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Canakinumab
 
JOURNAL ONKOLOGIE – STUDIE

Immunotherapy (Nivolumab and Ipilimumab) Before and After Surgery for the Treatment of Recurrent or Progressive High Grade Glioma in Children and Young Adults

Rekrutierend

NCT-Nummer:
NCT04323046

Studienbeginn:
Oktober 2020

Letztes Update:
04.06.2021

Wirkstoff:
Ipilimumab, Nivolumab, Placebo Administration

Indikation (Clinical Trials):
Glioblastoma, Glioma

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
Phase 1

Sponsor:
Sabine Mueller, MD, PhD

Collaborator:
Bristol-Myers Squibb, Pacific Pediatric Neuro-Oncology Consortium,

Studienleiter

Tom Davidson (tdavidson@chla.usc.edu), MD
Study Chair
Children's Hospital Los Angeles

Kontakt

Studienlocations
(3 von 7)

Alle anzeigen

Studien-Informationen

Detailed Description:

PRIMARY OBJECTIVES:

I. To measure the relative changes in cell cycle-related genetic signature of the tumor

microenvironment post administration of neoadjuvant nivolumab and placebo, ipilimumab and

placebo, and nivolumab and ipilimumab in children and young adults with recurrent or

progressive high grade glioma (HGG) when compared to a cohort of archived non-treated

recurrent pediatric HGG samples.

II. To characterize the safety and tolerability of neoadjuvant nivolumab and placebo,

neoadjuvant ipilimumab and placebo, and neoadjuvant ipilimumab and nivolumab followed by

adjuvant ipilimumab and nivolumab in children and young adults with recurrent or progressive

HGG.

SECONDARY OBJECTIVES:

I. To determine the 6 month and 12 month overall survival (OS) in children and young adults

with recurrent or progressive HGG treated with neoadjuvant nivolumab and placebo, ipilimumab

and placebo, or nivolumab and ipilimumab followed by adjuvant nivolumab and ipilimumab.

II. To determine the 6 month and 12 month progression-free survival (PFS) in children and

young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab and

placebo, ipilimumab and placebo, or nivolumab and ipilimumab followed by adjuvant nivolumab

and ipilimumab.

EXPLORATORY OBJECTIVES:

I. To measure relative changes in interferon gamma associated genetic signature within the

tumor microenvironment post administration of neoadjuvant nivolumab and placebo, ipilimumab

and placebo, or nivolumab and ipilimumab in children and young adults with recurrent or

progressive HGG compared to archived non-treated recurrent pediatric HGG samples.

II. To explore the correlation of interferon-gamma-associated genetic signature, cell

cycle-related genetic signature and infiltrating T lymphocyte (TIL) density and clonality

with clinical responses for each treatment arm.

III. To measure TIL density post administration of neoadjuvant nivolumab and placebo compared

to neo-adjuvant ipilimumab and placebo, and neoadjuvant nivolumab and ipilimumab in children

and young adults with recurrent or progressive HGG.

IV. To estimate the objective response rate (ORR) in children and young adults with recurrent

or progressive HGG treated with neoadjuvant nivolumab and placebo, neoadjuvant ipilimumab and

placebo, or neoadjuvant ipilimumab and nivolumab followed by adjuvant ipilimumab and

nivolumab.

V. To evaluate the association between advanced magnetic resonance imaging (MRI) parameters

(apparent diffusion coefficient (ADC) on diffusion weighted imaging (DWI), relative cerebral

blood volume (rCBV) on dynamic susceptibility contrast (DSC) perfusion MRI, pre-contrast T1

shortening on T1-weighed images, and/or magnetization transfer ratio with asymmetric analysis

(MTRasym) on pH-weighted amine chemical exchange saturation transfer (CEST)-echo planar

imaging (EPI)) and tumor and peripheral blood immune responses.

VI. To measure relative change in peripheral T-cell response and post administration of

neo-adjuvant nivolumab and placebo, ipilimumab and placebo, or nivolumab and ipilimumab in

children and young adults with recurrent or progressive HGG.

VII. To measure PD-1 and PDL-1 expression by immunohistochemistry for children and young

adults with recurrent or progressive HGG post neoadjuvant nivolumab and placebo, neoadjuvant

ipilimumab and placebo, or neoadjuvant ipilimumab and nivolumab, and evaluate the differences

between the three arms as well as between each group and archived non-treated recurrent

pediatric HGG samples.

VIII. To explore the correlation of tumor mutational load with clinical response for children

and young adults with recurrent or progressive HGG treated with neoadjuvant nivolumab and

placebo, neoadjuvant ipilimumab and placebo, or neoadjuvant ipilimumab and nivolumab followed

by adjuvant ipilimumab and nivolumab.

IX. To assess quality of life (QOL) and cognitive measures in children and young adults with

recurrent or progressive HGG treated with neoadjuvant nivolumab and placebo, neoadjuvant

ipilimumab and placebo, or neoadjuvant ipilimumab and nivolumab followed by adjuvant

ipilimumab and nivolumab.

OUTLINE: Patients are randomized to 1 of 3 groups.

GROUP A:

NEOADJUVANT: Patients receive nivolumab intravenously (IV) over 30 minutes and placebo IV

over 30 minutes 14 days before undergoing standard of care surgical resection.

ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards),

patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.

Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or

unacceptable toxicity.

ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV

over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease

progression or unacceptable toxicity.

GROUP B:

NEOADJUVANT: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes

14 days before undergoing standard of care surgical resection.

ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards),

patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.

Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or

unacceptable toxicity.

ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV

over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease

progression or unacceptable toxicity.

GROUP C:

NEOADJUVANT: Patients receive placebo IV over 30 minutes and ipilimumab IV over 30 minutes 14

days before undergoing standard of care surgical resection.

ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards),

patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1.

Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or

unacceptable toxicity.

ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV

over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease

progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 2

months for up to 5 years.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Participants with recurrent or progressive high-grade gliomas (HGG) (World Health

Organization (WHO) grade III or grade IV) who are candidates for surgical tumor

debulking will be enrolled in this trial

2. All assessments are to occur within 14 days of registration except where otherwise

noted. The participant and their legal parent/guardian must be thoroughly informed

about all aspects of the study, including the study visit schedule and required

evaluations and all regulatory requirements for informed consent. The written informed

consent must be obtained from the participant and legal parent/guardian prior to

enrollment

3. Have a history of previously treated histologically confirmed World Health

Organization grade III or IV HGG. Previous first line therapy with radiation and/or

chemotherapy

4. Have evidence of recurrence or progression of disease by MRI scan

5. Participants must be adequate medical candidates for surgical resection. The intent of

surgical resection is to allow both cytoreduction and tumor debulking as part of

standard of care, and also collect a minimum of 100 mg of tumor tissue for the study

tissue endpoints

6. A primary goal of surgery must be cytoreduction, and not solely on diagnostic biopsy

7. Age: Participants must be > 6 months and < 22 years of age at time of enrollment

8. Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants

=< 16 years of age. Participants who are unable to walk because of paralysis, but who

are up in a wheelchair, will be considered ambulatory for the purpose of assessing the

performance score

9. Prior Therapy: Participants must have fully recovered from the acute toxic effects of

all prior anti-cancer therapy and must meet the following minimum duration from prior

anti-cancer directed therapy prior to enrollment. If after the required timeframe, the

defined eligibility criteria are met, e.g. blood count criteria, the patient is

considered to have recovered adequately

- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.

At least 21 days after the last dose of cytotoxic or myelosuppressive

chemotherapy (42 days if prior nitrosourea)

- An interval of at least 12 weeks from the completion of radiation therapy to

registration unless there is unequivocal histologic confirmation of tumor

progression

- Hematopoietic growth factors: At least 14 days after the last dose of a

long-acting growth factor (e.g. pegfilgrastim) or 7 days for short acting growth

factor. For agents that have known adverse events occurring beyond 7 days after

administration, this period must be extended beyond the time during which adverse

events are known to occur. The duration of this interval must be discussed with

the study chair

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with

reduced platelet or absolute neutrophil count [ANC] counts): At least 7 days

after the last dose of agent

- Interleukins, interferons and cytokines (other than hematopoietic growth

factors): >= 21 days after the completion of interleukins, interferon or

cytokines (other than hematopoietic growth factors)

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,

and toxicity related to prior antibody therapy must be recovered to grade =< 1

- Participants must not have received prior exposure to PD-1, PD-L1 or CTLA4

inhibitors

- Stem cell infusion (with or without total-body irradiation (TBI)):

- Autologous stem cell infusion including boost infusion: >= 42 days

10. Participants must be willing to forego cytotoxic anti-tumor therapies except

study-defined therapy while being treated on study

11. Organ Function Requirements:

- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

- Platelet count >= 100,000/mm^3

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70

mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

- Age: Maximum Serum Creatinine (mg/dL)

- 6 months to < 3 years: 0.6 (male and female)

- 3 to < 6 years: 0.8 (male and female)

- 6 to < 10 years: 1 (male and female)

- 10 to < 13 years: 1.2 (male and female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit of normal

(ULN) for age (except participants with Gilbert syndrome who must have a total

bilirubin level of < 3.0

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN

- Serum albumin >= 2

12. Pregnancy: The effects of nivolumab and ipilimumab on the developing human fetus are

unknown. For this reason women of child-bearing potential must agree to use adequate

contraception (hormonal or barrier method of birth control; abstinence) prior to study

entry, for the duration of study participation and 5 months after completion of

therapy. Should a woman become pregnant or suspect she is pregnant while she or her

partner is participating in this study, she should inform her treating physician

immediately

13. MRI within 28 days prior to registration

Exclusion Criteria:

1. Current or planned participation in a study of an investigational agent or using an

investigational device

2. Has a diagnosis of immunodeficiency

3. Has tumor primarily localized to the brainstem or spinal cord

4. Has presence of diffuse leptomeningeal disease or extracranial disease

5. Has received systemic immunosuppressive treatments (such as methotrexate, chloroquine,

azathioprine, etc.), aside from anti-neoplastic chemotherapy or systemic

corticosteroids within six months of registration

6. Participants with a concurrent condition requiring systemic treatment with either

corticosteroids (> 0.25 mg/kg daily prednisone equivalent) or other immunosuppressive

medications within 14 days of start of study treatment. Inhaled or topical steroids,

and adrenal replacement steroid doses > 0.25 mg/kg daily prednisone equivalent, are

permitted in the absence of active autoimmune disease

7. Unable to taper steroids due to ongoing mass effect; a maximum dexamethasone dose of

0.1 mg/kg/day is allowed, but preferably have been discontinued (inhaled or topical

use of steroids is allowed)

8. Has a known history of active TB (Bacillus tuberculosis)

9. Has a known additional malignancy that is progressing or requires active treatment

within 3 years of registration. Exceptions include basal cell carcinoma of the skin,

squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone

potentially curative therapy

10. Has active autoimmune disease that has required systemic treatment in the past 2 years

(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive

drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid

replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a

form of systemic treatment

11. Has known history of, or any evidence of active non-infectious pneumonitis

12. Has an active infection requiring systemic therapy

13. Has a known hypersensitivity to any of the study therapy products

14. Has a known history of positive test for human immunodeficiency virus (HIV) or known

acquired immunodeficiency syndrome (AIDS)

- NOTE: Testing for HIV must be performed at sites where mandated locally

15. Any prior positive test result for hepatitis B virus or hepatitis C virus indicating

presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen)

positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid

(RNA) negative)

16. Participants who have had prior allogenic hematopoietic stem cell transplant (HSCT)

17. Any serious or uncontrolled medical disorder that, in the opinion of the investigator

may increase the risk associated with study participation or study drug

administration, impair the ability of the participant to receive protocol therapy or

interfere with interpretation of study results

Studien-Rationale

Primary outcome:

1. Percentage change in cell cycle-related genetic signature (Time Frame - From screening to surgery visit (neoadjuvant treatment groups); at time of recurrent high grade glioma (HGG) tissue collection (for archived non-treated samples)):
Will assess the percentage change in cell cycle-related genetic signature post administration of neoadjuvant treatments in all 3 treatment groups compared to archived recurrent pediatric HGG group. The number of participants with high cell cycle gene signature (positive median gene set variation analysis (GSVA) score) will be tabulated. Variables involved in the primary analyses will be examined graphically and summarized by descriptive statistics.

2. Proportion of participants with treatment-related adverse events (Time Frame - Up to 2 years):
Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 from initiation of study treatment until 2 years after treatment discontinuation or until study treatment related adverse events resolve or return to baseline, Adverse experiences (specific terms as well as system organ class terms) and predefined limits of change in laboratory, and vital sign parameters that are not pre-specified as events of interest will be summarized with descriptive statistics (counts, percentage, mean, standard deviation, etc.).

Secondary outcome:

1. Overall survival (Time Frame - Up to 12 months):
Survival will be assessed at 6 months and 12 months from the time of randomization until the time of death. Kaplan-Meier survival analyses will be performed. Medians together with 2-sided 95% confidence intervals will be computed using a log-log transformation.

2. Progression-free survival (PFS) (Time Frame - Up to 12 months):
PFS is defined as the the time of randomization until the time of progressive disease or death. Kaplan-Meier survival analyses will be performed. Medians together with 2-sided 95% confidence intervals will be computed using a log-log transformation.

Studien-Arme

  • Experimental: Group A (neoadjuvant nivolumab and placebo)
    NEOADJUVANT: Patients receive nivolumab IV over 30 minutes and placebo IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards), patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Experimental: Group B (neoadjuvant nivolumab and ipilimumab)
    NEOADJUVANT: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards), patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Experimental: Group C (neoadjuvant placebo and ipilimumab)
    NEOADJUVANT: Patients receive placebo IV over 30 minutes and ipilimumab IV over 30 minutes 14 days before undergoing standard of care surgical resection. ADJUVANT COMBINATION INFUSION: After recovery from surgery (no more than 35 days afterwards), patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ADJUVANT MAINTENANCE: After completion of combination infusion, patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Geprüfte Regime

  • Ipilimumab (Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody / BMS-734016 / MDX-010 / MDX-CTLA4 / Yervoy / ):
    Given IV
  • Nivolumab (BMS-936558 / MDX-1106 / NIVO / ONO-4538 / Opdivo / ):
    Given IV
  • Placebo Administration:
    Given IV
  • Quality-of-Life Assessment (Quality of Life Assessment):
    Ancillary studies
  • Questionnaire Administration:
    Ancillary studies

Quelle: ClinicalTrials.gov


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