Clinical trial NCT06603818: Immunotherapies in Combination With Stereotactic Body Radiation Radiotherapy in Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)
Official title: A Phase II Study of Immunotherapies (Tiragolumab and Atezolizumab) in Combination With Stereotactic Body Radiation Radiotherapy in Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Microsatellite Stable Metastatic Colorectal Cancer
Metastatic Colorectal Cancer
Colorectal Cancer
Keywords: Stereotactic Body Radiation Radiotherapy
Immunotherapy
Radiation Therapy
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2024-09-19
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Primary outcomes:
measure: Confirm the recommended phase II dose (RP2D) of the combination therapy
timeFrame: Start of therapy through cycle 1 day 21
measure: Determine the proportion of participants without progression after 9 weeks of the combination therapy
timeFrame: After 9 weeks of treatment
Secondary outcomes:
measure: Safety
timeFrame: Start of therapy through 28 days after last study treatment intervention.
measure: Tolerability
timeFrame: Start of therapy through 28 days after last study treatment intervention.
measure: Best overall response (Partial Response + Complete Response) according to RECIST v1.1
timeFrame: Every 9 weeks during the study treatment and every 3 months after that until progression or 3 years after treatment initiation
measure: Progression Free Survival
timeFrame: Every 9 weeks during the study treatment and every 3 months after that until progression or 3 years after treatment initiation
measure: Overall Survival
timeFrame: Start of therapy until death or 3 years after treatment initiation
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Tim F Greten, M.D.
role: PRINCIPAL_INVESTIGATOR
References: