Clinical Trials /

Pembrolizumab, Capecitabine, and Bevacizumab in Treating Patients With Microsatellite Stable Colorectal Cancer That Is Locally Advanced, Metastatic, or Cannot Be Removed by Surgery

NCT03396926

Description:

This phase II trial studies the side effects and best dose of capecitabine when given together with pembrolizumab and bevacizumab, and to see 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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab, Capecitabine, and Bevacizumab in Treating Patients With Microsatellite Stable Colorectal Cancer That Is Locally Advanced, Metastatic, or Cannot Be Removed by Surgery
  • Official Title: Phase II Study of Pembrolizumab Plus Capecitabine and Bevacizumab in Microsatellite Stable Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 174517
  • SECONDARY ID: NCI-2017-02324
  • SECONDARY ID: 17-22920
  • SECONDARY ID: 174517
  • NCT ID: NCT03396926

Conditions

  • Microsatellite Stable
  • Mismatch Repair Protein Proficient
  • Stage III Colorectal Cancer AJCC v7
  • Stage IIIB Colorectal Cancer AJCC v7
  • Stage IIIC Colorectal Cancer AJCC v7
  • Stage IV Colorectal Cancer AJCC v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

Interventions

DrugSynonymsArms
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGFTreatment (pembrolizumab, bevacizumab, capecitabine)
CapecitabineRo 09-1978/000, XelodaTreatment (pembrolizumab, bevacizumab, capecitabine)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, bevacizumab, capecitabine)

Purpose

This phase II trial studies the side effects and best dose of capecitabine when given together with pembrolizumab and bevacizumab, and to see 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:

      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).

      TERTIARY 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 IHC (immunohistochemistry)
      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:

      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 or start of new anti-cancer therapy, and then every 12 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, bevacizumab, capecitabine)ExperimentalPatients 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.
  • Capecitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Have histologically confirmed, locally advanced unresectable or metastatic (stage IV)
             colorectal adenocarcinoma

          -  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 (MLH1, MSH2, MSH6 and PMS2) by
             immunohistochemistry

          -  Have stable disease or progression on a prior regimen containing infusional 5-FU or
             capecitabine according to the interpretation of the treating provider

          -  Be willing and able to provide written informed consent/assent for the trial

          -  Have measurable disease based on RECIST 1.1

          -  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

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 10 days of treatment
             initiation)

          -  Platelets >= 100,000 / mcL (performed within 10 days of treatment initiation)

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment) (performed within 10 days of treatment
             initiation)

          -  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 (performed within 10 days of treatment initiation) (glomerular
             filtration rate [GFR] can also be used in place of creatinine or creatinine clearance
             [CrCl])

               -  Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation)

          -  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 (performed within 10 days of
             treatment initiation)

          -  Albumin >= 2.5 mg/dL (performed within 10 days of treatment initiation)

          -  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 (performed within 10 days of treatment
             initiation)

          -  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 (performed within 10 days of treatment initiation)

          -  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

          -  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

          -  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

          -  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

        Exclusion Criteria:

          -  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

          -  Has a known history of active tuberculosis (TB) (Bacillus Tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients

          -  Hypersensitivity/intolerance to capecitabine, infusional 5-flurouracil, or bevacizumab

          -  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

          -  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

          -  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

          -  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

          -  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

          -  Has known history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  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

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  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

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  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)

          -  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

          -  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

          -  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

          -  Has 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

          -  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

          -  Has a history of non-healing wounds or ulcers, or bone re-fractures within 3 months of
             fracture

          -  Has a history of arterial thromboembolism within 12 months of start of study drug

          -  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
             antihypertensive medications to control blood pressure is permitted

          -  Has a history of hypertensive crisis or hypertensive encephalopathy within 6 months
             prior to planned start of study drug

          -  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

          -  Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
             abscess within 6 months prior to planned start of study drug

          -  Known reversible posterior leukoencephalopathy syndrome (RPLS)

          -  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

          -  Has received a live vaccine within 30 days of planned start of study therapy

               -  Note: Seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
                  are live attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Time Frame:Up to 4 years
Safety Issue:
Description:The point estimate and 95% confidence interval, will be provided using exact binomial method proposed by Clopper and Pearson (1934).

Secondary Outcome Measures

Measure:Disease control rate (DCR) is defined as the percentage of subjects who have achieved confirmed CR or PR or have demonstrated stable disease (SD) for at least 24 weeks prior to any evidence of progression
Time Frame:Up to 4 years
Safety Issue:
Description:Will be assessed by RECIST and immune-related RECIST (irRECIST). The point estimate and 95% confidence interval, will be provided using exact binomial method proposed by Clopper and Pearson (1934).
Measure:Duration of response (DOR) assessed by RECIST and irRECIST
Time Frame:From first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first, assessed for up to 4 years
Safety Issue:
Description:Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate.
Measure:Overall survival (OS)
Time Frame:From first day of study treatment to death due to any cause, whichever occurs first, assessed for up to 4 years
Safety Issue:
Description:KM curves and median estimates from the KM curves will be provided as appropriate.
Measure:Progression-free survival (PFS) assessed by RECIST and irRECIST
Time Frame:From first day of study treatment to the first documented disease progression or death due to any cause, whichever occurs first, assessed for up to 4 years
Safety Issue:
Description:KM curves and median estimates from the KM curves will be provided as appropriate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

April 4, 2018