| Eligibility |
Inclusion Criteria:
Cohort 1a
1. Ability to comprehend and willingness to provide written informed consent (ICF) for
the study.
2. Age = 18 years.
3. Patient with histologically or cytologically confirmed stage IV CRC who has failed
standard therapies.
4. Must have received Standard of Care systemic treatment consisting of fluoropyrimidin-
oxaliplatin and/or irinotecan based therapy for stage IV CRC disease.
5. Presence of at least 1 measurable lesion by computed tomography or magnetic resonance
imaging per RECIST v1.1 as determined by the local site investigator/radiologist
assessment.
6. Presence of at least one liver lesion amenable to repeated biopsy, ideally not the one
being used for measuring.
7. Willingness to undergo two fresh liver biopsies (pre-treatment and on-treatment).
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
9. Life expectancy of at least 3 months.
10. Resolution of all toxicities and any toxic effect(s) of the most recent prior therapy
to Grade 1 or less (except alopecia). Patients with = Grade 2 neuropathy and Grade = 2
fatigue are an exception and may enroll.
11. Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters
= 7 days before study treatment initiation.
12. Absolute neutrophil count (ANC) = 1.5 × 109/L.
13. Absolute lymphocyte count = 0.5 × 109/L.
14. Platelets = 100 × 109/L.
15. Hemoglobin level = 9 g/dL.
16. Measured or calculated creatinine clearance (glomerular filtration rate can also be
used in place of creatinine clearance) = 50 mL/min according to the formula of
Cockcroft-Gault.
17. Total bilirubin = 1.5 × upper limit of normal (ULN); if total bilirubin is > 1.5 x ULN
then direct bilirubin must be = 1.5 × ULN. Patients with known Gilbert's Syndrome may
enroll if total bilirubin = 3 × ULN.
18. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) = 2.5 × ULN or = 5 x ULN
in patients with hepatic involvement.
19. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly
effective contraceptive methods during the treatment period and for at least 180 days
after the last dose of study treatment and refrain from egg donation during this
period.
20. A male patient must agree to use a contraceptive during the treatment period and for
at least 180 days after the last dose of study treatment and refrain from donating
sperm during this period.
Cohorts 1b, 2a, 2c, 3 and 4a:
1. Ability to comprehend and willingness to provide written informed consent (ICF) for
the study.
2. Age = 18 years.
3. Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed
by polymerase chain reaction (PCR)/ immunohistochemistry or next generation sequencing
(NGS) assay at local institution.
4. Must have received a first line of SoC systemic therapy (physician choice) for stage
IV disease and completed the therapy. They must have an ongoing partial response (PR)
or a stable disease (SD) at the completion of this therapy, completion of therapy as
defined by the investigator, however, with a minimum number of 4 months.
Note: Patient may have also received prior adjuvant therapy for stage II or III
colorectal cancer, however the adjuvant treatment for stage II and III will not be
considered as a prior line of therapy in case of relapse more than 6 months after the
end of treatment.
5. Presence of at least 1 measurable lesion by computed tomography or magnetic resonance
imaging per RECIST v1.1 as determined by the local site investigator/radiologist
assessment.
6. Presence of at least one metastatic lesion amenable to paired biopsies (same lesion to
be biopsied twice, at baseline and on D36), ideally not the one being used for
measuring. However, liver lesions must be prioritized. Non-liver metastatic lesion
biopsies may be collected only if the patient has no liver lesion or if the liver
lesion is not amenable to paired biopsies (e.g. due to its size or location) or if the
liver biopsy represents a risk or an undue inconvenience for the patient
health/condition per Investigator judgment. In such cases, where a patient has no
lesion amenable to biopsy at all, the paired biopsies may be waived by the Sponsor on
a case-by-case basis.
7. Willingness to undergo two biopsies (liver lesion must be prioritized). If the
Investigator judges the biopsies to be a risk or an undue inconvenience for the
patient health/condition, they may be waived by the Sponsor on a case-by-case basis.
8. ECOG performance status 0 to 2.
9. Life expectancy of at least 6 months.
10. Has resolution of all toxicities and any toxic effect(s) of the most recent prior
therapy to Grade 1 or less (except alopecia). Patients with = Grade 2 neuropathy and
Grade = 2 fatigue are an exception and may enroll.
11. Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory
parameters = 7 days before study treatment initiation.
12. Absolute neutrophil count = 1.5 × 109/L.
13. Absolute lymphocyte count = 0.5 × 109/L.
14. Platelets = 100 × 109/L.
15. Hemoglobin level = 9 g/dL.
16. Measured or calculated creatinine clearance (glomerular filtration rate can also be
used in place of creatinine clearance) = 50 mL/min according to the formula of
Cockcroft-Gault (see Appendix 6).
17. Total bilirubin = 1.5 × ULN; if total bilirubin is > 1.5 x ULN then direct bilirubin
must be = 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total
bilirubin = 3 × ULN.
18. ALT/AST = 2.5 × ULN or = 5 × ULN in patients with hepatic involvement.
19. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly
effective contraceptive methods during the treatment period and for at least 180 days
after the last dose of study treatment and refrain from egg donation during this
period.
20. A male patient must agree to use a contraceptive during the treatment period and for
at least 180 days after the last dose of study treatment and refrain from donating
sperm during this period.
Specific to Cohorts 3, 4a, 4b:
1. Patient agrees to follow the instructions and precautions (see Section 4.4.1) related to
potential VSV-GP128 shedding.
Cohorts 2b and 4b:
1. Ability to comprehend and willingness to provide written informed consent (ICF) for
the study.
2. Age = 18 years.
3. Histologically or cytologically confirmed CRC and MSS/MMR proficient status confirmed
by PCR/immunohistochemistry or NGS assay at local institution.
4. Radiological evidence (CT/MRI) of liver-limited stage IV CRC.
5. Must have received first line neoadjuvant SoC systemic therapy (physician choice) for
stage IV disease. May have received up to 16 weeks of this systemic SoC therapy.
Note: Patient may have also received prior adjuvant therapy for stage II or III
colorectal cancer, however the adjuvant treatment for stage II and III will not be
considered as a prior line of therapy in case of relapse more than 6 months after the
end of treatment.
6. Absence of disease progression following neoadjuvant chemotherapy.
7. Eligible for R0 complete liver metastasectomy (in case the primary tumor was already
removed) or for R0 complete simultaneous combined resection (resection of both liver
metastases and primary tumor in case the primary tumor is still in place) with
curative intent.
8. ECOG performance status 0 to 2.
9. Life expectancy of at least 12 months.
10. Adequate renal, hepatic, thyroid and hematologic functions as defined by laboratory
parameters = 7 days before study treatment initiation.
11. Absolute neutrophil count = 1.5 × 109 /L.
12. Absolute lymphocyte count = 0.5 × 109 /L.
13. Platelets = 100 × 109/L.
14. Hemoglobin level = 9 g/dL.
15. Measured or calculated creatinine clearance (glomerular filtration rate can also be
used in place of creatinine clearance) = 50 mL/min according to the formula of
Cockcroft-Gault (see Appendix 6).
16. Total bilirubin = 1.5 × ULN; if total bilirubin is > 1.5 x ULN then direct bilirubin
must be = 1.5 × ULN. Patients with known Gilbert's Syndrome may enroll if total
bilirubin = 3 × ULN.
17. ALT/AST = 2.5 × ULN or = 5 × ULN in patients with hepatic involvement.
18. A female patient is eligible to participate if she is not pregnant, not breastfeeding,
and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to use highly
effective contraceptive methods during the treatment period and for at least 180 days
after the last dose of study treatment and refrain from egg donation during this
period.
19. A male patient must agree to use a contraceptive during the treatment period and for
at least 180 days after the last dose of study treatment and refrain from donating
sperm during this period.
Exclusion Criteria:
All Cohorts:
1. Unwilling or unable to follow protocol requirements or to give informed consent.
2. Gastro-intestinal bowel obstruction (partial or complete).
3. Participation in any other study with an investigational study drug or device requires
Medical Monitor approval.
4. Prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) before
administration of study treatment with the exception of bevacizumab (Avastin®),
cetuximab (Erbitux®) and panitumumab (Vectibix®) which may have been received within
15 days from initiation of study treatment. Supportive care (e.g. denosumab) may be
used before and during study treatment.
5. Prior therapy with checkpoint inhibitors (anti-programmed death 1 (anti-PD-1),
anti-programmed death-ligand 1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated
protein 4 (anti-CTLA-4)). Patients must not have received any investigational
immunotherapy neither.
6. Prior chemotherapy or targeted small molecule therapy within 15 days from initiation
of study treatment.
7. Prior radiotherapy within 2 weeks of enrolment or within 4 weeks of enrolment in the
case of radiation to central nervous system (CNS), which requires = 4-week washout.
Patients must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis.
8. Major (according the Investigator's judgment) surgery within 12 weeks before
enrolment.
9. Known additional malignancy that is progressing or requires active treatment, or
history of other malignancy within 2 years of study entry with the exception of cured
basal cell or squamous cell carcinoma of the skin, superficial bladder cancer,
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, ductal or lobular
carcinoma in situ of the breast, or other non-invasive or indolent malignancy, or
cancers from which the patient has been disease-free for > 1 year, after treatment
with curative intent.
10. Immunosuppression including the continued use of systemic (at prednisone dose
equivalent of > 10 mg) or topical steroids at or near the injection site (excluding
inhaled and eye drop-containing corticosteroids) or the use of immunosuppressive
agents for any concurrent condition. All other corticosteroids must be discontinued >
4 weeks prior to first study treatment administration.
11. Previous vaccination (either therapeutic and/or prophylactic) against mCRC.
12. Pregnant/nursing women or unwilling to comply with acceptable contraceptive methods
during study course.
13. History of autoimmune disease including any active autoimmune disease except vitiligo
or childhood asthma.
14. Dermatological disease requiring local immunosuppressive agent.
15. Chronic or concurrent active infectious disease requiring systemic antibodies,
antifungal, or antiviral treatment.
16. Known medical history of human immunodeficiency virus (HIV) infection or known medical
history of acquired immunodeficiency syndrome (AIDS). HIV testing is not required
unless mandated by the local health authority.
17. Has known history of or is positive for hepatitis B (hepatitis B virus surface antigen
[HBsAg] reactive) or hepatitis C (HCV RNA).
Note: Testing must be performed to determine eligibility. - Hepatitis B virus DNA must
be undetectable and HBsAg negative at screening visit.- Hepatitis C antibody testing
is allowed for screening purposes in countries where HCV RNA is not part of standard
of care. In these cases, HCV antibody positive patients will be excluded.- Patients
who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at
screening visit.
18. Known active CNS metastasis and/or carcinomatous meningitis.
19. Known cerebral oedema.
20. Live vaccine received within 30 days before initiation of study treatment. Examples of
live vaccines include, but are not limited to, the following: measles, mumps, rubella,
chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine.
Seasonal influenza vaccines for injection are generally killed virus vaccines and are
allowed. however, intranasal influenza vaccines (FluMist®) are live attenuated
vaccines and are not allowed. COVID-19 vaccines that are not live vaccines are allowed
before and during study treatment. However, a COVID-19 vaccination should not occur
within ± 2 days of ATP128 study drug and ± 15 days of VSV-GP128 study drug.
21. History of allergy or hypersensitivity to any of the study drugs or study drug
components.
22. Any condition in the judgment of the Investigator which makes the patient unsuitable
for trial participation.
Cohorts 1b, 2a, 2b, 2c, 3, 4a and 4b:
23. Has received more than 1 line of therapy for stage IV disease (neoadjuvant therapy in
Cohort 2b counts as 1 line).
24. History of pneumonitis within the last 5 years.
25. Active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis
requiring treatment with systemic steroids and/or whose pulse oximetry is less than
92% "on room air".
26. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec.
- Any clinically important abnormalities (as assessed by the Investigator) in
rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle
branch block, third degree heart block.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years old, or
any concomitant medication known to prolong the QT interval (according to
institutional guidelines).
- Ejection fraction (EF) < 55% or the lower limit of normal of the institutional
standard will be excluded. Only in cases where the Investigator (or the treating
physician or both) suspects cardiac disease with negative effect on the EF will
the EF be measured during screening using an appropriate method according to
local standards to confirm eligibility (e.g. echocardiogram [ECHO], multi-gated
acquisition scan [MUGA]. A historic measurement of EF no older than 6 months
prior to first study treatment administration can be accepted provided that there
is clinical evidence that the EF value has not worsened since this measurement in
the opinion of the Investigator or the treating physician or both.
Specific to Cohorts 3, 4a, 4b:
1. Previous treatment with VSV-based agents.
2. Use of Tamoxifen within one month prior the initiation of study treatment.
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