Trial Title:
RP2/RP3 in Combination With Atezolizumab and Bevacizumab for the Treatment of Patients With CRC
NCT ID:
NCT05733611
Condition:
Refractory Metastatic Colorectal Cancer
pMMR
MSS
Conditions: Official terms:
Colorectal Neoplasms
Bevacizumab
Atezolizumab
Conditions: Keywords:
Colorectal Carcinoma
Immunotherapy
Immuno-oncology
Oncolytic virus
Oncolytic immuno-gene therapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Active, not recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
RP2
Description:
Genetically modified herpes simplex type 1 virus
Arm group label:
RP2 and atezolizumab plus bevacizumab in advanced MSS and pMMR CRC
Intervention type:
Biological
Intervention name:
RP3
Description:
Genetically modified herpes simplex type 1 virus
Arm group label:
RP3 and atezolizumab plus bevacizumab in advanced MSS and pMMR CRC
Intervention type:
Biological
Intervention name:
atezolizumab
Description:
anti-PD-L1 monoclonal antibody
Arm group label:
RP2 and atezolizumab plus bevacizumab in advanced MSS and pMMR CRC
Arm group label:
RP3 and atezolizumab plus bevacizumab in advanced MSS and pMMR CRC
Intervention type:
Biological
Intervention name:
bevacizumab
Description:
anti-VEGF therapy
Arm group label:
RP2 and atezolizumab plus bevacizumab in advanced MSS and pMMR CRC
Arm group label:
RP3 and atezolizumab plus bevacizumab in advanced MSS and pMMR CRC
Summary:
This is an open-label, Phase 2 clinical trial evaluating therapy with an oncolytic
immunotherapy (RP2 or RP3) in combination with atezolizumab and bevacizumab in patients
with advanced Microsatellite Stable and Mismatch Repair Proficient Colorectal Carcinoma.
Detailed description:
RP2 and RP3 are selectively replication competent herpes simplex viruses 1 (HSV-1) that
express exogenous genes (RP2: GM-CSF, GALV, and anti-CTLA-4; RP3: GALV, and anti-CTLA-4
hCD40L, and h4-1BBL) intended for direct injection into suitable nonneurological solid
tumors. They are genetically engineered to provide direct oncolytic tumor destruction
combined with the induction of a systemic antitumor immune response.
This study will evaluate whether the use of oncolytic immunotherapy, either with RP2 or
RP3, can provide meaningful efficacy in combination with an anti-PD-L1 therapy
(atezolizumab) and anti-VEGF therapy (bevacizumab) in patients with advanced MSS and pMMR
CRC.
Criteria for eligibility:
Criteria:
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 (β-hCG) test with a minimum sensitivity of 25 IU/L or
equivalent units of β-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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
USC Norris Comprehensive Cancer Center
Address:
City:
Los Angeles
Zip:
90033
Country:
United States
Facility:
Name:
University of Washington Seattle Cancer Care Alliance
Address:
City:
Seattle
Zip:
98109
Country:
United States
Start date:
June 29, 2023
Completion date:
March 1, 2027
Lead sponsor:
Agency:
Replimune Inc.
Agency class:
Industry
Collaborator:
Agency:
Roche Pharma AG
Agency class:
Industry
Source:
Replimune Inc.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05733611
