Trial Title:
Botensilimab, Balstilimab and Regorafenib or Botensilimab and Balstilimab for the Treatment of Advanced or Metastatic Microsatellite Stable Colorectal Cancer
NCT ID:
NCT06575725
Condition:
Advanced Colon Adenocarcinoma
Advanced Colorectal Adenocarcinoma
Advanced Rectal Adenocarcinoma
Metastatic Colon Adenocarcinoma
Metastatic Colorectal Adenocarcinoma
Metastatic Rectal Adenocarcinoma
Stage III Colon Cancer AJCC v8
Stage III Colorectal Cancer AJCC v8
Stage III Rectal Cancer AJCC v8
Stage IV Colon Cancer AJCC v8
Stage IV Colorectal Cancer AJCC v8
Stage IV Rectal Cancer AJCC v8
Conditions: Official terms:
Colorectal Neoplasms
Adenocarcinoma
Rectal Neoplasms
Colonic Neoplasms
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Balstilimab
Description:
Given IV
Arm group label:
Arm BB (botensilimab, balstilimab)
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
AGEN 2034
Other name:
AGEN-2034
Other name:
AGEN2034
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Arm BB (botensilimab, balstilimab)
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Arm BB (botensilimab, balstilimab)
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Biological
Intervention name:
Botensilimab
Description:
Given IV
Arm group label:
Arm BB (botensilimab, balstilimab)
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
AGEN 1181
Other name:
AGEN-1181
Other name:
AGEN1181
Other name:
Anti-CTLA-4 Monoclonal Antibody AGEN1181
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Arm BB (botensilimab, balstilimab)
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Arm BB (botensilimab, balstilimab)
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Drug
Intervention name:
Regorafenib
Description:
Given PO
Arm group label:
Arm BBR (botensilimab, balstilimab, regorafenib)
Other name:
BAY 73-4506 Monohydrate
Other name:
BAY-73-4506 Monohydrate
Other name:
Regorafenib Monohydrate
Other name:
Stivarga
Summary:
This phase II trial studies how well the combination of botensilimab, balstilimab and
regorafenib works compared to botensilimab and balstilimab in treating patients with
microsatellite stable colorectal cancer that may have spread from where it first started
to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread
from where it first started (primary site) to other places in the body (metastatic).
Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help
the body's immune system attack the cancer, and may interfere with the ability of tumor
cells to grow and spread. Regorafenib is in a class of medications called kinase
inhibitors. It works by blocking the action of an abnormal protein that signals tumor
cells to multiply. This helps to slow or stop the spread of tumor cells. The combination
of botensilimab, balstilimab and regorafenib or botensilimab and balstilimab may be a
safe and effective treatment for advanced or metastatic microsatellite stable colorectal
cancer.
Detailed description:
COPRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
botensilimab, balstilimab and regorafenib (BBR) in microsatellite stable (MSS) metastatic
colorectal cancer (mCRC) patients without metastatic liver lesions in the safety run-in.
(Safety lead-in) II. Compare the overall response rate in microsatellite stable (MSS)
metastatic colorectal cancer (mCRC) patients without metastatic liver lesions receiving
botensilimab, balstilimab and regorafenib (BBR) versus botensilimab and balstilimab (BB),
by treatment arm. (Phase II)
SECONDARY OBJECTIVES:
I. Estimate the overall survival in MSS mCRC patients without metastatic liver lesions
receiving BBR and BB, by treatment arm.
II. Estimate the progression free survival in MSS mCRC patients without metastatic liver
lesions receiving BBR and BB, by treatment arm.
III. Estimate the duration of response (DOR) in MSS mCRC patients without metastatic
liver lesions receiving BBR and BB that experience a response to therapy, by treatment
arm.
IV. Describe the safety of giving to BBR and BB to patients with MSS mCRC without
metastatic liver lesions, by treatment arm.
EXPLORATORY OBJECTIVE:
I. Through the performance of baseline and on treatment biopsies and serial blood work
(cytokines and flow cytometry), explore potential biomarkers of response to BBR and BB
therapy given to MSS mCRC patients without metastatic liver lesions, by treatment arm.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM BBR: Patients receive botensilimab intravenously (IV) over 60 minutes on day 1 of
each cycle, balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle, and
regorafenib orally (PO) once daily (QD) on days 1-7, 15-21, and 29-35 of each cycle or on
days 1-5, 15-19, and 29-33 of each cycle. Cycles repeat every 42 days for up to 2 cycles
of botensilimab and up to 2 years of balstilimab and regorafenib in the absence of
disease progression or unacceptable toxicity. Patients also undergo computed tomography
(CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the
trial. Patients also undergo tumor biopsy during screening and on study.
ARM BB: Patients receive botensilimab IV over 60 minutes on day 1 of each cycle and
balstilimab IV over 30 minutes on days 1, 15, and 29 of each cycle. Cycles repeat every
42 days for up to 2 cycles of botensilimab and up to 2 years of balstilimab in the
absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI
and blood sample collection throughout the trial. Patients also undergo tumor biopsy
during screening and on study.
After completion of study treatment, patients are followed up at 30 and 90 days and then
every 2-3 months for 5 years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Documented informed consent of the participant
- In the phase II randomized portion of the study only, until two biopsies are
obtained on ten patients receiving BBR and ten patients receiving BB: Agreement to
biopsy of the same tumor at baseline and at 4 weeks
- Agreement to biopsy of the same tumor at baseline and at 4 weeks
- This applies only to patients with easily accessible tumors, where the
risk of a biopsy is deemed acceptable. If a biopsy is determined to be
unsafe patients will be exempt from this requirement
- Agreement to allow the collection of blood for correlatives at baseline, 1 week, 2
weeks, 4 weeks, 8 weeks, and at the time progressive disease
- Age: ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) ≤ 1
- Histologically or cytologically confirmed advanced or metastatic progressive
proficient mismatch repair (pMMR)/MSS adenocarcinoma of the colon or rectum
- No active brain metastases or leptomeningeal metastases, except for patients who
underwent definitive surgery or radiation without progression following repeat
imaging (at least 4 weeks after the intervention) and were systemic steroids have
been discontinued at least 2 weeks prior study treatment
- Known extended RAS and BRAF status, as per local standard of practice. Tumor
mutation burden (TMB) and PD-L1 status will be collected when available but are not
mandated for enrollment
- Patients must have progressed following exposure to all of the following agents in
the advanced/metastatic setting OR in the neoadjuvant/adjuvant setting if disease
recurred within 6 months of last treatment. Patients who were intolerant to prior
systemic chemotherapy regimens are eligible if there is documented evidence of
clinically significant intolerance despite adequate supportive measures
- Fluoropyrimidines (capecitabine or 5-FU)
- Irinotecan
- Oxaliplatin
- Anti-EGFR therapy if RAS and BRAF wild type with left colon primary
- Patients must have evidence of progression on or after the last treatment received
and within 6 months prior to study enrollment
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version
(v)1.1
- Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior
anti-cancer therapy, excluding endocrinopathies stable on medication, stable
neuropathy that is grade 2 or less, and alopecia
- Patients may not have metastatic liver disease defined as: No history of liver
metastatic disease OR history of resected or ablated liver metastases without
evidence of disease recurrence in the liver for at least 4 months before enrollment
- Total bilirubin ≤ 1.5 X upper limit of normal (ULN)
- Aspartate aminotransferase (AST) ≤ 2.5 x ULN
- Alanine aminotransferase (ALT) ≤ 2.5 x ULN
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min (measured or
calculated using the Cockroft-Gault formula)
- Hemoglobin ≥ 9 g/dl
- Absolute neutrophil count (ANC) ≥ 1,500/µl
- Platelets ≥ 75,000/mm^3
- Albumin ≥ 3.0 g/dl
- Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test
- If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- Agreement by females and males of childbearing potential to use an effective method
of birth control or abstain from heterosexual activity for the course of the study
through at least 120 days after the last dose of protocol therapy
- Childbearing potential defined as not being surgically sterilized (men) OR have
not been free from menses for > 1 year and ≥ 50 years of age (women only) OR
amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and
a follicle-stimulating hormone value in the postmenopausal range upon pre-study
(screening) evaluation (women only) OR status is post-hysterectomy, bilateral
oophorectomy, or tubal ligation (women only)
Exclusion Criteria:
- Prior allogeneic organ transplantation
- Prior immunotherapy with PD-1 or PD-L1 or CTLA-4 targeting agents
- Prior regorafenib
- Surgical intervention within 4 weeks prior to study treatment, except for minor
procedures such as port placement
- Patients with a condition requiring systemic treatment with corticosteroids (> 10 mg
daily prednisone equivalent) within 14 days or another immunosuppressive medication
within 30 days of the first dose of study treatment. Inhaled or topical steroids,
and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are
permitted in the absence of active autoimmune disease
- Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days or
five half-lives (whichever is shorter for non-radiation therapy) prior to day 1 of
protocol therapy
- Strong CYP3A4 inducers or CYP3A4 inhibitors within 14 days prior to day 1 of
protocol therapy
- Patients unwilling to refrain from drinking grapefruit juice and taking St. John's
Wort while on study
- Herbal medications other than cannabidiol (CBD) unless reviewed by the principal
investigator (PI) and deemed to unlikely interact with study drugs
- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke or myocardial infarction within 12 months of enrollment, unstable
angina, congestive heart failure (New York Heart Association class ≥ III), or
serious uncontrolled cardiac arrhythmia requiring medication
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to study agent
- Patients must not have uncontrolled hypertension as defined by systolic blood
pressure (SBP) > 150mmHg or diastolic blood pressure (DBP) > 90mmHg despite optimal
medical management. Patients whose blood pressure can be controlled medically are
allowed to be rescreened once blood pressure (BP) is under control
- Active autoimmune disease or history of autoimmune disease that required systemic
treatment within 2 years before starting treatment, i.e., with use of
disease-modifying agents or immunosuppressive drugs
- History of acute thrombotic venous events in the last 30 days before enrollment. If
within 30 days, the patient should be on anticoagulants and without symptoms
- Obstructive bowel symptoms related to unresected primary or carcinomatosis
- Inability to swallow and absorb oral tablets (such as but not limited to inability
to swallow pills, malabsorption issues, ongoing nausea or vomiting)
- Non-healing wounds
- Symptomatic active bleeding
- Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids
- History or current evidence of any condition, co-morbidity, therapy, any active
infections, or laboratory abnormality that might confound the results of the study,
interfere with the patient's participation for the full duration of the study, or is
not in the best interest of the patient to participate, in the opinion of the
treating Investigator
- Known previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection within 10 days for mild or asymptomatic infections or 20 days for
severe/critical illness prior to cycle 1 day 1 (C1D1)
- Uncontrolled infection with human Immunodeficiency virus (HIV). Patients on stable
highly active antiretroviral therapy (HAART) with undetectable viral load and normal
CD4 counts for at least 6 months prior to study entry are eligible. Serological
testing for HIV at screening is not required
- Known to be positive for hepatitis B virus (HBV) surface antigen, or any other
positive test for HBV indicating acute or chronic infection. Patients who are
receiving or who have received anti-HBV therapy and have undetectable HBV
deoxyribonucleic acid (DNA) for at least 6 months prior to study entry are eligible.
Serological testing for HBV at screening is not required
- Known active hepatitis C virus (HCV) as determined by positive serology and
confirmed by polymerase chain reaction (PCR). Patients on or who have received
antiretroviral therapy are eligible provided they are virus-free by PCR for at least
6 months prior to study entry. Serological testing for HCV at screening is not
required
- Dependence on total parenteral nutrition or intravenous hydration
- Clinically significant uncontrolled illness
- Concurrent non-colorectal second malignancy (present during screening) requiring
treatment or history of a non-colorectal second primary metastatic malignancy within
2 years prior to the first dose of study treatment. Patients with history of prior
early-stage basal/squamous cell skin cancer, low-risk prostate cancer eligible for
active surveillance or noninvasive or in situ cancers who have undergone definitive
treatment at any time are also eligible. Patients with a prior or concurrent
malignancy whose natural history or treatment does not have the potential to
interfere with the safety or efficacy assessment of the investigational regimen are
eligible for this trial after PI approval
- Females only: Pregnant or breastfeeding
- Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the study
- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope Medical Center
Address:
City:
Duarte
Zip:
91010
Country:
United States
Contact:
Last name:
Marwan G. Fakih
Phone:
626-256-4673
Email:
mfakih@coh.org
Investigator:
Last name:
Marwan G. Fakih
Email:
Principal Investigator
Start date:
November 1, 2024
Completion date:
January 28, 2027
Lead sponsor:
Agency:
City of Hope Medical Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
City of Hope Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06575725
