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 metastatic CRC.
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.
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 capecitabine plus oxaliplatin(CapeOx).
- Prior dose modifications and growth factor support are permissible.
- Some or all chemotherapy may be administered at an outside, non-University of
California San Francisco (non-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/microliter (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 (HCV) (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.
