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Imfinzi NSCLC
Imfinzi NSCLC
JOURNAL ONKOLOGIE – STUDIE

Safety and Efficacy of Pembrolizumab (MK-3475) in Children and Young Adults With Classical Hodgkin Lymphoma (MK-3475-667/KEYNOTE-667)

Rekrutierend

NCT-Nummer:
NCT03407144

Studienbeginn:
April 2018

Letztes Update:
16.07.2021

Wirkstoff:
Pembrolizumab, Doxorubicin, Vinblastine, Dacarbazine, Cyclophosphamide, Vincristine, prednisone/prednisolone, Bleomycin, Etoposide

Indikation (Clinical Trials):
Lymphoma, Hodgkin Disease

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 2

Sponsor:
Merck Sharp & Dohme Corp.

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck Sharp & Dohme Corp.

Kontakt

Studienlocations
(3 von 77)

Memorial Regional Hospital/Joe DiMaggio Children's Hospital ( Site 0048)
33021 Hollywood
United StatesAbgeschlossen» Google-Maps
Severance Hospital Yonsei University Health System ( Site 0221)
03722 Seoul
Korea, Republic ofAbgeschlossen» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

Group 1 will consist of low-risk participants with cHL Stages IA, IB and IIA without bulky

disease. Group 2 will consist of high-risk participants with cHL Stages IIEB, IIIEA, IIIEB,

IIIB, IVA and IVB.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Group 1: Must have newly diagnosed, pathologically confirmed classical Hodgkin

Lymphoma (cHL) at Stages IA, IB and IIA without bulky disease. Group 2: Must have

newly diagnosed, pathologically confirmed cHL at Stages IIEB, IIIEA,IIIEB, IIIB, IVA

and IVB

- Has measurable disease per investigator assessment

- Male participants are eligible to participate if they agree to the following during

the intervention period: refrain from donating sperm plus either be abstinent from

heterosexual intercourse as their preferred and usual lifestyle and agree to remain

abstinent or must agree to use contraception per protocol unless confirmed to be

azoospermic

- Female participants who are not pregnant or breastfeeding, and who are either not a

woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved

contraception during the intervention period and for at least 120 days after the last

dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or

freeze/store for her own use for the purpose of reproduction during this period

- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before

the first dose of study intervention

- Performance status: Lansky Play-Performance Scale ≥50 for children up to and including

16 years of age OR Karnofsky score ≥50 for participants >16 years of age

- Has adequate organ function

Exclusion Criteria:

- Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic

stem cell transplantation within the last 5 years

- WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of

study treatment

- Baseline left ventricular ejection fraction value <50% or shortening fraction of <27%

- Has received prior therapy with an anti-Programmed Death (PD)-1, anti-Programmed

Death-Ligand 1 (PD-L1), or anti-PD-L2 agent or with an agent directed to another

co-inhibitory T-cell receptor or has previously participated in a Merck pembrolizumab

(MK-3475) clinical study

- Has received any prior anti-cancer therapy, monoclonal antibody, chemotherapy, or an

investigational agent or device before the first dose of study treatment, or has not

recovered from AEs due to previously administered agents

- Is expected to receive a live vaccine within 30 days prior to the first dose of

pembrolizumab

- Is currently participating in or has participated in a study of an investigational

agent or has used an investigational device within 4 weeks prior to the first dose of

study treatment

- Has a diagnosis of lymphocyte-predominant Hodgkin Lymphoma (HL)

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy

or any other form of immunosuppressive therapy within 7 days prior to the first dose

of pembrolizumab

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

- Has radiographically detectable central nervous system metastases and/or carcinomatous

meningitis as assessed by local site investigator at the time of diagnosis

- Has severe hypersensitivity (≥Grade 3) to any study therapies including any excipients

- Has an active autoimmune disease that has required systemic treatment in past 2 years

- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required

steroids or has current pneumonitis/interstitial lung disease

- Has an active infection requiring systemic therapy

- Has a known history of human immunodeficiency virus (HIV) infection

- Has a known history of Hepatitis B or known active Hepatitis C virus infection

- Has a history or current evidence of any condition, therapy, or laboratory abnormality

that might confound the results of the study, interfere with the participant's

participation for the full duration of the study, or is not in the best interest of

the participant to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with

cooperating with the requirements of the study

Studien-Rationale

Primary outcome:

1. Objective Response Rate (ORR) in SER Participants By Risk Group (Low, High) as Assessed by Blinded Independent Central Review (BICR) (Time Frame - Up to 5 years):
ORR is defined as the percentage of SER participants who have a Complete Response ([CR], disappearance of all evidence of disease) or Partial Response ([PR], regression of measurable disease and no new sites) using IWG revised response criteria and determined by BICR. The ORR will be estimated by risk group in SER participants.



Secondary outcome:

1. Rate of Positron Emission Tomography (PET) Scan Negativity in SER Participants By Risk Group (Low, High) After AVD or COPDAC-28 Chemotherapy (Time Frame - Up to 5 years):
The rate of PET negativity for SER participants is the percentage of participants with PET negativity (defined as Deauville score 1, 2 or 3) after two cycles of AVD (Group 1) or four cycles of COPDAC-28 (Group 2), in combination with pembrolizumab. The Deauville 5-point scoring system is an internationally accepted and utilized five-point scoring system for the Fluorodeoxyglucose (FDG) avidity of a Hodgkin's lymphoma or Non-Hodgkin's lymphoma tumor mass as seen on FDG PET scan: Score 1= No uptake above the background, Score 2= Uptake ≤ mediastinum, Score 3= Uptake > mediastinum but ≤ liver, Score 4= Uptake moderately increased compared to the liver at any site, Score 5= Uptake markedly increased compared to the liver at any site or new lesions, Score X= New areas of uptake unlikely to be related to lymphoma. In the present study, scores of 1, 2 and 3 are considered to be negative and scores of 4 and 5 are considered to be positive.

2. Event-Free Survival (EFS) in SER Participants By Risk Group (Low, High) as Assessed by BICR (Time Frame - Up to 5 years):
EFS is defined as the time from study enrollment to the first documented disease progression or recurrence, or death due to any cause, whichever occurs first. Progression/disease recurrence will be determined by BICR using IWG criteria.

3. Overall Survival (OS) in SER Participants By Risk Group (Low, High) (Time Frame - Up to 5 years):
OS is defined as the time from study enrollment to death due to any cause. Participants without documented death will be censored at the date of the last follow-up.

4. Exposure to Radiotherapy (RT) in SER Participants By Risk Group (Low, High) (Time Frame - Up to 5 years):
The frequency of RT received by eligible participants (positive PET response, i.e. Deauville score of 4 or 5) will be reported.

5. Rate of PET Scan Negativity In Group 1 Participants After ABVD Induction Therapy (Time Frame - Up to 5 years):
The rate of PET negativity for Group 1 participants is the percentage of participants with PET negativity (defined as Deauville score 1, 2 or 3) after two cycles of ABVD induction as per investigator assessment. The Deauville 5-point scoring system is an internationally accepted and utilized five-point scoring system for the FDG avidity of a Hodgkin's lymphoma or Non-Hodgkin's lymphoma tumor mass as seen on FDG PET scan: Score 1= No uptake above the background, Score 2= Uptake ≤ mediastinum, Score 3= Uptake > mediastinum but ≤ liver, Score 4= Uptake moderately increased compared to the liver at any site, Score 5= Uptake markedly increased compared to the liver at any site or new lesions, Score X= New areas of uptake unlikely to be related to lymphoma. In the present study, scores of 1, 2 and 3 are considered to be negative and scores of 4 and 5 are considered to be positive.

6. EFS in Rapid Early Responder (RER) Participants By Risk Group (Low, High) as Assessed by Investigator (Time Frame - Up to 5 years):
EFS is defined as the time from study enrollment to the first documented disease progression or recurrence, or death due to any cause, whichever occurs first. Progression/disease recurrence will be determined by the investigator.

7. OS in RER Participants By Risk Group (Low, High) (Time Frame - Up to 5 years):
OS is defined as the time from study enrollment to death due to any cause. Participants without documented death will be censored at the date of the last follow-up.

8. Serum Thymus and Activation-Regulated Chemokine (TARC) Levels in SER Participants By Risk Group (Low, High) (Time Frame - Up to 5 years):
Serum TARC levels will be measured and evaluated as a potential biomarker in SER participants by risk group at screening, early, and late response assessments.

9. Number of SER Participants Experiencing an Adverse Event (AE) By Risk Group (Low, High) (Time Frame - Up to 5 years):
An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of SER participants who experience an AE will be reported for each arm.

10. Number of SER Participants Discontinuing Study Treatment Due to AEs By Risk Group (Low, High) (Time Frame - Up to 5 years):
An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of SER participants who discontinue study treatment due to an AE will be reported for each arm.

Studien-Arme

  • Experimental: Pembrolizumab + AVD (Group 1)
    After receiving two 4-week cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) induction therapy, SER participants in Group 1 will receive pembrolizumab 2 mg/kg up to a maximum of 200 mg (3 to 17 years of age) or 200 mg (18 to 25 years of age) on Day 1 of each 3-week cycle (Q3W) in combination with two cycles of AVD chemotherapy (doxorubicin 25 mg/m^2, vinblastine 6 mg/m^2 and dacarbazine 375 mg/m^2 on Days 1 and 15; cycle frequency every 4 weeks [Q4W]). All SERs in Group 1 will receive radiotherapy (RT) after completing AVD chemotherapy.
  • Experimental: Pembrolizumab + COPDAC-28 (Group 2)
    After receiving two 4-week cycles of OEPA (vincristine, etoposide/etopophos, prednisone/prednisolone and doxorubicin) induction therapy, SER participants in Group 2 will receive pembrolizumab 2 mg/kg up to a maximum of 200 mg (3 to 17 years of age) or 200 mg (18 to 25 years of age) Q3W, in combination with 4 cycles of COPDAC-28 chemotherapy (cyclophosphamide 500 mg/m^2 on Days 1 and 8, vincristine 1.5 mg/m^2 with maximum single dose 2 mg on Days 1 and 8, prednisone/prednisolone 40 mg/m^2/day divided in 3 doses on Days 1 to 15, dacarbazine 250 mg/m^2 on Days 1 to 3; cycle frequency Q4W). SERs in Group 2 will receive RT if they have a positive Positron Emission Tomography (PET) response after completing COPDAC-28 chemotherapy.

Geprüfte Regime

  • pembrolizumab (MK-3475):
    2 mg/kg intravenous (IV) up to a max of 200 mg (3 to 17 years of age) or 200 mg IV (18 to 25 years of age); cycle frequency Q3W
  • doxorubicin:
    25 mg/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1) 40 mg/m^2 IV on Days 1 and 15 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2) 25 mg/m^2 IV on Days 1 and 15 as part of AVD chemotherapy (cycle frequency: Q4W, Group 1)
  • vinblastine:
    6 mg/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1) 6 mg/m^2 IV on Days 1 and 15 as part of AVD chemotherapy (cycle frequency: Q4W, Group 1)
  • dacarbazine:
    375 mg/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1) 375 mg/m^2 IV on Days 1 and 15 as part of AVD chemotherapy (cycle frequency: Q4W, Group 1) 250 mg/m^2 IV on Days 1 to 3 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
  • cyclophosphamide:
    500 mg/m^2 IV on days 1 and 8 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
  • vincristine:
    1.5 mg/m^2 IV with maximum single dose 2 mg on Days 1, 8, and 15 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2) 1.5 mg/m^2 IV with maximum single dose 2 mg on Days 1 and 8 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
  • prednisone/prednisolone:
    60 mg/m^2/day orally divided in 3 doses on Days 1 to 15 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2) 40 mg/m^2/day orally divided in 3 doses on Days 1 to 15 as part of COPDAC-28 chemotherapy (cycle frequency: Q4W, Group 2)
  • bleomycin:
    10 units/m^2 IV on Days 1 and 15 as part of ABVD induction therapy (cycle frequency: Q4W, Group 1)
  • etoposide (Etoposide Phosphate):
    125 mg/m^2 IV on Days 1 to 5 as part of OEPA induction therapy (cycle frequency: Q4W, Group 2)
  • Radiotherapy (RT):
    RT administered daily, dose dependent on randomization group and disease response.

Quelle: ClinicalTrials.gov


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