Kurzfassung

This is a two arm, multicenter, international, randomized, open label, controlled trial of
pembrolizumab (MK-3475) monotherapy versus standard chemotherapy in subjects who
have stage IV Microsatellite instability high (MSI-H) or Mismatch Repair Deficient (dMMR)
colorectal carcinoma (CRC). MSI, a form of genomic instability, occurs through the insertion
or deletion of repeating nucleotides during DNA replication and failure of the mismatch
repair system to correct errors in nucleotide repeat...This is a two arm, multicenter, international, randomized, open label, controlled trial of
pembrolizumab (MK-3475) monotherapy versus standard chemotherapy in subjects who
have stage IV Microsatellite instability high (MSI-H) or Mismatch Repair Deficient (dMMR)
colorectal carcinoma (CRC). MSI, a form of genomic instability, occurs through the insertion
or deletion of repeating nucleotides during DNA replication and failure of the mismatch
repair system to correct errors in nucleotide repeat markers (Refer to 4.2.4.4 for further
details). Subjects will be required to have at least one measureable lesion by Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) for response assessment. Su bjects will be
randomized in a 1:1 ratio to receive pembrolizumab (experimental arm) or the Investigator’s
choice of standard of care (SOC) chemotherapy (control arm). The chemotherapy to be used
must be chosen before randomization.
Pembrolizumab (MK-3475) arm subjects will receive up to 35 administrations of
pembrolizumab (approximately 2 years) in the Initial Treatment Phase. Subjects who stop
pembrolizumab (MK-3475) with complete response (CR), or stable disease (SD) or better at
the end of the Initial Treatment Phase may be treated in a Second Course Treatment Phase
with up to 17 administrations of pembrolizumab (MK-3475) if they meet criteria outlined in
Section 7.1.6.3. Control arm subjects with progressive disease (PD) per RECIST 1.1 as
verified by blinded independent central imaging vendor who meet all crossover criteria will
have an option to receive pembrolizumab (MK-3475) in the Crossover Phase. See section
7.1.6.4 for crossover criteria and guidance.
The primary objective of the trial is Progression Free Survival (PFS) per RECIST 1.1
assessed by an independent central imaging vendor based the first radiologic progressive
disease (PD) from the primary treatment subjects are randomized to. On study imaging
assessments, performed every 9 weeks (Q9W), will be calculated from the date of
randomization and independent of treatment delays for both treatment arms. RECIST 1.1 will
be used by the site for the treatment decisions until verification of initial site assessed PD by
the blinded independent central imaging vendor. For subjects receiving pembrolizumab
(MK-3475), following verification of PD by the central imaging vendor, further treatment
decisions may be made by the adaptation of RECIST 1.1 as described in Section 4.2.4.2.1
termed immune-related RECIST (irRECIST) to accommodate for the tumor response
patterns seen with pembrolizumab (MK-3475) treatment (e.g. tumor flare). For a clinically
stable subject with first radiologic evidence of PD per RECIST 1.1 as verified by central
imaging vendor, per irRECIST, it is at the discretion of the site Investigator to continue
treating the subject with pembrolizumab (MK-3475) until PD is confirmed at least 4 weeks
from the date of first radiologic PD by RECIST 1.1. If radiologic PD is confirmed by the
subsequent tumor imaging, the subject should be discontinued from treatment unless, in the
opinion of the Investigator, the subject is achieving a clinically meaningful benefit, in which
case an exception to continue treatment may be considered following consultation with the
sponsor (see Section 7.1.4.6).
Subjects will continue to be treated with study treatment until PD, unacceptable adverse
events (AEs), intercurrent illness that prevents further administration of treatment,
Investigator’s decision to withdraw the subject, subject withdraws consent, pregnancy of the
subject, noncompliance with trial treatment or procedure requirements, administrative
reasons, or the subject has received 35 trial treatments (approximately 2 years)
(pembrolizumab arm only). Subjects who discontinue treatment for reasons other than PD
will have post-treatment follow-up for disease status until PD, initiation of a non-study
cancer treatment, withdrawal of consent, or loss to follow-up. All subjects will be followed
by telephone contact for overall survival (OS) until death, withdrawal of consent or end of
the study, whichever comes first.
Subjects may undergo resection of the primary tumor and metastasectomy with curative
intent after achieving a response to trial therapy converting unresectable to resectable disease
if deemed eligible per Investigator’s discretion in a multidisciplinary approach according to
his/her institutional standard. After surgery, standard of care arm subjects may resume the
same therapy that they were receiving pre-operatively when clinically appropriate. The
duration of post-operative therapy is at the Investigator’s discretion per institutional
standard. Pembrolizumab (MK-3475) subjects may also resume therapy post-operatively, and
receive up to 35 total treatments inclusive of both pre- and post-operative periods. Subjects
who progress post-operatively will have an option to receive pembrolizumab (MK-3475) in
the Second Treatment Course/Crossover Phase with up to 17 administrations (approximately
1 year) of pembrolizumab (MK-3475) if clinically appropriate. Subjects from both arms of
the study who develop isolated lesion/tumor growth in the setting of overall clinical benefit
may resume the assigned therapy after completing local treatment for the isolated
lesion/tumor growth provided there is mutual agreement between the Investigator and
Sponsor.
Subjects who receive pembrolizumab (MK-3475) and attain locally confirmed CR by 2
tumor imaging assessments at least 4 weeks apart and who have received at least 8 treatments
(approximately 6 months) with pembrolizumab (MK-3475) may discontinue treatment at the
discretion of the Investigator after receiving at least 2 treatments beyond the initial
determination of a CR.
Adverse events will be monitored throughout the trial and graded in severity according to the
guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0 (Section 12.6). Each subject will be followed for 30
days after study drug discontinuation for AE monitoring. Serious adverse events (SAEs) will
be collected for 90 days after the end of treatment or 30 days after the end of treatment if the
subject initiates new anticancer therapy, whichever is earlier.
This study will be conducted in conformance with Good Clinical Practices (GCP).
Specific procedures to be performed during the trial, as well as their prescribed times and
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each
procedure are provided in Section 7.0 – Trial Procedures.
 
PFS analysis will be conducted when approximately 141 PFS events have been observed.
Additional details are found in section 8.0.
An external data monitoring committee (eDMC) will serve as the primary reviewer of the
treatment-level results and will make recommendations for discontinuation of the study or
modification to an executive oversight committee of the SPONSOR . The eDMC
responsibilities and review schedules will be outlined in the eDMC charter.» weiterlesen» einklappen