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Clinical Trial of Lurbinectedin (PM01183) in Patients With Advanced Solid Tumors

27. september 2021 opdateret af: PharmaMar

An Open-Label, Multicenter Study to Assess the Potential Effects of Itraconazole (a Strong CYP3A4 Inhibitor) on the Pharmacokinetics of Lurbinectedin (PM01183) in Patients With Advanced Solid Tumors

Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors

Studieoversigt

Status

Rekruttering

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors.

The study will include a pre-treatment (screening) phase (within 14 days before the first lurbinectedin or itraconazole administration) followed by a treatment phase consisting of two lurbinectedin cycles, one cycle in combination with itraconazole and one cycle as single agent (in different order depending on the study sequence), and one additional third cycle of lurbinectedin as a single agent for patients who meet the continuation criteria and obtain a clinical benefit after the first two cycles, and then follow-up of adverse events if any.

Undersøgelsestype

Interventionel

Tilmelding (Forventet)

11

Fase

  • Fase 1

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiekontakt

Studiesteder

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år og ældre (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

Inclusion Criteria:

  1. Voluntary signed and dated written informed consent prior to any specific study procedure.
  2. Male or female with age ≥ 18 years.
  3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1 (App. 1).
  4. Life expectancy > 3 months.
  5. Pathologically confirmed diagnosis of advanced solid tumors [except for primary central nervous system (CNS) tumors], for which no standard therapy exists.
  6. Recovery to grade ≤ 1 from drug-related adverse events (AEs) of previous treatments, excluding alopecia and grade 1/2 asthenia or fatigue, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v.5).
  7. Laboratory values within fourteen days prior to Day 1 of Cycle 1
  8. Left ventricular ejection fraction (LVEF) by echocardiography (ECHO) or multiple-gated acquisition (MUGA) within normal range (according to institutional standards).
  9. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six months after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in App. 2. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.

Exclusion Criteria:

  1. Concomitant diseases/conditions:

    1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular disease within last year.
    2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
    3. Known cirrhosis, alcohol induced steatosis, or chronic active hepatitis. For hepatitis B, this includes positive test for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR or HVB-DNA+). For hepatitis C, this includes positive test for both Hepatitis C antibody and quantitative Hepatitis C by PCR (or HVC-RNA+).
    4. History of obstructive cholestatic liver disease (suitable for stenting procedure) or biliary sepsis in the past 2 months.
    5. Known of active COVID-19 disease (this includes positive test for SARS-CoV- 2 in nasopharyngeal/oropharyngeal swabs or nasal swabs by PCR).
  2. Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement. Patients with asymptomatic documented stable brain metastases not requiring corticosteroids during the last four weeks are allowed.
  3. Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1.
  4. Use of CYP3A4 substrates such as HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin for which concomitant administration with strong CYP3A4 inhibitor is contraindicated (App 3).
  5. Treatment with any investigational product within the 30 days before Day 1 of Cycle 1.
  6. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception (see App 2).
  7. Psychiatric illness/social situations that would limit compliance with study requirements.

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Randomiseret
  • Interventionel model: Crossover opgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Aktiv komparator: Sequence TR

Sequence 1 (TR)

  • Cycle 1: Itraconazole + lurbinectedin 0.8 mg/m²
  • Cycle 2: Lurbinectedin alone 3.2 mg/m²
  • Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional)

PART A The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m². In Part A, all patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional).

PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences.
Medicin: Lurbinectedin alone
The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.
Medicin: Lurbinectedin+Itraconazole co-administration
The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A.
Aktiv komparator: Sequence RT

Sequence 2 (RT):

  • Cycle 1: Lurbinectedin alone 3.2 mg/m²
  • Cycle 2: Itraconazole + lurbinectedin 0.8 mg/m²
  • Cycle 3: Lurbinectedin alone 3.2 mg/m² (optional)
Medicin: Lurbinectedin alone
The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole.
Medicin: Lurbinectedin+Itraconazole co-administration
The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A.

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Pharmacokinetic Analysis: AUC(0-∞)
Tidsramme: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
The primary parameter of interest for the statistical analysis will be plasma doseadjusted AUC(0-∞)
Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Pharmacokinetic Analysis: AUC(0-t)
Tidsramme: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
The area under the concentration-time curve (AUC) will be calculated using the linear-log trapezoidal rule with extrapolation to infinity.
Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Pharmacokinetic Analysis: Cmax
Tidsramme: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
The maximum plasma concentration (Cmax) will be obtained directly from the experimental data.
Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Pharmacokinetic Analysis: T1/2
Tidsramme: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Terminal half-life (T1/2) will be obtained from the terminal rate constant calculated by linear regression using at least 3 observations.
Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Pharmacokinetic Analysis: Total body clearance
Tidsramme: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Total body clearance (CL), calculated by dividing the administered dose by the AUC with extrapolation to infinity.
Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Pharmacokinetic Analysis: Volume of distribution
Tidsramme: Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Volume of distribution (both at steady state and based on the terminal phase) (Vss and Vz, respectively): Vss is an estimate that equals mean residence time times total body clearance. Vz, calculated dividing the administered dose by the product of the AUC with extrapolation to infinity by the terminal rate constant
Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days)
Pharmacogenetics
Tidsramme: Before treatment start along with PK sample on Day 1 of Cycle 1 (each cycle is 21 days)
A genotype evaluation in genes relevant for lurbinectedin metabolism and transport will be investigated and reported in an independent report in order to determine whether the observed differences between patients in PK parameters are related to these genetic features.
Before treatment start along with PK sample on Day 1 of Cycle 1 (each cycle is 21 days)

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

PharmaMar

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

7. oktober 2020

Primær færdiggørelse (Forventet)

1. november 2022

Studieafslutning (Forventet)

1. december 2022

Datoer for studieregistrering

Først indsendt

2. september 2021

Først indsendt, der opfyldte QC-kriterier

27. september 2021

Først opslået (Faktiske)

1. oktober 2021

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

1. oktober 2021

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

27. september 2021

Sidst verificeret

1. september 2021

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • PM1183-A-018-20

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

produkt fremstillet i og eksporteret fra U.S.A.

Ingen

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