Microsatellite Stable, Mismatch Repair Protein Proficient, Stage IIIB Colorectal Cancer AJCC v7, Stage IIIC Colorectal Cancer AJCC v7, Stage III Colorectal Cancer AJCC v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7, Stage IV Colorectal Cancer AJCC v7
Conditions
Brief summary
This phase II trial studies the side effects and best dose of capecitabine when given together with pembrolizumab and bevacizumab, and investigates how well they work in treating patients with microsatellite stable colorectal cancer that has spread to nearby tissues or lymph nodes, has spread to other places in the body, or that cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab and bevacizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, 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. Giving capecitabine together with pembrolizumab and bevacizumab may work better in treating patients with colorectal cancer.
Detailed description
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD) of capecitabine when administered with pembrolizumab and bevacizumab. (Safety Lead-In Cohort) II. To evaluate the overall response rate (ORR) to pembrolizumab plus capecitabine and bevacizumab (complete or partial response rate per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) in subjects with metastatic or locally advanced unresectable microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal carcinoma (CRC) that is stable or progressing on fluorouracil (5FU)-based therapy. (Phase II Expansion Cohort) SECONDARY OBJECTIVES (Phase II Expansion Cohort): I. To determine the safety and tolerability of pembrolizumab in combination with capecitabine and bevacizumab. II. To evaluate ORR per immune-related RECIST (irRECIST). III. To evaluate duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) per RECIST 1.1 and irRECIST and overall survival (OS). EXPLORATORY OBJECTIVES: I. Correlation of outcomes to line of therapy; stable disease or progression on a prior regimen containing infusional 5-FU or capecitabine; prior exposure to bevacizumab; and primary tumor location. II. To explore baseline immune profiles via PD-L1, and multiplex Immunohistochemistry (IHC) for identification of potentially predictive biomarkers in patients with metastatic or locally advanced, unresectable CRC treated with pembrolizumab-based combination therapy. III. To characterize the change in the populations of tumor-infiltrating immune cells (TIICs) by IHC induced by pembrolizumab-based combination therapy in paired pre- and on-treatment tumor biopsies from patients with metastatic or locally advanced, unresectable MSS / pMMR CRC. IV. To determine the change in T cell repertoire via next generation sequencing (NGS) within blood and tumor biopsy samples induced by pembrolizumab-based combination therapy in patients with metastatic or locally advanced, unresectable MSS/pMMR CRC. V. To establish human immune system (HIS) patient-derived xenograft (PDX) models from pre-treatment biopsies to a) analyze change in immune cell profiles HIS PDX models using the same techniques as described for corresponding patients, above and b) correlate response to pembrolizumab-containing therapy in patients and HIS PDX. OUTLINE: An initial safety lead-in will be performed to define the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 9 weeks until disease progression, start of new anti-cancer therapy, death, or end of the study whichever comes first
Interventions
BIOLOGICALBevacizumab
Given intravenously (IV)
DRUGCapecitabine
Given orally (PO)
PROCEDURESpecimen collection
For use in correlative studies
BIOLOGICALPembrolizumab
Given IV
Sponsors
Merck Sharp & Dohme LLC
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have histologically confirmed, locally advanced unresectable or metastatic (stage IV) colorectal adenocarcinoma 2. Have locally confirmed MSS or pMMR CRC; MSS is defined as 0-1 allelic shifts among 3-5 tumor microsatellite loci using a PCR-based assay; pMMR is defined as presence of protein expression of 4 MMR enzymes (DNA mismatch repair protein Mlh1 (MLH1), DNA mismatch repair protein Msh2 (MSH2), mutS homolog 6 (MSH6) and Mismatch repair endonuclease postmeiotic segregation increased 2 (PMS2) by immunohistochemistry. 3. Have stable disease or progression on a prior regimen containing infusional 5-FU or capecitabine according to the interpretation of the treating provider 4. Be willing and able to provide written informed consent/assent for the trial 5. Be 18 years of age on day of signing informed consent 6. Have measurable disease based on RECIST 1.1 7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion (phase II dose expansion cohort only); newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor 8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale 9. Demonstrate adequate organ function performed within 10 days of treatment initiation as defined below: 1. Absolute neutrophil count (ANC) \>= 1,500 /mcL 2. Platelets \>= 100,000 / microliter (mcL) 3. Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) 4. Serum creatinine =\< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance \>= 60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN. Glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)). Creatinine clearance should be calculated per institutional standard 5. Serum total bilirubin =\< 1.5 X ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN. Patients with Gilbert's disease may be included if their direct bilirubin is ≤ 1.5 X ULN. 6. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) =\< 2.5 X ULN OR =\< 5 X ULN for subjects with liver metastases 7. Albumin \>= 2.5 mg/dL 8. 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 9. 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 10. Female subject of childbearing potential should have a negative urine or serum pregnancy 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 11. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication 12. Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy * 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 investigational device within 4 weeks of the first dose of treatment 2. 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 3. Has a known history of active tuberculosis (TB) (Bacillus Tuberculosis) 4. Hypersensitivity to pembrolizumab or any of its excipients 5. Hypersensitivity/intolerance to capecitabine, Infusional 5-Fluorouracil (5-FU), or bevacizumab 6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier 7. Has had prior 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 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 8. Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer 9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability 10. Has active autoimmune disease that has required systemic treatment in the 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 11. Has known history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease. 12. Has an active infection at the time of cycle 1 day 1 requiring systemic therapy 13. 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 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 pre-screening or screening visit through 120 days after the last dose of trial treatment 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 17. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) 18. Has known active hepatitis B (e.g., hepatitis B surface antigen (HBsAg) reactive) or hepatitis C (e.g., hepatitis C virus (HCV) ribonucleic acid \[RNA\] \[qualitative\] is detected) 19. Requires therapeutic anticoagulation with warfarin at baseline. Patients must be off warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting study drug, however, therapeutic or prophylactic therapy with low-molecular weight heparin is allowed 20. Has history of known coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of start of study drug 21. Known bleeding risk including serious hemorrhage or hemoptysis within the last 3 months; major surgery within the past 8 weeks or minor surgery within the past 4 weeks 22. Has known gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology Criteria for Adverse Events (CTCAE) grade \> 3 within 6 months of start of study drug 23. Has greater than 1+ proteinuria on a urine dipstick or equivalent routine laboratory analysis will require further testing with a urine protein to creatinine ratio (UPCR); UPCR must be calculated as follows: UPCR = protein concentration (mg/dL)/creatinine (mg/dL); if the UPCR \>= 1, then the patient will not be eligible for study entry; however, if urinalysis or equivalent routine laboratory analysis shows no protein, then UPCR testing is not required 24. Has a history of non-healing wounds or ulcers, or bone re-fractures within 3 months of fracture 25. Has a history of arterial thromboembolism within 12 months of start of study drug 26. Has inadequately controlled hypertension (defined as systolic blood pressure greater than 150 mm Hg or diastolic blood pressure greater than 95 mm Hg). The use of anti-hypertensive medications to control blood pressure is permitted. Retesting is permitted. 27. Has a history of hypertensive crisis or hypertensive encephalopathy within 6 months prior to planned start of study drug 28. Has had clinically significant cardiovascular disease within 12 months of planned start of study drug, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent 29. Has a known history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to planned start of study drug 30. Known reversible posterior leukoencephalopathy syndrome (RPLS) 31. Difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of capecitabine 32. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Treatment-related, Dose-limiting Toxicities (DLT) (Safety Lead-In Cohort) | Up to 1 cycle (each cycle is 21 days) | A DLT evaluation of the first 6 participants will be conducted to confirm the safety of administering pembrolizumab at 200 mg (flat dosing) every three weeks with capecitabine and bevacizumab and include all participants in the safety lead in cohort who received at least 1 dose of study treatment. At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis including a baseline measure. Dose-limiting toxicity (DLT) must be clinically-significant toxicities which are at least possibly treatment-related per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4 |
| Overall Response Rate (ORR) | Up to 4 years | ORR is defined as the percentage of the participants in the ASaT population who have a confirmed complete response (CR) or a partial response (PR) (Overall Response (OR) = CR + PR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 on Computerized Tomography (CT) or magnetic resonance imaging or (MRI) imaging if a CT cannot be obtained. The ORR and 95% confidence interval will be provided using exact binomial method proposed by Clopper and Pearson (1934). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Up to 4 years | DCR is defined as the percentage of participants who have achieved confirmed CR or PR or have demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression assessed by RECIST and immune-related RECIST (irRECIST). The percentage of participants and 95% confidence interval, will be provided using exact binomial method proposed by Clopper and Pearson (1934). |
| Median Duration of Response (DOR) | Up to 4 years | Duration of response is defined as the time from first documented evidence of CR or PR assessed by RECIST and irRECIST until disease progression or death due to any cause, whichever occurs first. Kaplan-Meier (KM) curves and median estimates from will be reported |
| Median Overall Survival (OS) | Up to 4 years | OS is defined as the time from first day of study treatment to death due to any cause. Subjects without documented death at the time of the final analysis will be censored at the date of the last follow-up. KM curves and median estimates from the KM curves will be provided as appropriate. |
| Median Progression-Free Survival (PFS) | Up to 4 years | PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Median estimates in months and the 95% confidence interval will be reported. |
Countries
United States
Participant flow
Pre-assignment details
Participants in safety lead in cohort will be included in expansion cohort as All Subjects as Treated (ASaT) population. ASaT population will be used for analysis of objective response (ORR), disease control (DCR), progression-free survival (PFS) and overall survival (OS) and consist of participants who received at least one dose of study treatment (200mg pembrolizumab, 7.5mg/kg bevacizumab and 1000mg/m2 capecitabine). Participants ineligible for safety analysis will be replaced.
Participants by arm
| Arm | Count |
|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) Participants receive pembrolizumab IV over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice a day (BID) on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity. | 7 |
| Expansion Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) Participants receive pembrolizumab IV over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity. | 37 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Expansion Cohort | Participants did not complete follow-up scan required for disease response outcomes | 0 | 4 |
Baseline characteristics
| Characteristic | Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Expansion Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Total |
|---|---|---|---|
| Age, Customized 20-29 years old | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized 30-39 years old | 2 Participants | 7 Participants | 9 Participants |
| Age, Customized 40-49 years old | 0 Participants | 7 Participants | 7 Participants |
| Age, Customized 50-59 years old | 4 Participants | 11 Participants | 15 Participants |
| Age, Customized 60-69 years old | 1 Participants | 7 Participants | 8 Participants |
| Age, Customized 70-79 years old | 0 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 7 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 27 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) White | 5 Participants | 25 Participants | 30 Participants |
| Region of Enrollment United States | 7 participants | 37 participants | 44 participants |
| Sex: Female, Male Female | 3 Participants | 19 Participants | 22 Participants |
| Sex: Female, Male Male | 4 Participants | 18 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 1 / 37 |
| other Total, other adverse events | 7 / 7 | 35 / 37 |
| serious Total, serious adverse events | 4 / 7 | 11 / 37 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR is defined as the percentage of the participants in the ASaT population who have a confirmed complete response (CR) or a partial response (PR) (Overall Response (OR) = CR + PR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 on Computerized Tomography (CT) or magnetic resonance imaging or (MRI) imaging if a CT cannot be obtained. The ORR and 95% confidence interval will be provided using exact binomial method proposed by Clopper and Pearson (1934).
Time frame: Up to 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Overall Response Rate (ORR) | 5 percentage of participants |
Primary
Proportion of Participants With Treatment-related, Dose-limiting Toxicities (DLT) (Safety Lead-In Cohort)
A DLT evaluation of the first 6 participants will be conducted to confirm the safety of administering pembrolizumab at 200 mg (flat dosing) every three weeks with capecitabine and bevacizumab and include all participants in the safety lead in cohort who received at least 1 dose of study treatment. At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis including a baseline measure. Dose-limiting toxicity (DLT) must be clinically-significant toxicities which are at least possibly treatment-related per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4
Time frame: Up to 1 cycle (each cycle is 21 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Proportion of Participants With Treatment-related, Dose-limiting Toxicities (DLT) (Safety Lead-In Cohort) | 0.33 proportion of participants |
Secondary
Disease Control Rate (DCR)
DCR is defined as the percentage of participants who have achieved confirmed CR or PR or have demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression assessed by RECIST and immune-related RECIST (irRECIST). The percentage of participants and 95% confidence interval, will be provided using exact binomial method proposed by Clopper and Pearson (1934).
Time frame: Up to 4 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Disease Control Rate (DCR) | 25 percentage of participants |
Secondary
Median Duration of Response (DOR)
Duration of response is defined as the time from first documented evidence of CR or PR assessed by RECIST and irRECIST until disease progression or death due to any cause, whichever occurs first. Kaplan-Meier (KM) curves and median estimates from will be reported
Time frame: Up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Median Duration of Response (DOR) | 13.5 months |
Secondary
Median Overall Survival (OS)
OS is defined as the time from first day of study treatment to death due to any cause. Subjects without documented death at the time of the final analysis will be censored at the date of the last follow-up. KM curves and median estimates from the KM curves will be provided as appropriate.
Time frame: Up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Median Overall Survival (OS) | 10.1 months |
Secondary
Median Progression-Free Survival (PFS)
PFS is defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first. Median estimates in months and the 95% confidence interval will be reported.
Time frame: Up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead in Cohort: Treatment (Pembrolizumab, Bevacizumab, Capecitabine) | Median Progression-Free Survival (PFS) | 4.29 months |