View Cancer Clinical Trials

Details

Title A Phase III Randomized Open-label Study of Single Agent Pembrolizumab vs Physicians’; Choice of Single Agent Docetaxel, Paclitaxel, or Irinotecan in Subjects with Advanced/Metastatic Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus that have Progressed after First-Line Standard Therapy (KEYNOTE-181)

IRB MRK1216

CC 16-536

Hospital Main Campus

Phase Phase 3

Disease Esophageal

Drug Docetaxel, Irinotecan , Paclitaxel , Pembrolizumab

Description

Primary Objectives

1. To compare PFS per RECIST 1.1 assessed by central imaging vendor in GEP high subjects.
2. To compare PFS per RECIST 1.1 assessed by central imaging vendor in all subjects.
3. To compare OS in GEP high subjects.
4. To compare OS in all subjects.

Secondary Objectives

1. To evaluate the Overall Response Rate (ORR) per RECIST 1.1 assessed by central vendor review among GEP high subjects and all subjects, when treated with pembrolizumab compared to investigator's choice of paclitaxel , docetaxel or irinotecan.
2. Evaluate the safety and tolerability profile of pembrolizumab in GEP high subjects and all subjects, when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel or irinotecan.

Exploratory Objectives

1. To evaluate the Time to Progression (TTP) per RECIST 1.1 assessed by blinded central vendor review among GEP high subjects and all subjects, when treated with pembrolizumab compared to investigator's choice of paclitaxel , docetaxel or irinotecan.
2. To evaluate PFS per irRECIST assessed by blinded central vendor review among GEP high subjects and all subjects when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel or irinotecan.
3. To explore the relationship between PD-L1 expression by IHC and response to the treatment administered for subjects when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel or irinotecan.
4. To explore the concordance of GEP in archival compared to newly obtained tumor tissue.
5. To evaluate score change of health related quality of life using the EORTC QLQ-C30 and the EORTC QLQ-OES18 from baseline among subjects when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel or irinotecan.
6. To characterize utilities using EuroQol EQ-5D among subjects when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel or irinotecan.
7. To explore the relationship between genetic variation and response to the treatment administered. Variation across the human genome will be analyzed for association with clinical data collected in this study.

Inclusion Criteria

1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be ≥ 18 years of age on day of signing informed consent (or acceptable age according to local regulations, whichever is older).
3. Have histologically or cytologically-confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ (defined as adenocarcinomas of the lower esophagus with the center located within 1cm to 5cm above the anatomic EGJ).
   • Subjects with Siewert type 1 adenocarcinoma of the EGJ with HER-2/neu negative tumors are eligible. Subjects with HER2/neu positive tumors or those with an unknown tumor status, need to match the following:
     • If HER2/neu positive, subject must have documentation of disease progression on treatment containing trastuzumab.
     • Subjects with unknown status must have their HER2/neu status determined locally. If HER2/neu negative, the subject will be eligible. If HER2/neu positive, the subject must have documentation of disease progression on treatment containing trastuzumab.
4. Have metastatic disease or locally advanced, unresectable disease.
5. Have a life expectancy of greater than 3 months.
6. Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Note: The same image acquisition and processing parameters should be used throughout the study for a given subject.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
8. Have experienced documented objective radiographic or clinical disease progression during or after first-line locally or globally recommended therapy.
   • To be considered as second-line, the subject needs to have documentation of disease progression on first-line treatment per local/global guidelines. The disease progression can be confirmed by CT scan or by clinical evidence (such as cytology report from newly developed ascites and pleural effusion).
   • To be eligible, the subject is required to have received at least one dose of first-line therapy (first-line therapy as defined by local/global recommendations; taxanes are allowed for the first-line therapy). The dose reduction and discontinuation of one of first-line therapy drugs, switching to/adding new drugs on the first-line treatment is allowed.
   • Neoadjuvant/adjuvant treatment (chemotherapy or chemoradiotherapy) will count as a line of therapy if disease progression occurs during treatment or within 6 months of cessation of treatment.
9. Provide a tissue sample for intratumoral immune-related GEP analysis. Newlyobtained tissue is preferred (no intervening treatment [local or systemic] involving the site of tissue biopsy once tissue biopsy is obtained up to the time of study enrollment). Formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides. Repeat samples may be required if adequate tissue is not provided
   • Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) an archived specimen may be submitted.
   • Collection of an archived tissue sample will also be requested (where available) to support evaluation of the clinical utility of immune-related GEP assessment in newly obtained vs. archived tissue samples; however, a subject will not be precluded from participating in the study if an archived tissue sample is not available for collection or is otherwise insufficient for analysis.
10. Demonstrate adequate organ function as defined:
    • Absolute neutrophil count (ANC) ≥1,500 /mcL
    • Platelets ≥100,000 / mcL
    • Hemoglobina ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency within 7 days.
    • Creatinine OR Measured or calculateda creatinine clearance ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl) Note: Creatinine clearance should be calculated per institutional standard
    • Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
    • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
    • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
11. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
12. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
13. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate method of contraception as outlined in Section 5.7.2- Contraception, and not to donate sperm starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or through 180 days after the last dose of paclitaxel, docetaxel or irinotecan. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria

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. Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent or device.
2. Has active autoimmune disease that has required systemic treatment in 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.
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. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
4. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable brain metastases for at least four weeks prior to the first dose of trial treatment; also, any neurologic symptoms must have returned to baseline]. See Section 7.1.4.1.1 for additional details.
5. Has had 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. Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting 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. 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.
8. Has received a live vaccine within 30 days of planned start of study therapy. Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed.
9. 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.
10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
11. Has known active Hepatitis B (e.g., Hepatitis B surface Antigen reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
12. Has known history of, or any evidence of interstitial lung disease or active, noninfectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. 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.
16. Has a known allergy, hypersensitivity, or contraindication to paclitaxel, docetaxel, or irinotecan or any components used in their preparation or has a contraindication to taxane therapy.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.