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Bortezomib and Pemetrexed Disodium in Treating Patients With Advanced Non-Small Cell Lung Cancer or Other Solid Tumors

5. ledna 2018 aktualizováno: University of California, Davis

Phase I/II Study of Two Different Schedules of Bortezomib (VELCADE, PS-341) and Pemetrexed (ALIMTA) in Advanced Solid Tumors, With Emphasis on Non-Small Cell Lung Cancer (NSCLC)

RATIONALE: Bortezomib and pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving bortezomib together with pemetrexed disodium may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of two different schedules of bortezomib when given together with pemetrexed disodium and to see how well they work in treating patients with advanced non-small cell lung cancer or other solid tumors.

Přehled studie

Postavení

Dokončeno

Podmínky

Intervence / Léčba

Detailní popis

OBJECTIVES:

Primary

  • Determine the safety, including dose-limiting toxicities, and feasibility of combining bortezomib with pemetrexed disodium in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. (Phase I)
  • Determine the response rate in patients with advanced NSCLC treated with this regimen. (Phase II)

Secondary

  • Compare the toxicity of 2 different schedules of bortezomib and pemetrexed disodium in patients with advanced solid tumors. (Phase I)
  • Determine the maximum tolerated dose (MTD) of bortezomib when administered with pemetrexed disodium in 2 different treatment schedules in these patients. (Phase I)
  • Determine, preliminarily, the efficacy of the combination of bortezomib and pemetrexed disodium in patients with advanced solid tumors. (Phase I)
  • Assess the overall survival and progression-free survival of these patients. (Phase II)
  • Evaluate the frequency and severity of toxicities associated with this regimen. (Phase II)

Tertiary

  • Perform laboratory correlative studies on tumor tissue and blood samples to investigate potential predictors of response. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II, open-label study.

  • Phase I: Patients will be accrued, in an alternating fashion, to 1 of 2 treatment groups.

    • Group I: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on days 1, 4, 8, and 11.
    • Group II: Patients receive pemetrexed disodium IV on day 1 and bortezomib IV on days 1 and 8.

In both groups, treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients per group receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

  • Phase II: Patients receive pemetrexed disodium bortezomib (at the MTD) as in either group I or group II of the phase I portion of the study. Selection of the treatment schedule is based upon observed toxicity, safety, tolerability, efficacy, and clinical practicality.

Blood is drawn at baseline and prior to courses 2 and 3 for correlative and molecular studies.

Tumor tissue and blood samples from patients enrolled in the phase II portion of the study are examined for various biological markers. Immunohistochemistry is used to measure BCL-2 gene, BCL-xL gene, BAX gene, and p27. Reverse transcriptase-polymerase chain reaction is used to assay the expression of thymidylate synthase, folsyl-polyglutamate synthase, and reduced folate carrier. Levels of plasminogen-activator inhibitor 1 gene, vascular endothelial growth factor, and osteopontin are measured by immunoenzyme techniques. The nuclear expression of NF-kB and p27 in blood is compared before and after study treatment by flow cytometry.

After completion of study treatment, patients in phase I are followed for 30 days and patients in phase II are followed periodically.

Typ studie

Intervenční

Zápis (Aktuální)

27

Fáze

  • Fáze 2
  • Fáze 1

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

  • Spojené státy
    • California
      • Sacramento, California, Spojené státy, 95817
        • University of California Davis Cancer Center

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let až 120 let (Dospělý, Starší dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

DISEASE CHARACTERISTICS:

  • Cytologically or histologically confirmed diagnosis of 1 of the following:

    • Advanced solid tumor that progressed after standard therapy or for which no effective curative therapy exists (phase I)

    • Stage IIIB (pleural effusion) or IV non-small cell lung cancer (NSCLC) (phase II)

      • Disease must have progressed or recurred after 1 platinum-based therapy regimen
      • NSCLC that has progressed or recurred after first-line therapy for stage IIIA or IIIB disease allowed

  • Measurable disease

    • Disease in previously irradiated sites is considered measurable if there is clear disease progression following radiotherapy
    • Evaluable disease (bone metastases, pleural fluid, ascites) allowed (phase I)

  • No symptomatic brain metastasis or disease requiring steroids and anticonvulsants

    • Asymptomatic, previously treated (surgical resection or radiotherapy) brain metastases allowed provided patient is neurologically stable and has been off steroids and anticonvulsants for ≥ 4 weeks

PATIENT CHARACTERISTICS:

  • Zubrod performance status 0-2 (phase I) or 0-1 (phase II)
  • Life expectancy ≥ 3 months
  • Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
  • Bilirubin normal
  • AST ≤ 2.5 times upper limit of normal
  • Granulocyte count ≥ 1,500/mm³
  • Platelet count of ≥ 100,000/mm³
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 3 months after completion of study treatment
  • No pre-existing neuropathy ≥ grade 2

  • No other prior malignancy except for the following (phase II):

    • Adequately treated basal cell or squamous cell skin cancer
    • In situ cervical cancer
    • Adequately treated stage I or II cancer currently in complete remission
    • Any other cancer from which the patient has been disease free for > 5 years
  • No hypersensitivity to bortezomib, boron, or mannitol

  • No cardiovascular complications, including any of the following:

    • Myocardial infarction within the past 6 months
    • New York Heart Association class III-IV heart failure
    • Uncontrolled angina
    • Severe uncontrolled ventricular arrhythmias

    • Electrocardiographic (ECG) evidence of acute ischemia or active conduction system abnormalities

      • Any ECG abnormality at screening must be documented as not medically relevant

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No prior bortezomib or pemetrexed disodium
  • Any number of prior chemotherapy regimens allowed (phase I)
  • More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C) and recovered
  • More than 2 weeks since prior radiotherapy and recovered
  • No nonsteroidal anti-inflammatory drugs (NSAIDs) or salicylates 2 days prior and 2 days after (5 days pre and post for long-acting NSAIDs) administration of pemetrexed disodium
  • No concurrent anticonvulsants that are metabolized by the cytochrome P450 pathway

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: N/A
  • Intervenční model: Přiřazení jedné skupiny
  • Maskování: Žádné (otevřený štítek)

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Number of Patients Experiencing a Dose-limiting Toxicity (Phase I)
Časové okno: Up to 36 months
Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding, requirement for transfusion or lasting >7 days; febrile neutropenia; grade 3 neutropenia associated with infection; any other grade >/=3 non-hematologic toxicity considered by the investigator to be related to study drug.
Up to 36 months
Number of Participants Who Experience Adverse Events (Phase I)
Časové okno: Throughout the entire study (up to 36 months).
Number of participants with treatment-related adverse events as assessed by CTCAE v3.0 (Phase I).
Throughout the entire study (up to 36 months).
Number of Patients With Grade ≥ 3 Toxicity (Phase I)
Časové okno: First cycle of treatment (3 weeks)
Grade 3/4 toxicity occurring in a patient within 1 cycle.
First cycle of treatment (3 weeks)
Number of Patients Who Responded to Study Treatment (Phase II)
Časové okno: From start of treatment until disease progression/recurrence.
To determine the response rate of bortezomib in combination with pemetrexed in patients with advanced NSCLC. Response rate was assessed by CT scan. CT scans was performed at baseline and every two cycles (prior to 3rd and 5th cycle). The evaluation of response was based on standard RECIST criteria.
From start of treatment until disease progression/recurrence.

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Number of Patients With Toxicity by NCI CTC v3.0 (Phase I)
Časové okno: Up to 36 months
Adverse events possibly related to treatment, graded according to the NCI CTCAE v3.0.
Up to 36 months
Maximum Tolerated Dose of Bortezomib in Combination With Pemetrexel (Phase I)
Časové okno: Up to 36 months
Up to 36 months
Number of Participants With Response to Therapy as Measured by RECIST (Phase I)
Časové okno: Up to 36 months
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Best overall response is the best response recorded from the start of the treatment until disease progression/recurrence.
Up to 36 months
Number of Participants With Toxicities (Phase II)
Časové okno: Up to 36 months
Each adverse event will be determined by using the NCI CTCAE, Version 3.0.
Up to 36 months
Analysis of Molecular Determinants in Tumor Samples (Phase II)
Časové okno: Up to 36 months
Expression of relevant molecular targets of the proteasome, which is inhibited by bortezomib.
Up to 36 months
Importance of Folate-associated Gene Expression and Response or Outcome (Phase II)
Časové okno: Up to 36 months
Overexpression of reduced folate carrier (RFC) protein is thought to contribute to decreased resistance to pemetrexed. Levels of expression will be studied by measuring mRNA transcripts using quantitative Reverse Transcriptase-Polymerase Chain Reaction in archival patient tumor specimens.
Up to 36 months
Effect of Bortezomib on Over Expression of NF-kB, BCL-2, and BCL-xL (Phase II)
Časové okno: Up to 36 months
Tumor levels of BCL-2, BCL-xL and BAX will be assessed by immunohistochemistry (IHC).
Up to 36 months

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

University of California, Davis

Spolupracovníci

Eli Lilly and Company

Vyšetřovatelé

  • Studijní židle: Angela Davies, MD, University of California, Davis

Publikace a užitečné odkazy

Osoba odpovědná za zadávání informací o studiu tyto publikace poskytuje dobrovolně. Mohou se týkat čehokoli, co souvisí se studiem.

Obecné publikace

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia

1. března 2005

Primární dokončení (Aktuální)

1. prosince 2006

Dokončení studie (Aktuální)

1. června 2007

Termíny zápisu do studia

První předloženo

18. října 2006

První předloženo, které splnilo kritéria kontroly kvality

18. října 2006

První zveřejněno (Odhad)

19. října 2006

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

31. října 2018

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

5. ledna 2018

Naposledy ověřeno

1. září 2017

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • UCDCC#158
  • 200412739 (Jiný identifikátor: UC Davis)
  • H3E-US-X038 (Jiný identifikátor: Eli Lilly)

Informace o lécích a zařízeních, studijní dokumenty

Studuje lékový produkt regulovaný americkým FDA

Ano

Studuje produkt zařízení regulovaný americkým úřadem FDA

Ne

Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .

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