Samstag, 4. Mai 2024
Navigation öffnen
Anzeige:
Wefra Programatic
 
JOURNAL ONKOLOGIE – STUDIE

Study of Efficacy and Safety of Ribociclib (LEE011) in Combination With Topotecan and Temozolomide (TOTEM) in Pediatric Patients With Relapsed or Refractory Neuroblastoma and Other Solid Tumors

Rekrutierend

NCT-Nummer:
NCT05429502

Studienbeginn:
Dezember 2022

Letztes Update:
23.10.2023

Wirkstoff:
Topotecan, Temozolomide, Ribociclib

Indikation (Clinical Trials):
Neuroblastoma

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
-

Sponsor:
Novartis Pharmaceuticals

Collaborator:
Innovative Therapies For Children with Cancer Consortium

Studienleiter

Novartis Pharmaceuticals
Study Director
Novartis Pharmaceuticals

Kontakt

Studienlocations
(3 von 9)

Novartis Investigative Site
50937 Koeln
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
St Jude s Childrens Research Hospital Dept of Regulatory
38105-2794 Memphis
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Dana Hawkins
Phone: 901-595-5597
E-Mail: dana.hawkins@stjude.org» Ansprechpartner anzeigen
Novartis Investigative Site
2130 Randwick
AustraliaRekrutierend» Google-Maps
Novartis Investigative Site
94800 Villejuif
FranceRekrutierend» Google-Maps
Novartis Investigative Site
119074 Singapore
SingaporeRekrutierend» Google-Maps
Novartis Investigative Site
229899 Singapore
SingaporeRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

The study consists of Phase I -part A (dose finding) and Phase I - part B (multiple expansion

cohorts). Phase II may begin after evaluation of Phase I data (safety, tolerability,

efficacy, pharmacokinetics and biomarker data), with consideration of other emerging data

that may impact on the treatment landscape, before initiating Phase II in patients with

relapsed or refractory NB and/or other tumors studied in Phase I.

- Phase I-Part A (dose finding): a dose finding to determine the maximum tolerated dose

(MTD) and/or recommended Phase II dose (RP2D) of ribociclib in combination with TOTEM.

- Phase I- Part B (multiple expansion cohorts): it will be initiated to confirm RP2D

identified from Phase I-part A. Multiple expansion cohorts have been planned to assess

the preliminary antitumor activity and safety of ribociclib in combination with TOTEM in

participants with r/r NB (cohort 1), MB (cohort 2), HGG (cohort 3), MRT (cohort 4), and

RMS (cohort 5)

- Phase II- Double-blind, randomized, placebo controlled in r/r NB: It is a two-arm

randomized, double blinded, placebo controlled, parallel group trial in participants

with r/r NB.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Participants and/or guardian have the ability to understand and the willingness to

sign a written informed consent document.

2. Age ≥ 12 months and ≤ 21 years at the time of signing consent form Note: The first

dose level of Phase I - part A (dose finding) will enroll participants ≥ 12 years - 21

years old, and may expand to younger participants (≥ 12 months to < 12 years) as

determined by the data.

3. Histologically or cytologically confirmed solid tumors listed below that have

progressed despite standard therapy or for which no effective standard therapy exists.

1. Neuroblastoma (for Phase I and Phase II): Histologically proven neuroblastoma as

per International Neuroblastoma Staging System (INSS); Relapsed or refractory

disease; Measurable disease per International Neuroblastoma Response criteria

(INRC); Bone marrow only disease not eligible; Available MYCN status before

screening

2. Medulloblastoma (for Phase I) regardless of genetic status (i.e. Groups 3 or 4

WNT-activated or non-WNT, SHH-activated or non-SHH)

3. High-grade glioma (for Phase I): including HGG NOS, WHO Grade III or Grade IV;

Glioblastoma, IDH-wildtype or IDH-mutant; Anaplastic astrocytoma, IDH-mutant;

Anaplastic oligodendroglioma, IDH-mutant; Anaplastic pleomorphic

xanthoastrocytoma; Diffuse midline gliomas, H3 K27-altered; Diffuse hemispheric

glioma, H3 G34-mutant; Diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype.

4. Malignant rhabdoid tumor (for Phase I) includes diagnoses of atypical

teratoid/rhabdoid tumor (AT/RT), and rhabdoid tumor of the kidney (RTK), and

other soft tissues as defined by 2 of the 3 following criteria; either (1)+(2) or

(1)+(3): (1) Morphology and immunophenotypic panel consistent with rhabdoid

tumor; (2) Loss of SMARCB1 confirmed by immunohistochemistry; (3) Molecular

confirmation of tumor-specific bi-allelic SMARCB1 loss/mutation is encouraged in

cases where SMARCB1 immunohistochemistry is equivocal, and required if SMARCB1

immunohistochemistry is not available

5. Rhabdomyosarcoma (for Phase I) independent of fusion status and subtype

4. Participants with CNS disease who are on corticosteroids should take stable doses for

at least 7 days prior to first dose of ribociclib with no plans for escalation.

5. Performance status:

1. ≤ 16 years: Lansky Play score ≥ 50%

2. >16 years: Karnofsky performance status ≥ 50% or ECOG < 3

6. Life expectancy of ≥ 12 weeks at the time of enrollment

7. Adequate bone marrow function (bone marrow may be involved with tumor) and organ

function

8. Adequate hepatic, renal, cardiac function

9. Females who are sexually active must agree to use highly effective contraception

during and for 6 months after treatment. Additionally, females of childbearing

potential must have a negative serum pregnancy test within 7 days prior to the first

dose of study medication. Pregnant or lactating females are not eligible for the

study.

10. Sexually active males (including those that have had a vasectomy), who do not agree to

abstinence, must be willing to use a condom during intercourse while on study

treatment and for 6 months after stopping treatment.

Exclusion Criteria:

1. Known hypersensitivity to any of the excipients of ribociclib or topotecan or

temozolomide.

2. Not recovered from clinical and laboratory acute toxicities related to prior

anti-cancer therapies

3. Concurrent severe and/or uncontrolled concurrent medical conditions (serious

infections or significant cardiac, pulmonary, hepatic, psychiatric, GI disease, or

other organ dysfunction) that in the investigator's judgement could compromise their

ability to tolerate or absorb protocol therapy or would interfere with the study

procedures or results

4. Clinically significant, uncontrolled heart disease and/or cardiac repolarization

abnormality

5. History of QTc prolongation; taking medications with a known risk to prolong the QT

interval hat cannot be discontinued or replaced by safe alternative medication

6. Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrow

therapeutic index, strong inducers or inhibitors of CYP3A4/5, herbal

preparations/medications and dietary supplements

7. Vaccinated with live, attenuated vaccines within 4 weeks

8. Participated in a prior investigational study within 30 days

9. Received prior treatment with a CDK4/6 inhibitor

10. Received last dose of anticancer therapy (including experimental) within 4 weeks

11. Previous myeloblative therapy with autologous hematopoietic stem cell rescue within 8

weeks

12. Allogeneic stem cell transplant within 3 months

13. Has last fraction of radiation within 4 weeks

14. Major surgery within 2 weeks

Other protocol-defined inclusion/exclusion criteria may apply

Studien-Rationale

Primary outcome:

1. Phase 1- Part A: Percentage of participants with Dose Limiting Toxicities (DLTs) in Cycle 1 (Time Frame - Up to 28 days):
Percentage of participants with DLTs during first cycle of treatment (each cycle is 28 days) for each dose level associated with administration of ribociclib in combination with TOTEM A DLT is defined as an adverse event or abnormal laboratory value suspected to be related with study treatment.

2. Phase I- Part B: Overall response rate (ORR) as assessed by Blinded Independent Review Committee (BIRC) (Time Frame - Up to 12 months):
ORR defined as the percentage of participants with confirmed best overall response of complete response (CR) or partial response (PR) as assessed by BIRC per: Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG International Neuroblastoma Response Criteria (INRC) for participants with NB Response evaluation criteria in solid tumors (RECIST) version 1.1 for participants with MB, MRT and RMS

3. Phase II- ORR as assessed by BIRC (Time Frame - Up to 12 months):
ORR defined as the percentage of participants with confirmed best overall response of CR or PR as assessed by BIRC using INRC

Secondary outcome:

1. Plasma concentrations of ribociclib (Phase I-Part A, Phase I-Part B, Phase II) (Time Frame - Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days):
Pharmacokinetic (PK) blood samples will be collected at selected time-points to determine ribociclib plasma concentrations from participants in Phase I-Part A, Phase I-Part B and Phase II

2. Area under the plasma concentration-time curve (AUC) of ribociclib (Phase I-Part A, Phase I-Part B, Phase II) (Time Frame - Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days):
PK blood samples will be collected at selected time-points to determine AUC of ribociclib from participants in Phase I-Part A, Phase I-Part B and Phase II

3. Maximum plasma concentration (Cmax) of ribociclib (Phase I-Part A, Phase I-Part B, Phase II) (Time Frame - Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days):
PK blood samples will be collected at selected time-points to determine Cmax of ribociclib from participants in Phase I-Part A, Phase I-Part B and Phase II

4. Time of maximum plasma concentration (Tmax) of ribociclib (Phase I-Part A, Phase I-Part B) (Time Frame - Cycle 1 day 1 and 15; Cycle 2 Day 15. Cycle=28 days):
PK blood samples will be collected at selected time-points to determine Cmax of ribociclib from participants in Phase I-Part A and Phase I-Part B.

5. Duration of response (DOR) as assessed by BIRC (Phase I-Part B) (Time Frame - Up to 42 months):
Duration of response is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due any cause. DOR will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B.

6. Progression Free Survival (PFS) as assessed by BIRC (Phase I-Part B) (Time Frame - Up to 42 months):
PFS is defined as the time from the date of start of treatment to the first documented progression or death due to any cause. PFS will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B.

7. Time to response (TTR) as assessed by BIRC (Phase I-Part B) (Time Frame - Up to 42 months):
TTR is defined as the time from the date of start of treatment to the first documented progression of either CR or PR. TTR will be assessed by BIRC per RANO for participants with HGG, INRC for participants with NB and RECIST 1.1 for participants with MB, MRT and RMS for participants in Phase I-Part B.

8. Overall survival (Phase I-Part B) (Time Frame - Up to 42 months):
OS is defined as the time from the date of start of treatment to the date of death, due to any cause. OS will be assessed for participants in Phase I-Part B.

9. Percentage of participants with dose interruptions and dose reductions (Phase I-Part A, Phase I-Part B, Phase II) (Time Frame - Up to 12 months):
Percentage of participants with dose interruptions and dose reductions for participants in Phase I-Part A, Phase I-Part B and Phase II

10. Duration of response (DOR) as assessed by BIRC (Phase II) (Time Frame - Up to 42 months):
Duration of response is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due any cause. DOR will be assessed by BIRC per RECIST 1.1 for participants in Phase II.

11. Progression Free Survival (PFS) as assessed by BIRC (Phase II) (Time Frame - Up to 42 months):
PFS is defined as the time from the date of start of treatment to the first documented progression or death due to any cause. PFS will be assessed by BIRC per INRC for participants in Phase II

12. Time to response (TTR) as assessed by BIRC (Phase II) (Time Frame - Up to 42 months):
TTR is defined as the time from the date of start of treatment to the first documented progression of either CR or PR. TTR will be assessed by BIRC per INRC for participants in Phase II

13. Clinical benefit rate (CBR) as assessed by BIRC (Phase II) (Time Frame - Up to 42 months):
CBR is defined as the percentage of participants with a best overall response of CR, PR or an overall response of stable disease lasting for a duration of at least 24 weeks. CBR will be assessed by BIRC per INRC for participants in Phase II

14. Overall survival (OS) (Phase II) (Time Frame - Up to 42 months):
OS is defined as the time from the date of start of treatment to the date of death, due to any cause. OS will be assessed for participants in Phase II

15. Change from baseline in Pediatric Quality of Life Inventory (PedsQL) questionnaire (Phase II) (Time Frame - Up to 42 months):
PedsQL is a generic instrument used to measure health related quality of life (HRQOL) in children and youth aged 0-25 years. The generic core instrument is available for different age groups and consist of 23 items covering 4 dimensions of HRQOL: Physical functioning (8 items), Emotional Functioning (5 items), Social Functioning (5 items) and School Functioning (5 items). Items are scored on a 5 point Likert-type response scale: 0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Items are reverse scored and linearly transformed to a 0-100 scale, where higher scores indicating better QoL. Change from baseline in PedsQL scores will be assessed for participants in Phase II.

Studien-Arme

  • Experimental: Phase I-part A: Ribociclib+TOTEM
    Participants with r/r NB, MB, HGG, MRT or RMS will be treated with ribociclib in combination with TOTEM to determine MTD and/or RP2D. Ribociclib dose will be scalated while topotecan and temozolomide will be administered at a fixed dose.
  • Experimental: Phase I- Part B: r/r NB Cohort
    Participants with r/r NB will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A
  • Experimental: Phase I- Part B: r/r MB Cohort
    Participants with r/r MB will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A
  • Experimental: Phase I-Part B: r/r HGG Cohort
    Participants with r/r HGG will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A
  • Experimental: Phase I-Part B: r/r MRT Cohort
    Participants with r/r MRT will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A
  • Experimental: Phase I- Part B: r/r RMS Cohort
    Participants with r/r RMS will be treated with ribociclib in combination with TOTEM at the PR2D identified from Phase I-Part A
  • Experimental: Phase II- Ribociclib+TOTEM
    Participants with r/r NB will be treated with ribocilib in combination with TOTEM at the RP2D defined from Phase I part A.
  • Placebo Comparator: Phase II: Placebo+TOTEM
    Participants with r/r NB will be treated ribociclib matching placebo in combination with TOTEM

Geprüfte Regime

  • Topotecan (Hycamtin):
    Topotecan administered at the standard dose given to neuroblastoma patients
  • Temozolomide (Temodar):
    Temozolamide administered at the standard dose given to neuroblastoma patients
  • Ribociclib (Kisqali / LEE011 / ):
    Ribociclib administered at the RP2D defined from Phase I-Part A.

Quelle: ClinicalTrials.gov


Sie können folgenden Inhalt einem Kollegen empfehlen:

"Study of Efficacy and Safety of Ribociclib (LEE011) in Combination With Topotecan and Temozolomide (TOTEM) in Pediatric Patients With Relapsed or Refractory Neuroblastoma and Other Solid Tumors"

Bitte tragen Sie auch die Absenderdaten vollständig ein, damit Sie der Empfänger erkennen kann.

Die mit (*) gekennzeichneten Angaben müssen eingetragen werden!

Die Verwendung Ihrer Daten für den Newsletter können Sie jederzeit mit Wirkung für die Zukunft gegenüber der MedtriX GmbH - Geschäftsbereich rs media widersprechen ohne dass Kosten entstehen. Nutzen Sie hierfür etwaige Abmeldelinks im Newsletter oder schreiben Sie eine E-Mail an: rgb-info[at]medtrix.group.