Trial Title:
Immunotherapies in Combination With Stereotactic Body Radiation Radiotherapy in Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)
NCT ID:
NCT06603818
Condition:
Microsatellite Stable Metastatic Colorectal Cancer
Metastatic Colorectal Cancer
Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Atezolizumab
Conditions: Keywords:
Stereotactic Body Radiation Radiotherapy
Immunotherapy
Radiation Therapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Tiragolumab
Description:
Tiragolumab is given intravenously (IV) every 3 weeks (21-day cycles) for up to 2 years
Arm group label:
Arm 1
Intervention type:
Biological
Intervention name:
Atezolizumab
Description:
Atezolizumab is given intravenously (IV) every 3 weeks (21-day cycles) for up to 2 years
Arm group label:
Arm 1
Intervention type:
Radiation
Intervention name:
Stereotactic Body Radiation Therapy (SBRT)
Description:
SBRT will occur on Days 1, 3, and 5 of Cycle 1 only
Arm group label:
Arm 1
Summary:
Background:
Metastatic colorectal cancer (mCRC) is cancer that has spread beyond the colon and
rectum. Most people with mCRC die within 5 years. New immune-based treatments are making
progress with some types of colon cancer. But these treatments do little for people with
a type of cancer that is microsatellite stable (MSS). MSS is a specific cancer biomarker.
Better treatments are needed.
Objective:
To test 2 drugs (tiragolumab and atezolizumab) combined with radiation therapy in people
with MSS mCRC.
Eligibility:
People aged 18 years and older with MSS mCRC.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will
have imaging scans and a test of their heart function. They will provide a tissue sample
from their tumor; if one is not already available, a new sample will be taken. Their
ability to perform normal tasks will be assessed.
Tiragolumab and atezolizumab are both administered through a tube attached to a needle
inserted into a vein. Participants will receive both drugs on day 1 of 3-week treatment
cycles. Each study visit should last about 8 hours.
Participants will receive radiation therapy on days 1, 3, and 5 of cycle 1 only.
Blood samples and rectal swabs will be collected on day 1 of every cycle.
Imaging scans will be repeated every 9 weeks. Additional tumor samples may be taken
during treatment.
Treatment will continue for up to 2 years.
Participants will have a follow-up visit 1 month after treatment ends. Follow-up visits
will continue every 3 months for 1 more year.
Detailed description:
Background:
- Metastatic colorectal cancer (mCRC) is incurable for most patients and carries a
poor diagnosis.
- Immune-based approaches in solid tumor malignancies have seen much progress but
these have limited efficacy for microsatellite stable (MSS) mCRC.
- The Gastrointestinal Malignancies Section at NCI conducted a Pilot Study of the PD-1
Targeting Agent AMP-224 with low-dose cyclophosphamide and stereotactic body
radiation therapy (SBRT) that supports potential antitumor efficacy of the
combination of immunotherapy and radiation in MSS mCRC (NCT02298946).
- T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor
expressed in multiple cancers on tumor-infiltrating cytotoxic T cells, helper T
cells, natural killer (NK) cells, and regulatory T cells. Its main ligand, CD155, is
expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells,
contributing to local immune-surveillance suppression.
- Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is
that it enhances not only anti-tumor effector T-cell responses, but also NK-cell
responses, and reduces the suppressive capacity of regulatory T cells.
- Pre-clinical studies show that the co-blockade of TIGIT and the programmed cell
death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) pathway may lead to
decreased tumor volume. Notably, this has been observed in anti-PD-1 resistant tumor
models.
- Preclinical and clinical evidence suggests further increased benefit to the double
immune checkpoint blockade through increased expression of PD-L1 and neoantigens in
response to SBRT.
- Early results from clinical trials suggest clinical activity of anti-TIGITplus
anti-PD-L1 in solid tumors and the effect of combining immunotherapy with radiation
in heavily pretreated MSS mCRC patients providing a proof of concept that radiation
enhances immunotherapy response.
- A combination of anti-PD-L1, anti-TIGIT, and SBRT may increase CRC susceptibility to
immune therapy given the promising activity of anti-TIGIT in combination with
anti-PDL1 in preclinical studies of mice bearing subcutaneous CT26 colon tumors.
Primary Objectives:
- To confirm the Recommended Phase II dose (RP2D) of the combination therapy
(tiragolumab and atezolizumab plus SBRT) in participants with MSS mCRC (Part A)
- To determine the proportion of participants without progression after 9 weeks of the
combination therapy (tiragolumab and atezolizumab plus SBRT) in participants with
MSS mCRC (Part B)
Eligibility:
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status <= 1
- Histopathologic confirmation of mCRC by the NCI Laboratory of Pathology (LP)
- Disease not amenable to curative resection
- At least 1 lesion amenable to SBRT and a second lesion outside the radiation field
to serve as a target lesion
- Adequate organ and marrow function
Design:
- This is a phase II, single-arm, non-randomized, trial using tiragolumab and
atezolizumab in combination with SBRT.
- A maximum of 30 participants with MSS mCRC will be enrolled.
- Participants will receive atezolizumab and tiragolumab intravenously (IV) every 3
weeks (21-day cycles) with SBRT occurring on Days 1, 3, and 5 of Cycle 1 for 2
years.
- Participants will be evaluated routinely for toxicity and will have re-staging
imaging every 9 weeks (every 3 cycles).
- Optional research biopsies will be done at baseline and during week 1 of cycle 2. If
the participant has disease progression after cycle 3, a post-treatment biopsy may
be performed.
- The proportion of participants that are progression-free at 9 weeks will be
evaluated as a binary endpoint.
Criteria for eligibility:
Criteria:
- INCLUSION CRITERIA:
- Histologically or cytologically confirmed colorectal cancer (CRC) by the NCI
Laboratory of Pathology (LP). Note: Participants must provide tumor sample or be
willing to undergo biopsy to confirm the diagnosis.
- Evidence of metastatic involvement.
- History of microsatellite stable (MSS) status.
- Age >= 18 years.
- Weight > 35 kg.
- ECOG performance status <= 1
- Must have measurable disease, per RECIST 1.1
- At least 2 lesions present, one of which must be amenable to SBRT and second lesion
outside the radiation field must serve as target lesion to evaluate measurable
disease.
- Must have progression of disease, been treated or intolerant to at least 2 lines of
systemic standard of care treatment in the metastatic setting (e.g.,
fluoropyrimidine-, oxaliplatin-, or irinotecan-based therapy [unless ineligible for
any of these drugs]).
- Participants with a history of RAS wild-type tumor must have progressed, been
intolerant of OR refused anti-EGFR based treatment.
- Participants must have adequate organ and marrow function as defined below:
- Leukocytes >= 3,000/microL
- Absolute neutrophil count >= 1,500/microL
- Lymphocyte count > 500/microL
- Platelets >= 100,000/microL without transfusion or at least > 48 hours
post-completion of blood transfusion
- Hemoglobin >= 9 g/dL without transfusion or at least > 48 hours post-completion
of blood transfusion
- International normalized ratio <=1.5 x institutional upper limit of normal
- (INR) and partial thromboplastin time (aPTT) (ULN) (if not receiving
therapeutic anticoagulation)
- Serum albumin > 2.5 g/dL
- Total bilirubin <= 1.5 x ULN
- Aspartate aminotransferase (AST) <= 2.5 x institutional ULN
- Alanine transaminase (ALT) <= 2.5 x institutional ULN
- Alkaline phosphatase (ALP) <= 2.5 x institutional ULN
- Creatinine clearance calculated by Chronic Kidney Disease Epidemiology
Collaboration (CKDEPI) equation >= 50 mL/min/1.73 m^2 for participants with
creatinine levels >= 1.5 mg/dL
- Participants receiving therapeutic anticoagulation must be on an established, stable
anticoagulation regimen prior to starting the study therapy.
- Negative human immunodeficiency virus (HIV) serological testing at screening.
- Participants seropositive for hepatitis B virus (HBV) antibody test are eligible if
at screening:
- have a negative HBV DNA test and
- not on treatment with anti-viral therapy for HBV.
- Participants seropositive for hepatitis C virus (HCV) antibody test, are eligible if
have a negative HCV RNA test at screening.
- Participants seropositive for Epstein-Barr virus (EBV) viral capsid antigen
immunoglobulin M (IgM) test are eligible if have a negative EBV polymerase chain
reaction (PCR) test at screening.
- Participants must have recovered from prior toxicity or adverse events to grade <= 2
per Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.
- Women of child-bearing potential (WOCBP) must agree to use a highly effective method
of contraception (hormonal, intrauterine device [IUD], surgical sterilization,
abstinence) at the study entry and up to 5 months after the last dose of the study
drugs (restriction period).
Note: A woman is considered to be of child-bearing 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
(i.e., removal of ovaries, fallopian tubes, and/or uterus).
- Breastfeeding participants must be willing to discontinue breastfeeding from study
treatment initiation through 5 months after the last dose of the study drugs.
- Participants must be willing to co-enroll in protocol 11-C-0112, Acquisition of
Blood and Tumor Tissue Samples from Patients with Gastrointestinal Cancer .
- Participants must understand and be willing to sign a written informed consent
document.
EXCLUSION CRITERIA:
- Disease amenable to curative resection.
- Chemotherapy, radiation therapy, or biologic therapy within 3 weeks (or >= 5
half-lives, whichever is shorter) prior to starting the study therapy.
- Treatment with an investigational therapy within 42 days prior to starting the study
therapy.
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is
longer) prior to starting the study therapy.
- History of prior treatment with TIGIT-directed treatment agents or other types of
immunotherapies (e.g., prior treatment with CD137 agonists or investigational immune
checkpoint blockade therapies, including anti-TIGIT, anti-PD1/anti-PDL1,
anti-CTLA-4, anti-LAG3).
- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
antitumor necrosis factor-alpha [TNF-alpha] agents) within 2 weeks prior to starting
the study therapy, or anticipation of a need for systemic immunosuppressive
medication during study therapy, with the following exceptions:
--acute, low-dose systemic immunosuppressant medication (< 10 mg of prednisone
daily) or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48
hours of corticosteroids for a contrast allergy).
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to starting
the study therapy.
- Treatment with a live, attenuated vaccine within 4 weeks prior to starting the study
therapy.
- Major surgery within 4 weeks prior to starting the study therapy.
- Prior allogeneic stem cell or solid organ transplantation.
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to tiragolumab and atezolizumab or other agents used in a study
or known hypersensitivity to Chinese hamster ovary cell products.
- History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins.
- History of central nervous system (CNS) metastasis or leptomeningeal disease.
- Current uncontrolled tumor-related pain. Participants requiring pain medication must
be on a stable regimen at study entry.
- Current or history of chronic autoimmune disease or immune deficiency (e.g., Addison
s disease, multiple sclerosis, Graves disease, Hashimoto s thyroiditis, rheumatoid
arthritis, hypophysitis, systemic lupus erythematosus, Wegener s granulomatosis,
sarcoidosis syndrome, etc.) or other connective tissue diseases except:
- Participants with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone;
- Participants with controlled Type 1 diabetes mellitus who are on an insulin
regimen.
- Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., participants with psoriatic arthritis
are excluded) are eligible for the study provided all following conditions are
met:
- Rash must cover < 10% of body surface area
- The disease is well controlled at screening and requires only low-potency
topical corticosteroids
- There has been no occurrence of acute exacerbations of the underlying
condition requiring psoralen plus ultraviolet, radiation, methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors, or high potency
or oral corticosteroids within 12 months prior to starting the study
therapy.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently).
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >
12 mg/dL or corrected serum calcium > ULN).
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest computed tomography (CT) scan.
- Severe infection within 4 weeks prior to starting the study therapy. This includes
but is not limited to, hospitalizations for complications of infection, bacteremia,
severe pneumonia, or any active infection that could impact participant safety.
- Active tuberculosis.
- History of 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 starting the study therapy, unstable arrhythmia,
or unstable angina within 1 year prior to starting the study therapy.
- Prior invasive malignancy, (with the exception of non-melanomatous skin cancer)
unless disease-free per standard of care for a minimum of 3 years prior to starting
the study therapy.
- Women of childbearing potential must have a negative serum pregnancy test result at
screening.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that contraindicates the use of investigational drugs, may affect
the interpretation of the results or may render the participants at high risk of
treatment complications.
Gender:
All
Minimum age:
18 Years
Maximum age:
120 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Contact:
Last name:
NCI Medical Oncology Referral Office
Phone:
888-624-1937
Email:
ncimo_referrals@nih.gov
Start date:
November 17, 2024
Completion date:
June 1, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Institutes of Health Clinical Center (CC)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06603818
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_001589-C.html
