| Eligibility |
Inclusion Criteria:
- Documented informed consent of the participant and/or legally authorized
representative
- Assent, when appropriate, will be obtained per institutional guidelines
- Age: >= 18 years
- Eastern Cooperative Oncology Group (ECOG) =< 1
- Life expectancy >= 3 months
- Patients should have a pathologically proven diagnosis of colorectal adenocarcinoma
- Histological or cytological confirmed microsatellite stable (MSS) adenocarcinoma of
colon or rectum. Microsatellite status should be performed per local standard of
practice (immunohistochemistry [IHC] and or polymerase chain reaction [PCR], or
next-generation sequencing, the presence of POLE mutations will be collected if
available through next-generation sequencing)
- Patients should have measurable metastatic disease as per Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1 guidelines
- Patients should not have a history of perforations or fistulas
- For the safety cohorts (phase I): Metastatic colorectal cancer with 0 to 2 prior lines
of therapy prior to enrollment on study and without prior progression within 3 months
from last dose of oxaliplatin, in the event of prior oxaliplatin exposure. Evidence of
radiographic progression after last treatment before enrollment should be documented
- Patients with prior FOLFOX therapy should not have required dose modifications
and should not have experienced unacceptable toxicities
- Patients with other prior 5-FU-based therapies should not have required prior
fluorouracil (5-FU) dose modifications below 2400 mg/m^2 every 2 weeks
- No prior oxaliplatin hypersensitivity
- 4 weeks should have elapsed from last prior chemotherapy and initiation of study
treatment
- For the efficacy cohorts (phase II): No prior treatment for metastatic disease. If
prior FOLFOX adjuvant therapy was administered, there should be no evidence of disease
relapse within the first 12 months after completion of adjuvant therapy
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 7 days prior to day 1 of
protocol therapy)
- Aspartate aminotransferase (AST) =< 2.5 x ULN, unless presence of liver metastases for
which =< 5 x ULN is allowed (within 7 days prior to day 1 of protocol therapy)
- Alanine aminotransferase (ALT) =< 2.5 x ULN, unless presence of liver metastases for
which =< 5 x ULN is allowed (within 7 days prior to day 1 of protocol therapy)
- Creatinine clearance >= 40 ml/min (within 7 days prior to day 1 of protocol therapy)
- Alkaline phosphatase =< 3 x ULN (within 7 days prior to day 1 of protocol therapy)
- Hemoglobin >= 9 g/dl (within 7 days prior to day 1 of protocol therapy)
- Absolute neutrophil count (ANC) >= 1500/ul (within 7 days prior to day 1 of protocol
therapy)
- Platelets >= 100,000/mm^3 (within 7 days prior to day 1 of protocol therapy)
- Albumin >= 3.0 g/dl (within 7 days prior to day 1 of protocol therapy)
- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
(within 7 days prior to day 1 of protocol therapy)
- If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required
- Females of non-childbearing potential defined as:
- >= 50 years of age and has not had menses for greater than 1 year
- 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
- Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation
- Women patients of reproductive potential must use effective contraception while
receiving oxaliplatin and for 9 months after the final dose. Men with female partners
of reproductive potential must use effective contraception while receiving oxaliplatin
and for 6 months after the final dose. If patients discontinue oxaliplatin more than 9
months (females) or 6 months (males) before discontinuation of balstilimab and/or
botensilimab, females and males of childbearing potential must use an effective method
of birth control or abstain from sexual activity for the course of the study through
at least 90 days after the last dose of balstilimab and/or botensilimab
Exclusion Criteria:
- Prior immunotherapy
- Patients with a condition requiring systemic treatment with either 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
- Prior allogeneic organ transplantation
- Surgical intervention within 4 weeks prior to study treatment, except for minor
procedures such as port placement
- Prior allergic reaction or hypersensitivity to any of the study drug components
- 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
- Uncontrolled hypertension, defined as systolic blood pressure (SBP) >150, diastolic
blood pressure (DBP) > 90
- 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
- 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
- Obstructive bowel symptoms related to unresected primary or carcinomatosis
- Any persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE]
grade >= 2) from prior cancer therapy, excluding endocrinopathies stable on
medication, stable neuropathy that is grade 1 or less, and alopecia
- Non-healing wounds
- Symptomatic active bleeding
- Grade >= 2 proteinuria as demonstrated by >= 2+ protein and >= 1.0 g of protein with
24-hour urine collection (patients found to have >= 2+ protein on dipstick urinalysis
must have 24-hour urine collection and demonstrate < 1 g of protein in 24 hours in
order to be eligible for the study)
- Active brain metastases or leptomeningeal metastases with the following exceptions:
- Treated brain metastases require a) surgical resection, or b) stereotactic
radiosurgery. These patients must be off steroids >= 10 days prior to
randomization for the purpose of managing their brain metastases. Repeat brain
imaging following surgical resection or stereotactic radiosurgery at least 4
weeks from treatment should document lack of progression
- Concurrent malignancy (present during screening) requiring treatment or history of
prior malignancy active within 2 years prior to the first dose of study treatment,
i.e., patients with a history of prior malignancy are eligible if treatment was
completed at least 2 years before the first dose of study treatment and the patient
has no evidence of disease. 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
- Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids
- Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the study
- 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
- Grade 2 or above neuropathy at the time of enrollment
- Dependence on total parenteral nutrition or intravenous hydration
- 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)
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