criteri di controllo qualità

25 aprile 2007

Primo Inserito (Stima)

27 aprile 2007

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Stima)

16 dicembre 2015

Ultimo aggiornamento inviato che soddisfa i criteri QC

15 dicembre 2015

Ultimo verificato

1 aprile 2007

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • 3557-07-C

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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