Primary:1) To compare OS in subjects with squamous cell carcinoma of the Esophagus.2) To compare OS in subjects with PD-L1 Combined Positive Score (CPS)*10%3) To compare OS in all subjectsSecondary:1) To evaluate the progression free survival (PFS)…
ID
Source
Brief title
Condition
- Benign neoplasms gastrointestinal
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Overall Survival (OS) in subjects with squamous cell carcinoma of the
Esophagus.
2. Overall Survival (OS) in subjects with PD-L1 CPS*10%
3. Overall Survival (OS) in all subjects.
Secondary outcome
1.Progression-free survival (PFS) * RECIST 1.1 by central imaging
vendor review in all subjects, defined as the time from randomization to
the first documented disease progression per RECIST 1.1 or death.
2.Objective Response Rate (ORR) * RECIST 1.1 by central imaging
vendor review in all subjects, defined as the proportion of the subjects in
the analysis population who have a complete response (CR) or partial
response (PR).
3. Safety and tolerability Endpoints
Background summary
Esophageal cancer is the 6th most common cause of cancer deaths in the world
and is more prevalent in men than women. However, in the developing countries
esophageal cancer is endemic and is the 4th most common cause of cancer
deaths. Globally close to 480000 cases occur annually. In the US, in 2015, an
estimated 15980 esophageal cancers will be diagnosed and it is estimated that
15590 people will eventually die of their disease. Majority of the patients are
diagnosed with advanced/metastatic cancer and in this setting response to
chemotherapeutic agents is poor. Given the high incidence and mortality
worldwide and lack of good therapeutic options esophageal cancer patients
represent a high unmet need for drug development.
*
The incidence of esophageal cancer represents one of the widest variations with
a 60-fold difference between high and low prevalence regions. High prevalence
areas include Asia, Africa and France where squamous esophageal cancers
predominate. A dramatic shift in the histology and location of upper
gastrointestinal (GI) tumors has occurred over the past decades. In Western
countries, the most common site of esophageal cancer is in the lower third of
the esophagus, which often involves the EGJ . For the purpose of our study, we
will use the Siewert classification for adenocarcinoma of the EGJ and thus type
I patients (about 20% of the EGJ adenocarcinoma patients) will be eligible.
Siewert type I tumors are adenocarcinomas of the lower esophagus with the
center located within 1cm to 5cm above the anatomic EGJ. Type II and III
Siewert adenocarcinomas of the EGJ are managed as gastric cancer patients and
therefore participate in the second line (2L) gastric trial, KN-061.
Adenocarcinoma has been gradually increasing in men of all ethnic backgrounds
and also in women. Squamous cell carcinoma (SCC) seems to be more sensitive to
chemotherapy, chemoradiation, and radiation therapy than adenocarcinoma, but
the long-term outcome is similar for both histologies thus emphasizing the
need for better improved therapies in both histologies.
Study objective
Primary:
1) To compare OS in subjects with squamous cell carcinoma of the Esophagus.
2) To compare OS in subjects with PD-L1 Combined Positive Score (CPS)*10%
3) To compare OS in all subjects
Secondary:
1) To evaluate the progression free survival (PFS) per RECIST 1.1assessed by
central vendor review in all subjects, when treated with
pembrolizumab compared to investigator's choice of paclitaxel,docetaxel, or
irinotecan.
2) To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed by
central vendor review in all subjects, when treated with
pembrolizumab compared to investigator's choice of paclitaxel, docetaxel, or
irinotecan.
3) To evaluate the PFS and ORR per RECIST 1.1 assessed by central vendor review
in subjects with squamous cell carcinoma of the
esophagus and subjects with PD-L1 CPS*10%, when treated with pembrolizumab
compared to investigator's choice of paclitaxel,
docetaxel, or irinotecan.
4) Evaluate the safety and tolerability profile of pembrolizumab in all
subjects, when treated with pembrolizumab compared to investigator's
choice of paclitaxel, docetaxel, or irinotecan.
Study design
This is a Randomized, multi-center, open-label trial of pembrolizumab (MK-3475)
versus investigator*s choice of paclitaxel, docetaxel or irinotecan in subjects
with advanced/metastatic adenocarcinoma or squamous cell carcinoma of the
esophagus, or advanced/metastatic Siewert type I adenocarcinoma of the
esophagogastric junction (EGJ).
Intervention
Arm 1: Pembrolizumab (MK-3475) 200 mg IV every 3-weeks
Arm 2: Investigator*s choice of:
- Paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 28-day (4-week) cycle,
OR
- Docetaxel 75 mg/m2 on Day 1 of every 21-day (3-week) cycle, OR
- Irinotecan 180 mg/m2 on Day 1 of every 14-day (2 week) cycle
Study burden and risks
The patient will receive the study drug every 3 weeks for up to 24 months.
Additional treatment is possible (under certain conditions) for an extra year.
The patient will visit the doctor every week or every 3 weeks. The first visit
a tumor biopsy will take place (if necessary). Each visit, a physical
examination will be performed, and blood samples will be taken. The patient
will also fill in three questionnaires each visit concerning the quality of
life, namely the EORTC QLQ C30, the eEuroQoL EQ-5D and the EORTC QLQ-OES18.
The patient may experience physical and I or psychological discomfort with some
of the procedures performed during a visit, such as blood sampling, the IV
line, ECG, CT scan, MRI and tumor biopsy.
The main side effect reported with the use of MK3475 are fatigue, itching,
rash, frequent or excessive bowel movements, joint pain and nausea.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
Subjects must: ;1. Be * 18 years of age on the day of signing the informed consent. ;2. Have histologically or cytologically confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ. ;3. Have metastatic disease or locally advanced, unresectable disease. ;4. Have a life expectancy greater than 3 months. ;5. Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. ;6. Have an ECOG performance status of 0 or 1. ;7. Have experienced documented radiographic or clinical disease progression on one previous line of standard therapy. ;8. Provide either a newly obtained or archival tissue sample for intratumoral immune-related GEP analysis.;9. Demonstrate adequate organ function. ;10. Negative pregnancy test for females of child bearing potential prior to starting study and male and female subjects of childbearing potential must be willing to use an adequate method of contraception.
Exclusion criteria
The subject will be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment. ;2. Has an active autoimmune disease that has required systemic treatment in past 2 years. ;3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. ;4. Has known central nervous system (CNS) metastases and/or carcinomatous meningitis (includes past history or current metastasis). ;5. Has received prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., * Grade 1 or at baseline) from adverse events due to a previously administered agent. The specified 2-week period between last dose of prior therapy and first dose of pembrolizumab is the minimum amount of time required. Subjects may not receive study medication less than 2 weeks from the last dose of a prior therapy. However, a period of more than 2 weeks may be used if
indicated both clinically and due to concern between possible negative interactions
between prior therapy and study therapy.;6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or if the subject has previously participated in Merck pembrolizumab (MK-3475) clinical trials. ;7. Previously had a severe hypersensitivity reaction to treatment with another
monoclonal antibody (mAb);8. Has experienced documented objective radiographic or clinical disease progression during or after receiving more than 1 line of therapy.;9. Has a diagnosed additional malignancy within 5 years prior to treatment allocation with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers. ;10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject*s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.;11. Has a known history of Human Immunodeficiency Virus (HIV) infection. ;12. Has untreated known active Hepatitis B or known Hepatitis C. ;13. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis;14. Has an active infection requiring systemic therapy. ;15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. ;16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan.;17. Has a Known allergy, hypersensitivity, or contraindication to preselected
chemotherapy agent (i.e. paclitaxel, docetaxel, or irinotecan) or any components used
in their preparation. ;18. Experienced weight loss > 10% over approximately 2 months prior to first dose of study therapy.;19. Has clinically apparent ascites or pleural effusion by physical exam.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002782-32-NL |
| ClinicalTrials.gov | NCT02564263 |
| CCMO | NL55808.056.15 |