A Pilot Trial of Pembrolizumab Plus Chemoradiotherapy in Participants With Unresectable Gastroesophageal Cancer
Overview
- Phase
- Phase 1
- Intervention
- Docetaxel
- Conditions
- Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 16
- Locations
- 1
- Primary Endpoint
- Clinical complete response (cCR)
- Status
- Active, Not Recruiting
- Last Updated
- last month
Overview
Brief Summary
This phase I trial investigates how well pembrolizumab and chemoradiotherapy works in treating patients with gastroesophageal cancer that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as fluorouracil, oxaliplatin and docetaxel work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Giving pembrolizumab together with chemoradiotherapy may help to control gastroesophageal cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the clinical activity (as assessed by complete clinical response rate) of pembrolizumab plus chemoradiation. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of pembrolizumab plus chemoradiation. II. To determine the overall survival efficacy of pembrolizumab plus chemoradiation. III. Evaluate progression free survival (PFS) by local investigator review and by blinded central radiologists' review. EXPLORATORY OBJECTIVES: I. To explore the association between PD-L1 expression by immunohistochemistry, somatic gene expression profiling, and clinical efficacy of pembrolizumab. II. To explore the relationship between genomic variation and response to study treatment. III. To identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may correlate with clinical response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of pembrolizumab in combination with chemoradiation. IV. To determine the effect of pembrolizumab plus chemoradiation treatment on tumor T cell infiltration. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment with pembrolizumab repeats every 3 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive oxaliplatin IV over 2 hours on day 1 followed by fluorouracil IV over 48 hours once every 2 weeks (Q2W) for 8 weeks (4 cycles) in the absence of disease progression or unacceptable toxicity. CONSOLIDATION CHEMORADIATION: After a 3 week treatment free period, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive fluorouracil IV continuous over 5 days (Monday through Friday) for 5 weeks and docetaxel IV over 1 hour once a week (QW) for 5 weeks in the absence of disease progression or unacceptable toxicity. Starting no later than 3 days after the beginning of the Consolidation Chemoradiation period, patients also undergo 28 fractions of radiation therapy in the absence of disease progression or unacceptable toxicity. After a 6-9 week treatment free period, patients continue pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 3 weeks for up to 30 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 9-12 weeks thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants with histologically confirmed diagnosis of unresectable gastroesophageal adenocarcinoma will be enrolled in this study for systemic treatment first
- •Have histologically documented locally advanced unresectable cancer or localized cancer in a patient who declines surgery
- •Participant is able to provide endoscopic research biopsies and research blood
- •Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to treatment initiation
- •A male participant must agree to use a contraception during the treatment period and for at least 120 days, corresponding to time needed to eliminate any study treatment(s) after the last dose of study treatment and refrain from donating sperm during this period
- •A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- •Not a woman of childbearing potential (WOCBP) OR
- •A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days/weeks after the last dose of study treatment
- •Patients with stable brain metastasis and/or carcinomatous leptomeningeal disease as defined in
Exclusion Criteria
- •The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. The participant may also provide consent for future biomedical research. However, the participant may participate in the main trial without participating in future biomedical research
- •Absolute neutrophil count \>= 1500/uL (within 10 days prior to the start of study treatment)
- •Platelets \>= 100 000/uL (within 10 days prior to the start of study treatment)
- •Hemoglobin \>= 9.0 g/dL or \>= 5.6 mmol/L (within 10 days prior to the start of study treatment)
- •Criteria may be met with blood transfusion as these tumors are losing blood
- •Creatinine =\< 1.5 x upper limit of normal (ULN) OR measured or calculated\* creatinine clearance (CrCl) \>= 60 mL/min for participant with creatinine levels \> 1.5 x institutional ULN (within 10 days prior to the start of study treatment) (GFR can also be used in place of creatinine or CrCl)
- •Creatinine clearance (CrCl) should be calculated per institutional standard
- •Total bilirubin =\<1.5 x ULN OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 1.5 x ULN (within 10 days prior to the start of study treatment)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN (within 10 days prior to the start of study treatment)
- •International normalized ratio (INR) OR prothrombin time (PT), activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 10 days prior to the start of study treatment)
Arms & Interventions
Treatment (pembrolizumab, chemoradiotherapy)
See Detailed Description
Intervention: Docetaxel
Treatment (pembrolizumab, chemoradiotherapy)
See Detailed Description
Intervention: Fluorouracil
Treatment (pembrolizumab, chemoradiotherapy)
See Detailed Description
Intervention: Oxaliplatin
Treatment (pembrolizumab, chemoradiotherapy)
See Detailed Description
Intervention: Pembrolizumab
Treatment (pembrolizumab, chemoradiotherapy)
See Detailed Description
Intervention: Radiation Therapy
Outcomes
Primary Outcomes
Clinical complete response (cCR)
Time Frame: Up to 2 years
cCR, defined as at the time of post-chemoradiation staging, there is no evidence of cancer on endoscopic examination/histology/cytology and there is no evidence of cancer by imaging modality. Tumor assessment will be conducted every 9 weeks until the 54th week of the study and every 12 weeks after that. The best response will be recorded.
Secondary Outcomes
- Median progression free survival (PFS)(From date of first dose with study drug to the earliest date of progression or death by any cause (in the absence of progression), assessed up to 2 years)
- Number of participants experiencing adverse events (AEs)(Up to 90 days post treatment)
- Number of participants discontinuing study drug due to AEs(Up to 90 days post treatment)
- PFS at 6 months(From date of first dose with study drug to the earliest date of progression or death by any cause (in the absence of progression), assessed at 6 months)
- PFS at 24 months(From date of first dose with study drug to the earliest date of progression or death by any cause (in the absence of progression), assessed at 24 months)
- Overall survival (OS)(From start of treatment to death due to any cause, assessed up to 2 years)
- PFS at 12 months(From date of first dose with study drug to the earliest date of progression or death by any cause (in the absence of progression), assessed at 12 months)