Trial Title:
Neoadjuvant Chemoimmunotherapy for Resectable Non-Metastatic Proficient Mismatch Repair (PMMR) Colon Cancer
NCT ID:
NCT05870800
Condition:
Stage I Colon Cancer
Stage II Colon Cancer
Stage III Colon Cancer
Conditions: Official terms:
Colonic Neoplasms
Leucovorin
Capecitabine
Fluorouracil
Oxaliplatin
Atezolizumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Phase II open-label trial of neoadjuvant CAPEOX chemotherapy with Atezolizumab followed
by surgery and adjuvant chemotherapy for patients with localized resectable pMMR
adenocarcinoma of the colon
Primary purpose:
Treatment
Masking:
None (Open Label)
Masking description:
Open label
Intervention:
Intervention type:
Drug
Intervention name:
Tecentriq 1200 MG in 20 ML Injection + Capecitabine 1000 mg/m2 + Oxaliplatin 130 mg/m2
Description:
Enrolled Participant will receive 4 cycles of neoadjuvant Atezolizumab (Tecentriq)
followed by CAPEOX chemotherapy prior to surgery. Each cycle is every 3 weeks. (12 weeks)
Arm group label:
Neoadjuvant Therapy Arm
Other name:
Neoadjuvant Chemoimmunotherapy
Intervention type:
Drug
Intervention name:
Oxaliplatin injection 85mg/m2 + Leucovorin 400mg/m2 + 5-Fluorouracil 2400mg/m2
Description:
After Surgery, if patients are still considered at high risk (per treating investigator)
subjects will be eligible to receive adjuvant chemotherapy with mFOLFOX6 Q2 weeks x 6
cycles (12 weeks) or CAPEOX Q3 weeks x 4 cycles (12 weeks)
Arm group label:
Neoadjuvant Therapy Arm
Other name:
mFOLFOX6
Intervention type:
Drug
Intervention name:
Oxaliplatin 130mg/m2 + Capecitabine 1000mg/m2
Description:
After Surgery, if patients are still considered at high risk (per treating investigator)
subjects will be eligible to receive adjuvant chemotherapy with mFOLFOX6 Q2 weeks x 6
cycles (12 weeks) or CAPEOX Q3 weeks x 4 cycles (12 weeks)
Arm group label:
Neoadjuvant Therapy Arm
Other name:
CAPEOX
Summary:
This is an open-label Phase II trial that will investigate the use of neoadjuvant CAPEOX
chemotherapy with Atezolizumab followed by surgery and adjuvant chemotherapy for patients
with localized resectable pMMR adenocarcinoma of the colon with a target accrual of 30
patients.
The investigators will explore if appropriately timed neoadjuvant CAPEOX with anti-PD-L1
mAb (Atezolizumab) can be administered safely and feasibly for 12 weeks, and that this
combination will lead to improved clinical response associated with enhanced numbers of
immune cells in surgically resected colon tumors.
Participants will receive 4 cycles of atezolizumab in combination with 4 cycles of CAPEOX
(atezolizumab will be administered prior to chemotherapy) before standard of care
surgical resection. Each cycle of neoadjuvant therapy is 3 weeks. Following surgery,
participants still considered to be at high-risk of recurrence (per NCCN guidelines) will
receive further adjuvant chemotherapy (mFOLFOX6 or CAPEOX),for 6 and 4 cycles
respectively (for a total of 12 weeks), based on the discretion of the treating
oncologist/investigator.
Participants will be followed up for an EFFICACY follow-up phase every 2 months during
the first 6 months after surgery (months 1, 3, 6) and thereafter participants will enter
a SURVIVAL follow-up phase and will be seen every 6 months starting at month 12 until
month 36. During this the efficacy and survival follow up visits blood samples will be
obtained for purposes of obtaining circulating DNA and stool and optional blood samples
for storage for future exploratory analysis. Additionally, during these follow up visits,
participants will be asked to complete quality of life questionnaires
Detailed description:
Once participants' eligibility has been confirmed, and participants have been registered
in the study, the participants will receive immunotherapy treatment with Atezolizumab,
followed by administration of CAPEOX chemotherapy for a total of four cycles. Each cycle
is 3 weeks; a total of four cycles will be administered and must be completed within 15
weeks. Participants will receive growth factor support at the treating physician's
discretion.
Participants will receive 4 cycles (one cycle every 3 weeks) of Atezolizumab along with 4
cycles (one cycle every3 weeks) of CAPEOX before surgery. Atezolizumab will be initiated
starting with Cycle 1 Day 1 (during first chemotherapy session). Trial intervention(s)
should begin on the day of enrollment (the process of registering or entering a patient
into a clinical trial) or as close as possible to the date on which intervention is
allocated/assigned.
Following surgery, the treating investigator will monitor and determine the risk of
disease recurrence (the risk of the cancer coming back) after surgery. In addition,
investigators will collect a series of blood sample collections called ctDNA monitoring
assay. This blood test will be specific to each participant, and it may indicate if more
chemotherapy is needed after surgery. In case participants' ctDNA test comes back as
positive (+) at any point, the investigators will discuss with participant about the
possibility of receiving further chemotherapy for an additional 12 weeks. This
chemotherapy regimen will be either mFOLFOX6 (every 2 weeks for a total of 6 cycles= 12
weeks) or CAPEOX chemotherapy (every 3 weeks for a total of 4 cycles= 12 weeks).
Toxicities (undesirable effects of medications) for Atezolizumab and CAPEOX will be
continuously monitored to make sure their side effects are in line with prior experience
of their use, individually or combined.
Re-Staging Staging is a way to describe a cancer. The cancer's stage tells the
investigators where a cancer is located and its size, how far it has grown into nearby
tissues, and if it has spread to nearby lymph nodes (a small bean-shaped structure that
is part of the body's immune system) or other parts of the body.
For this study, the investigators will order for participants to have a Computerized
Tomography (CT), a series of X-ray images taken from different angles, or a Magnetic
Resonance Imaging (MRI), a medical imaging technique that uses a magnetic field and
computer-generated radio waves to create detailed images of the organs and tissues in the
body, done before any intervention, with the purpose of staging the cancer, determining
if it is removable by surgery.
Restaging with the same method of imaging used to meet initial eligibility requirements,
including either contrast-enhanced CT or MRI (for patients with an intravenous contrast
allergy) must be performed 2-4 weeks following completion of chemotherapy. All re-staging
imaging will be centrally reviewed for assessment of resectability (to determine if the
cancer can be removed).
SURGERY After participants have recovered sufficiently from any adverse effects of
neoadjuvant chemotherapy and still have removable cancer on re-staging, the investigator
should proceed to surgery at the participating site within 8 weeks following completion
of chemotherapy.
ADJUVANT CHEMOTHERAPY Following surgery, the treating investigator will monitor and
determine the risk of disease recurrence (the risk of the cancer coming back) after
surgery. In addition, the investigators will collect a series of blood sample collections
called ctDNA monitoring assay. This blood test will be specific to each participant, and
it may indicate if more chemotherapy is needed after surgery. In case participants' ctDNA
test comes back as positive (+) at any point, the investigator will discuss with
participants about the possibility of receiving further chemotherapy for an additional 12
weeks. This chemotherapy regimen will be either mFOLFOX6 (every 2 weeks for a total of 6
cycles= 12 weeks) or CAPEOX chemotherapy (every 3 weeks for a total of 4 cycles= 12
weeks).
FOLLOW UP VISITS Participants will be followed up for an efficacy follow-up phase every 2
months during the first 6 months after surgery (months 1, 3, 6), and thereafter they will
enter a survival follow-up phase and will be seen every 6 months starting at month 12
until month 36. During these visits the investigators are going to monitor participants
blood for ctDNA analysis and whole blood samples (for future research analysis), vital
status updates, quality of life questionnaires, routine laboratory assessments, and
standard of care imaging.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Signed Informed Consent Form
- Age >18 years at time of signing Informed Consent Form
- Ability to comply with the study protocol
- MSS or pMMR tumor determined by local CLIA-certified PCR or IHC testing
respectively.
- Histologically or cytologically confirmed resectable non-metastatic adenocarcinoma
of the colon (stages I-III)
- The distal extent of the tumor must be ≥12 cm from the anal verge on pre-surgical
endoscopy and/or imaging (i.e., excluding rectal adenocarcinomas warranting
treatment with chemoradiation). If the patient did not undergo a pre-surgical
endoscopy, then the distal extent of the tumor must be ≥12 cm from the anal verge as
determined by surgical examination or pre-operative imaging.
- Availability of a representative tumor specimen (preop biopsy or surgical tissue
specimen) for ctDNA assay design from tumor sample and for exploratory biomarker
research determination.
- One or more of the following high-risk features:
- High CEA levels (>5 ng/ml in non-smoker patients , >10ng/ml in smoker patients)
- Low Lymphocyte-to-monocyte Ratio (<2.38)
- Poor grade of tumor differentiation
- Evidence of Lymphovascular Invasion
- Evidence of Perineural Invasion
- CT evidence of T3 orT4 disease w/ ≥4 cm tumor longitudinal diameter
- CT evidence of regional lymphadenopathy
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
- Adequate hematologic and end-organ function, defined by the following laboratory
test results, obtained within 14 days prior to initiation of study treatment:
- ANC ≥ 1.5 x 10*9/L (1500/mL) without granulocyte colony-stimulating factor
support
- Lymphocyte count ≥ 0.5 x 10*9/L (500/µL)
- Platelet count ≥100 x 10*9/L (100,000/µL) without transfusion
- Hemoglobin ≥ 7 g/L (7 g/dL) Patients may be transfused to meet this criterion.
- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN)
- Serum bilirubin ≤ 1.5 x ULN with the following exception:
Patients with known Gilbert disease: serum bilirubin ≤ 3 x ULN
- Serum creatinine ≤1.5 x ULN or Creatinine clearance ≥ 50 mL/min (calculated using
the Cockcroft-Gault formula)
- Serum albumin ≥ 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
- For patients receiving therapeutic anticoagulation: stable anticoagulant
regimen
- Negative hepatitis B surface antigen (HBsAg) test at screening
- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV
antibody test followed by a negative HCV RNA test at screening The HCV RNA test
must be performed for patients who have a positive HCV antibody test.
- Negative HIV test at screening
- For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraceptive methods, and agreement to
refrain from donating eggs, as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per
year during the treatment period and for 5 months after the final dose of atezolizumab
and for 6 months following any of the adjuvant chemotherapy regimens (if applicable)
after the final dose of mFOLFOX6 or CAPEOX.Women must refrain from donating eggs during
this same period.
A woman is considered to be of childbearing potential if she is postmenarchal, has not
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified
cause other than menopause), and has not undergone surgical sterilization (removal of
ovaries, fallopian tubes and/or uterus) or another cause as determined by the
investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal
ligation is considered to be of childbearing potential. The definition of childbearing
potential may be adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation,
hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of
the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not adequate methods of contraception. If required per local guidelines or
regulations, locally recognized adequate methods of contraception and information about
the reliability of abstinence will be described in the local Informed Consent Form.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential who is not pregnant, men who are not
surgically sterile must remain abstinent or use a condom plus an additional contraceptive
method that together result in a failure rate of <1% per year during the treatment period
and for 5 months after the final dose of any chemotherapy regimen. Men must refrain from
donating sperm during this same period.
With a pregnant female partner, men must remain abstinent or use a condom during the
treatment period and for 5 months after any of the chemotherapy regimens to avoid
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of
the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not adequate methods of contraception. If required per local guidelines or
regulations, locally recognized adequate methods of contraception and information about
the reliability of abstinence will be described in the local Informed Consent Form.
Exclusion Criteria:
- Symptomatic, untreated, or any site actively progressing metastatic disease.
- History of leptomeningeal disease
- Uncontrolled tumor-related pain Patients requiring pain medication must be on a
stable regimen at study entry. Presence of any metastatic effusion (pleural,
pericardial, ascites)
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >
12 mg/dL or corrected serum calcium > ULN)
- Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré
syndrome, or multiple sclerosis (see Appendix 11 for a more comprehensive list of
autoimmune diseases and immune deficiencies), with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are
eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible
for the study provided all of following conditions are met:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- There has been no occurrence of acute exacerbations of the underlying condition
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within
the previous 12 months
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan History of
radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Active tuberculosis
- Significant cardiovascular disease (such as New York Heart Association Class II
or greater cardiac disease, myocardial infarction, or cerebrovascular accident)
within 3 months prior to initiation of study treatment, unstable arrhythmia, or
unstable angina
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to
initiation of study treatment, or anticipation of need for a major surgical
procedure during the study
- History of malignancy other than colon adenocarcinoma within 5 years prior to
screening, with the exception of malignancies with a negligible risk of
metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated
carcinoma in situ of the cervix, non melanoma skin carcinoma, localized
prostate cancer, ductal carcinoma in situ, Stage I uterine cancer or colonic
polyps
- Severe infection within 4 weeks prior to initiation of study treatment,
including, but not limited to, hospitalization for complications of infection,
bacteremia, or severe pneumonia, or any active infection that could impact
patient safety
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to
initiation of study treatment Patients receiving prophylactic antibiotics
(e.g., to prevent a urinary tract infection or chronic obstructive pulmonary
disease exacerbation) are eligible for the study.
- Prior allogeneic stem cell or solid organ transplantation
- Any other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding that contraindicates the use of an investigational
drug, may affect the interpretation of the results, or may render the patient
at high risk from treatment complications
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during atezolizumab
treatment or within 5 months after the final dose of atezolizumab
- Current treatment with anti-viral therapy for HBV
- Synchronous primary rectal and/ or colon cancers or history of prior invasive
colon malignancy, regardless of disease-free interval.
- Treatment with investigational therapy within 28 days prior to initiation of
study treatment
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents (including, but not limited
to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the
drug (whichever is longer) prior to initiation of study treatment
- Treatment with systemic immunosuppressive medication (including, but not
limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-TNF- agents) within 2 weeks prior to initiation of study
treatment, or anticipation of need for systemic immunosuppressive medication
during study treatment, with the following exceptions:
Patients who received acute, low-dose systemic immunosuppressant medication or a one-time
pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids
for a contrast allergy) are eligible for the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for
orthostatic hypotension or adrenal insufficiency are eligible for the study.
- History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation
- Known allergy or hypersensitivity to any component of the CAPEOX or mFOLFOX6
chemotherapy formulations
- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
or within 5 months for Atezolizumab and 6 months for any chemotherapy regimen after
the final dose of study treatment Women of childbearing potential must have a
negative serum pregnancy test result within 14 days prior to initiation of study
treatment.
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Baylor College of Medicine
Address:
City:
Houston
Zip:
77030
Country:
United States
Contact:
Last name:
Hector J Garcia-Chavez, MD
Phone:
713-798-6419
Email:
hector.garcia-chavez@bcm.edu
Contact backup:
Last name:
Tabish Iqbal, MD
Email:
tabish.iqbal@bcm.edu
Investigator:
Last name:
Atif Iqbal, MD
Email:
Principal Investigator
Investigator:
Last name:
Shalini Makawita, MD
Email:
Principal Investigator
Investigator:
Last name:
Benjamin Musher, MD
Email:
Sub-Investigator
Investigator:
Last name:
Yesenia Rojas-Khalil, MD
Email:
Sub-Investigator
Investigator:
Last name:
Tannaz Armaghany, MD
Email:
Sub-Investigator
Investigator:
Last name:
Ernest R. Camp, MD
Email:
Sub-Investigator
Investigator:
Last name:
Karen Riggins, MD
Email:
Sub-Investigator
Investigator:
Last name:
Ramon Jin, MD
Email:
Sub-Investigator
Investigator:
Last name:
Punam Parikh-Amin, MD
Email:
Sub-Investigator
Investigator:
Last name:
Eric Silberfein, MD
Email:
Sub-Investigator
Investigator:
Last name:
Cary Hsu, MD
Email:
Sub-Investigator
Investigator:
Last name:
Carlos Farinas, MD
Email:
Sub-Investigator
Investigator:
Last name:
Shilpa Jain, MD
Email:
Sub-Investigator
Start date:
September 1, 2024
Completion date:
January 1, 2028
Lead sponsor:
Agency:
Baylor College of Medicine
Agency class:
Other
Collaborator:
Agency:
Genentech, Inc.
Agency class:
Industry
Source:
Baylor College of Medicine
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05870800
