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JOURNAL ONKOLOGIE – STUDIE

Efficacy and Safety of Olaparib, Olaparib + Bevacizumab Compared to Bevacizumab + 5-Fluorouracil (FU)

Rekrutierend

NCT-Nummer:
NCT04456699

Studienbeginn:
August 2020

Letztes Update:
22.07.2021

Wirkstoff:
Olaparib, 5-FU, Bevacizumab

Indikation (Clinical Trials):
Colorectal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Merck Sharp & Dohme Corp.

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck, Sharpe & Dohme Corp.

Kontakt

Studienlocations
(3 von 117)

CHI Health St. Francis ( Site 1406)
68803 Grand Island
United StatesAbgeschlossen» Google-Maps
Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Okta-Klinikai Onkológiai és Sugárterápiás Ce
3526 Miskolc
HungaryRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +36302780644
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Brief Summary:

This is an efficacy and safety study of olaparib alone or in combination with bevacizumab

being compared to bevacizumab with Fluorouracil (5-FU) in participants with unresectable or

metastatic colorectal cancer (CRC) who have not progressed following first-line induction of

FOLFOX with bevacizumab. Hypothesis 1 - Olaparib + Bevacizumab is superior to 5-FU +

Bevacizumab with respect to progression-free survival (PFS) using Response Evaluation

Criteria In Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central

review (BICR) in the treatment of CRC. Hypothesis 2 - Olaparib is superior to 5-FU +

Bevacizumab with respect to PFS using RECIST 1.1 as assessed by BICR) in the treatment of

CRC.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Has a histologically-confirmed metastatic or unresectable (Stage IV as defined by

American Joint Committee on Cancer (AJCC eighth edition) colorectal adenocarcinoma

(National Comprehensive Cancer Network [NCCN] 2018).

2. Has not progressed (ie, achieved a stable disease [SD], partial response [PR], or

complete response [CR]) after a first-line induction course of at least 6 cycles of

FOLFOX with bevacizumab as first-line therapy.

- Participants must not have received an investigational agent during their FOLFOX

+ bevacizumab induction course.

- Determination of SD/PR/CR will be made by the investigator.

- "First-line therapy" is defined as the first systemic chemotherapy regimen given

for the diagnosis of unresectable or metastatic CRC. Participants may have

received prior adjuvant/neoadjuvant chemotherapy for CRC, as long as it was

completed at least 6 months prior to initiation of first-line FOLFOX +

bevacizumab induction treatment.

3. Has experienced unacceptable toxicity to oxaliplatin that, in the opinion of the

treating physician, requires/required the discontinuation of oxaliplatin. Note: As an

example, unacceptable toxicity may include (but is not limited to) severe or prolonged

neurotoxicity.

• Participants must be randomized within a minimum of 2 weeks and a maximum of 6 weeks

after their last dose of FOLFOX + bevacizumab (last dose is the day of the last

infusion).

4. Has provided to the imaging contract research organization (iCRO) at least 1 set of

radiographic images taken during the FOLFOX + bevacizumab induction period and at

least 42 days prior to the imaging performed during screening. The iCRO must determine

the images are of diagnostic quality prior to randomization.

5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within

10 days prior to randomization.

Exclusion Criteria:

1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU or

olaparib.

2. Has known active central nervous system (CNS) metastases and/or carcinomatous

meningitis. Participants with previously treated brain metastases may participate

provided they are radiologically stable (ie, without evidence of progression for at

least 28 days by repeat imaging (note that the repeat imaging should be performed

during study screening), clinically stable and without requirement of steroid

intervention for at least 14 days prior to first dose of study intervention.

3. Has an active infection requiring systemic therapy.

4. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is

required unless mandated by local health authority.

5. Has a known history of or is positive for hepatitis B surface antigen (HBsAg reactive)

or hepatitis C ribonucleic acid (HCV RNA [qualitative]) is detected). Note: No testing

for hepatitis B and hepatitis C is required unless mandated by local health authority.

6. Has a known psychiatric or substance abuse disorder that would interfere with the

participant's ability to cooperate with the requirements of the study.

7. Has myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or with features

suggestive of MDS/AML.

8. Has hemoptysis or hematemesis within 28 days prior to randomization.

9. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of

coagulation).

10. Has clinically significant bleeding within 28 days prior to randomization.

11. Is considered a poor medical risk due to a serious, uncontrolled medical disorder,

nonmalignant systemic disease or active, uncontrolled infection. Examples include, but

are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months)

myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord

compression, superior vena cava syndrome, extensive interstitial bilateral lung

disease on high-resolution computed tomography (HRCT) scan or any psychiatric disorder

that prohibits obtaining informed consent.

12. Has 1 or more conditions that, in the opinion of the treating physician, make the

participant ineligible for treatment with bevacizumab. These conditions may include:

- Uncontrolled hypertension (systolic blood pressure [SBP] >150 mm Hg or diastolic

blood pressure [DBP] >100 mm Hg) or a history of hypertensive crisis or

hypertensive encephalopathy

- History of nephrotic syndrome or moderate proteinuria

- History of gastrointestinal perforation

- History of non-gastrointestinal fistula formation

- History of possible reversible encephalopathy syndrome (RPLS)

13. Has received prior systemic anticancer therapy (other than FOLFOX + bevacizumab

induction) including investigational agents within 28 days prior to randomization.

Note: Participants must have recovered from all AEs due to previous therapies to

≤Grade 1 or baseline. Participants with persistent alopecia or Grade ≤3 neuropathy may

be eligible.

14. Has received prior therapy with olaparib or with any other polyadenosine

5'-diphosphoribose polymerase (PARP) inhibitor.

15. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin,

protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir,

nelfinavir, boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin,

diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 3A4 (CYP3A4) that

cannot be discontinued for the duration of the study. The required washout period

prior to randomization is 2 weeks.

16. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin,

rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or

moderate (eg. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be

discontinued for the duration of the study. The required washout period prior to

randomization is 5 weeks for phenobarbital and 3 weeks for other agents.

17. Has undergone major surgery within 2 weeks of randomization or has not recovered

adequately from toxicities and/or complications from any major surgery prior to

randomization.

Studien-Rationale

Primary outcome:

1. Progression-free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) (Time Frame - Up to approximately 6 years):
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions is also considered PD.



Secondary outcome:

1. Overall Survival (OS) (Time Frame - Up to approximately 6 years):
Overall survival is the time from randomization to death due to any cause.

2. Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR (Time Frame - Up to approximately 6 years):
ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

3. Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR (Time Frame - Up to approximately 6 years):
For participants who demonstrate a confirmed CR or confirmed PR per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death.

4. Number of Participants with One or More Adverse Events (AE) (Time Frame - Up to approximately 6 years):
An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention

5. Number of Participants Discontinuing Study Intervention Due to an AE (Time Frame - Up to approximately 6 years):
Tolerability is defined by the degree to which overt AEs of a drug can be tolerated by a participant without discontinuing from the study.

Studien-Arme

  • Experimental: Olaparib + Bevacizumab
    Olaparib (300 mg twice daily [BID] oral) + Bevacizumab (5 mg/kg intravenous [IV] once every 2 weeks [Q2W]) until progressive disease or end of study
  • Experimental: Olaparib
    Olaparib (300 mg BID) oral, until progressive disease or end of study
  • Active Comparator: Bevacizumab + 5-FU
    Bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W) until progressive disease or end of study

Geprüfte Regime

  • Olaparib (LYNPARZA^TM):
    300 mg BID, oral until progressive disease or end of study
  • 5-FU (Fluorouracil / Adrucil / Efudex / ):
    2400 mg/m2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study
  • Bevacizumab (MVASI^TM / Avastin / ):
    5 mg/kg Q2W IV infusion until progressive disease or end of study

Quelle: ClinicalTrials.gov


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