Clinical Trials /

Pembrolizumab After Chemotherapy in Treating Patients With Colorectal Cancer That Has Spread to the Liver and Who Are Undergoing Liver Surgery

NCT03844750

Description:

This phase II trial studies how well pembrolizumab works after chemotherapy and before liver surgery in patients with colorectal cancer that has spread to the liver. 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. Giving pembrolizumab after chemotherapy and before liver surgery may work better in treating patients with colorectal cancer that has spread to the liver.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab After Chemotherapy in Treating Patients With Colorectal Cancer That Has Spread to the Liver and Who Are Undergoing Liver Surgery
  • Official Title: A Phase II Study of Preoperative Immunotherapy in Patients With Colorectal Cancer and Resectable Hepatic Metastases

Clinical Trial IDs

  • ORG STUDY ID: 187015
  • SECONDARY ID: NCI-2018-03165
  • NCT ID: NCT03844750

Conditions

  • Metastatic Malignant Neoplasm in the Liver
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (FOLFOX, pembrolizumab, surgery)
FOLFOX regimen5-fluorouracil, Leucovorin, OxaliplatinTreatment (FOLFOX, pembrolizumab, surgery)

Purpose

This phase II trial studies how well pembrolizumab works after chemotherapy and before liver surgery in patients with colorectal cancer that has spread to the liver. 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. Giving pembrolizumab after chemotherapy and before liver surgery may work better in treating patients with colorectal cancer that has spread to the liver.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To characterize the change in the populations of tumor-infiltrating immune cells (TIICs)
      induced by neoadjuvant pembrolizumab following leucovorin calcium (calcium folinate),
      5-fluorouracil, and oxaliplatin (FOLFOX) in patients with metastatic colorectal cancer (CRC).

      SECONDARY OBJECTIVES:

      I. To describe the safety/toxicity profile of pembrolizumab following FOLFOX in the
      preoperative setting for patients with CRC with resectable hepatic metastases.

      II. To estimate the clinical efficacy of neoadjuvant pembrolizumab following FOLFOX in
      patients with CRC with resectable hepatic metastases.

      III. Pathologic response in resected tumor. IV. Objective response rate (ORR) by Response
      Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      V. Landmark progression-free survival (PFS) at 12 months.

      EXPLORATORY OBJECTIVES:

      I. To determine the impact of neoadjuvant pembrolizumab following FOLFOX on PD-L1 expression
      in tumor cells and TIICs, in patients with metastatic (m)CRC.

      II. To determine the change in T cell repertoire within the tumor and blood induced by
      neoadjuvant pembrolizumab following FOLFOX in patients with mCRC.

      III. To explore molecular profiles to identify potentially predictive biomarkers for patients
      with metastatic CRC treated with immunotherapy (including but not limited to microsatellite
      instability [MSI] testing).

      IV. To correlate change in TIICs, PDL-1 expression, and T cell repertoires as well as
      molecular profiles with response/resistance and toxicity.

      V. To establish human immune system patient-derived xenografts (HIS PDX) models from
      pre-treatment liver biopsy specimens and to correlate treatment effects in HIS PDX and
      corresponding patients.

      VI. To correlate contrast-enhanced computed tomography (CT) imaging metrics, such as
      quantitative enhancement characteristics, with change in TIICs in patients with CRC liver
      metastases treated with pembrolizumab preceded by FOLFOX.

      VII. To identify immune response messenger ribonucleic acid (mRNA) expression analysis to
      derive signatures associated with tumor response.

      VIII. To identify genomic mutations and gene copy aberrations associated with response and
      resistance to therapy.

      OUTLINE:

      Patients receive between 4 and 8 FOLFOX treatments, based on the treating physician's
      opinion. Approximately 2 weeks after the last dose of FOLFOX, patients receive pembrolizumab
      intravenously (IV) over 30 minutes on day 1. About 2 weeks later, patients undergo hepatic
      resection.

      After completion of study treatment, patients are followed up at 30 days and every 90 days
      for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (FOLFOX, pembrolizumab, surgery)ExperimentalPatients receive between 4 and 8 FOLFOX treatments, based on the treating physician's opinion. Approximately 2 weeks after the last dose of FOLFOX, patients receive pembrolizumab IV over 30 minutes on day 1. About 2 weeks later, patients undergo hepatic resection.
  • Pembrolizumab
  • FOLFOX regimen

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed CRC with liver
             metastases. In addition to liver metastases, extrahepatic metastases (e.g. pulmonary
             metastases) may be permitted if all other eligibility criteria are met. Patients are
             permitted to have primary tumor in situ.

          -  Achieved PR or stable disease (SD) on FOLFOX chemotherapy.

               -  The number of cycles of chemotherapy prior to study entry is expected to be
                  between 4 and 8 cycles. Any variation beyond this, including prior cancer
                  therapies, should be discussed with the study principal investigator and surgeon.

               -  Concurrent monoclonal antibody (mAb) therapy (bevacizumab, cetuximab, or
                  panitumumab) is acceptable, however the antibody must be omitted from the final
                  cycle of chemotherapy prior to pembrolizumab.

               -  FOLFOX may be substituted with CapeOx (capecitabine plus oxaliplatin).

               -  Prior dose modifications and growth factor support are permissible.

               -  Some or all chemotherapy may be administered at outside (non-University of
                  California San Francisco [UCSF]) facilities.

          -  Be an appropriate candidate to undergo liver biopsy and resection (+ - ablation) of
             liver metastases according to the interpretation of the Multidisciplinary
             Gastrointestinal (GI) Tumor Board.

          -  Be willing and able to provide written informed consent/assent for the trial. The
             patient may also provide consent for future biomedical research. However, the patient
             may participate in the main trial without participating in future biomedical research.

          -  Have measurable disease based on RECIST 1.1 as assessed by the investigator. Lesions
             situated in a previously irradiated area are considered measurable if progression has
             been demonstrated in such lesions.

          -  Be willing to provide tissue from a newly obtained core or excisional biopsy of a
             tumor lesion. Newly-obtained is defined as a specimen obtained after last dose of
             FOLFOX and prior to first dose of pembrolizumab.

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

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

          -  Platelets >= 100,000/uL (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).

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
             creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl]) >= 60 mL/min for patient with creatinine
             levels > 1.5 x institutional ULN (within 10 days of treatment initiation).

               -  Creatinine clearance should be calculated per institutional standard.

          -  Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
             bilirubin levels > 1.5 ULN (within 10 days of treatment initiation).

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x
             ULN (within 10 days of treatment initiation).

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

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants (within 10
             days of treatment initiation).

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants (within 10 days of treatment initiation).

          -  Female patients of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of study medication
             (day 1). If the urine test is positive or cannot be confirmed as negative, a serum
             pregnancy test will be required.

          -  Female patients 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.

               -  Note: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the patient.

          -  Male patients 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 patient.

        Exclusion Criteria:

          -  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.

               -  Note: Patients 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 use.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

          -  Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is
             required unless mandated by local health authority.

          -  Has an 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) is not considered a form
             of systemic treatment and is allowed.

          -  Has active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or
             active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.

          -  Has received prior anti-cancer monoclonal antibody (mAb), systemic anticancer therapy
             other than FOLFOX (including investigational agents), targeted small molecule therapy,
             or radiation therapy within 14 days prior to the first dose of study treatment (day
             1).

               -  Note: Patients must have recovered from all adverse events (AEs) due to a
                  previous therapies to =< grade 1 or baseline. Patients with grade 2 neuropathy or
                  alopecia are eligible. If a patient received major surgery, they must have
                  recovered adequately from the toxicity and/or complications from the intervention
                  prior to starting study treatment.

          -  Has received FOLFOX less than 7 days prior to the first dose of study treatment (day
             1). Has not recovered (i.e., =< grade 1 or at baseline) from AEs due to FOLFOX
             chemotherapy.

               -  Note: Patients with =< grade 2 neuropathy or alopecia are exceptions to this
                  criterion and may qualify for the study.

          -  Has not recovered adequately from toxicity or complications of a surgery or other
             procedure, per the assessment of the treating investigator.

          -  Has received liver-directed therapy such as radiotherapy or yttrium-90 in the past
             year.

          -  Has a known additional malignancy that is progressing or has required active treatment
             within 5 years prior.

               -  Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of
                  the skin, carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that
                  have undergone potentially curative therapy are not excluded.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Patients with previously treated brain metastases may participate provided
             they are radiologically stable (i.e., without evidence of progression by imaging for
             at least 4 weeks by repeat imaging [repeat imaging should be performed during the
             study screening]), clinically stable, and without requirement of steroid treatment for
             at least 14 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability.

          -  Has a history of (non-infectious) pneumonitis that required steroids or has 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 patient?s
             participation for the full duration of the trial, or is not in the best interest of
             the patient to participate, in the opinion of the treating investigator.
             Anticoagulation that cannot be safely held to perform the liver biopsy is an example
             of a contraindication to participation.

          -  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 any prior immunotherapy including anti?PD-1, anti?PD-L1, or anti-PD-L2 or
             with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.
             CTLA-4, OX-40, CD137).

          -  Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or to any of
             pembrolizumab?s excipients.

          -  Has received a live vaccine within 30 days prior to first dose of the trial drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacille
             Calmette?Gu?rin (BCG), and typhoid vaccine.

               -  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.

          -  Has inferior vena cava/cardiac involvement based on imaging.

          -  Has had encephalopathy in the last 6 months. Those patients on rifaximin or lactulose
             to control their encephalopathy are not allowed.

          -  Has had a solid organ or hematologic transplant.

          -  Has symptomatic ascites or pleural effusion. A patient who is clinically stable
             following treatment for these conditions (including therapeutic thora- or
             paracentesis) is eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients with a >= 2-fold increase in the tumor-infiltrating CD3+ T cells per unit area (5 high power fields) in post- versus pre pembrolizumab treatment tumor specimens.
Time Frame:Up to 1 year
Safety Issue:
Description:Tumor-infiltrating immune cells (TIICs) will be analyzed by immunohistochemistry (IHC) in pre- and post-pembrolizumab treatment tumor specimens. The proportion of patients with a >= 2-fold increase (from pre- to post-treatment) in the number of TIICs per unit area (5 high power fields) will be calculated.

Secondary Outcome Measures

Measure:Incidence of adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 1 year
Safety Issue:
Description:Adverse events (AEs) will be analyzed including but not limited to all AEs, serious (S)AEs, and fatal AEs. Furthermore, specific immune-related AEs (irAEs) will be collected and designated as immune-related events of clinical interest (ECIs). The study will use descriptive statistics to report on the safety/toxicity.
Measure:Objective response rate (ORR) to leucovorin calcium (calcium folinate), 5-fluorouracil, and oxaliplatin (FOLFOX)
Time Frame:Up to 1 year
Safety Issue:
Description:Using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Measure:Partial response [PR] rate to pembrolizumab
Time Frame:Up to 1 year
Safety Issue:
Description:Using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Measure:Complete response [CR] rate to pembrolizumab
Time Frame:Up to 1 year
Safety Issue:
Description:Using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Measure:Pathologic response rate
Time Frame:Up to 1 year
Safety Issue:
Description:The study will use descriptive statistics to report on pathologic response.
Measure:R0 resection rate
Time Frame:Up to 1 year
Safety Issue:
Description:The study will use descriptive statistics to report on R0 resection rate.
Measure:Progression-free survival (PFS) per RECIST 1.1
Time Frame:At 1 year
Safety Issue:
Description:The study will use descriptive statistics to report on PFS.

Details

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

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