| Eligibility |
Inclusion Criteria:
1. Male or female =18 years of age.
2. Histological or cytologic diagnosis of colorectal adenocarcinoma that is unresectable
or metastatic.
3. Have had disease progression or were intolerant to treatment protocols that included
irinotecan and oxaliplatin. Epidermal growth factor receptor (EGFR) or vascular
endothelial growth factor receptor (VEGFR) directed therapies are allowed as part of
the previous therapy if indicated.
4. Has at least 1 measurable tumor of =1 cm in longest diameter (or =1.5cm shortest
diameter for lymph nodes).
5. Has injectable tumor(s) of at least 1cm in aggregate total diameter.
6. Must be willing to consent to provide archival tumor biopsy samples obtained within 90
days prior to Screening, or a fresh tumor biopsy collected on Day 1 of treatment or
earlier.
7. Has adequate hematologic function, including:
- White blood cell count =2.0 × 10^9/L
- Absolute neutrophil count =1.5 × 10^9/L
- Platelet count =75 × 10^9/L
- Hemoglobin =8 g/dL(transfusions allowed; however, patient must not be
transfusion-dependent).
8. Has adequate hepatic function, including:
- Total bilirubin =1.5 × upper limit of normal (ULN; except patients with Gilbert
syndrome or liver metastases, who must have a total bilirubin of <2.0 × ULN)
- Serum albumin =2.8 g/dL
- Aspartate aminotransferase and alanine aminotransferase (ALT)=3.0 × ULN (or =5.0
× ULN, if liver metastases are present).
9. Has adequate renal function, defined as serum creatinine =1.5 × ULN or creatinine
clearance =30 mL/minute (measured using Cockcroft-Gault formula or by 24-hour urine
collection).
10. Prothrombin time =1.5 × ULN (or international normalization ratio [INR] =1.3) and
partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)
=1.5×ULN.
Note: Patients who are on chronic anticoagulant therapy may be enrolled if the
pretreatment INR<2.5. For patients requiring a deep injection of RP2/RP3, the INR must
be <1.5 at the time of injection.
11. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.
12. Female and male patients of reproductive potential must agree to avoid becoming
pregnant or impregnating a partner and adhere to highly effective contraception
requirements during the treatment period and for at least (a) 90 days after the last
dose of RP2 or RP3 or (b) 5 months after the last dose of atezolizumab or (c) 6 months
after the last dose of bevacizumab, whichever is longer.
13. Women of childbearing potential must have a negative serum beta-human chorionic human
chorionic gonadotropin (ß-hCG) test with a minimum sensitivity of 25 IU/L or
equivalent units of ß-hCG within 72 hours before the first dose and a negative urine
pregnancy test on D-1.
14. Capable of giving signed informed consent which includes willingness to comply with
the requirements and restrictions listed in the informed consent form (ICF) and in
this protocol.
Exclusion Criteria:
1. Prior treatment with regorafenib, trifluridine/tipiracil, fruquintinib, and
immunotherapies.
2. Has received more than 3 lines of therapy for CRC.
3. Has microsatellite instability-high (MSI-H)/deficient DNA mismatch repair
(dMMR)disease or BRAF V600E mutation.
4. Acute or chronic hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive)
or acute or chronic hepatitis C virus (HCV; defined as HCV RNA [qualitative] is
detected).
Note: Patients who have been effectively treated are eligible for enrollment. Patients
must be negative for HBsAg and HCV RNA.
5. Known human immunodeficiency virus (HIV) infection.
Note: Testing for HIV is not required unless mandated by local health authority or
clinically indicated.
6. Had systemic infection requiring intravenous (IV) antibiotics or other serious
infection within 14 days prior to dosing.
7. With active significant herpetic infections or prior complications of HSV-1 infection
(eg, herpetic keratitis or encephalitis).
Note: Patients with sporadic cold sores may be enrolled as long as no active cold
sores are present at the time of Day 1
8. Active or history of central nervous system (CNS) metastases and/or carcinomatous
meningitis.
9. Prior malignancy active within the previous 3 years, except for locally curable
cancers that have apparently been cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
10. Macroscopic intravascular invasion into any large blood vessel such as the main portal
vein, hepatic vein, pulmonary arteries or veins, aorta, or vena cava.
11. Had a significant bleeding event within the last 12 months that places the patient at
unjustifiable risk for bleeding from deep intratumoral injection procedures based on
Investigator assessment or interventional radiologist assessment.
12. History of significant cardiac vascular disease including myocarditis or congestive
heart failure (defined as New York Heart Association Functional Classification III or
IV), or unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial
infarction within 6 months of randomization.
13. Uncontrolled infection.
14. History or evidence of psychiatric disease, substance abuse, or any other clinically
significant disorder, condition, or disease (with the exception of those outlined
above) that, in the opinion of the Investigator or the Medical Monitor, would pose a
risk to patient safety or interfere with the study evaluation, procedures, or
completion.
15. History or current evidence of any condition, therapy, 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
16. Active, known, or suspected autoimmune disease such as autoimmune thyroiditis and
colitis requiring systemic immunomodulatory treatment. Note: Patients with diabetes
mellitus, dysthyroidism without an autoimmune mechanism, and rheumatoid arthritis that
do not require immunomodulatory treatment are permitted to enroll.
17. History of drug-induced interstitial lung disease, (noninfectious) pneumonitis that
required steroids, or currently has pneumonitis.
18. Requires intermittent or chronic use of systemic (oral or IV) antivirals with known
antiherpetic activity (eg, acyclovir).
19. Has received a live vaccine within 28 days prior to the first dose of study treatment.
Note: Seasonal influenza vaccines for injection or SARS-CoV-2 are generally
inactivated vaccines and are allowed (See Section6.11.2for additional guidance).
Live/attenuated vaccines (such as the intranasal influenza vaccines) are not allowed.
20. Is currently participating in or has participated in a study of an investigational
agent within 4 weeks prior to the first dose of study treatment.
Note: Patients who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks or 5 half-lives of the agent, whichever is
longer, after the last dose of the previous investigational agent.
21. Conditions requiring treatment with immunosuppressive medications within 30 days.
Inhaled or topical steroids, and adrenal replacement steroid dose are permitted in the
absence of active autoimmune disease.
Note: Patients who require a brief course (=7 days) of corticosteroids (eg, as
prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not
excluded. Physiologic replacement doses of systemic corticosteroids are permitted,
only if the dose does not exceed 10 mg/day prednisone equivalent.
22. Conditions in which anticoagulant therapies cannot be safely stopped in the
periprocedural period or patients on coumadin with a target INR >2.5 or that cannot be
temporarily reversed to INR =1.7.
23. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese
medicines) intended for general health support or to treat the disease under study
within 2 weeks prior to treatment.
24. Prior organ transplantation including allogenic stem-cell transplantation.
25. Bowel obstruction, Major surgery =28 days prior to starting bevacizumab or anticipated
major surgery while on study.
Note: If a patient received major surgery, they must have recovered adequately prior
to starting study treatment and must have adequate wound healing, based on
Investigator's assessment or surgeon's assessment, before starting bevacizumab.
26. History of life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4
or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting
T-cell co-stimulation or immune checkpoint pathways [eg, CD40, 4-1BB]) except those
that are unlikely to recur or are expected to be manageable with standard
countermeasures (eg, hormone replacement after adrenal crisis). Individual cases
should be discussed with a Medical Monitor if needed.
27. Presence of peritoneal disease, or lesions that are > 5 cm or liver tumors that are
estimated to invade more than one-third of the liver.
28. Prior chemoembolization, radioembolization, or other locoregional liver-directed
procedures to the lesion(s)selected for intratumoral injection.
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