Phase 2
N=34
A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination With Immune Checkpoint Inhibition in Refractory Colorectal Cancer
Colorectal Cancer · Colorectal Carcinoma · Colorectal Adenocarcinoma · Refractory Cancer · Colorectal Neoplasms
Bottom Line
View on ClinicalTrials.gov: NCT03206073 ↗Enrolled (actual)
34
Serious AEs
44.1%
Results posted
Oct 2021
Primary outcome: Primary: Number of Participants With Grade 1-5 Adverse Events — 4; 12; 4; 13 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Durvalumab (Drug); Tremelimumab (Drug); Pexa-Vec (Biological)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- National Cancer Institute (NCI)
- Primary completion
- Sep 2020
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Grade 1-5 Adverse Events |
4; 12; 4; 13; 4; 12 | — |
| SECONDARY Percentage of Participants With 5 Month Progression-free Survival |
0; 8.3; 0; 7.1 | — |
| SECONDARY Overall Progression-free Survival |
3; 2.3; 2.25; 1.65 | — |
| SECONDARY Overall Survival |
6.2; 8.6; 6.0; 5.2 | — |
| SECONDARY Number of Participants With Response |
0; 0; 0; 0; 0; 1 | — |
Summary
Background:
* Immune-based approaches in colorectal cancer have unfortunately with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease colorectal cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage
* Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus engineered for the expression of transgenes encoding human granulocyte- macrophage colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor cell death via the induction of innate and adaptive immune responses
* Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed against programmed death-ligand 1 (PD-L1).
* The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition.
Objective:
-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in patients with refractory metastatic colorectal cancer.
Eligibility:
* Histologically confirmed metastatic colorectal cancer.
* Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab based chemotherapy.
* Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
* Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy.
* Willingness to undergo mandatory tumor biopsy.
Design:
-The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in combination with immune checkpoint inhibition in patients with metastatic colorectal cancer.
Eligibility Criteria
- INCLUSION CRITERIA:
- Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study.
- Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and irinotecan-containing, fluorouracil-based, chemotherapeutic regimen and have disease that is not amenable to potentially curative resection. Patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumab-based chemotherapy.
- Patient's tumors must be documented to be microsatellite-stable (MSS) either by genetic analysis or immunohistochemistry OR microsatellite-high with documented disease progression following anti-Programmed cell death protein 1 (PD1)/Programmed death-ligand 1 (PDL1) therapy.
- Patients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy and be willing to undergo this. Ideally the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigators.
- All patients enrolled will be required to have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
- Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Pexa-Vec in combination with tremelimumab and/or durvalumab in patients 9g/dl
- Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (SGPT) less than or equal to 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be less than or equal to 5x upper limit of normal (ULN)
- Creatinine 1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
- Body weight >35kg
EXCLUSION CRITERIA
- Patients who have had anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents), large field radiotherapy, or major surgery must wait 4 weeks after completing treatment prior to entering the study.
- No prior exposure to immune-mediated therapy including, but not limited to, other anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, including therapeutic anticancer vaccines. The exception to this is those whose tumors are MSI-hi and are refractory to anti-PD1 monotherapy.
- Involvement in the planning and/or conduct of the study
- Previous IP assignment in the present study
- Patients who are receiving any other investigational agents.
- Inability to suspend treatment with anti-hypertensive medication (including but not limited to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors, aldosterone antagonists, etc.) for 48 hours pre and post each Pexa-Vec administration.
- Patients with severe hypertension who in the opinion of the investigator cannot withhold antihypertensive medication for 48 hours pre and post Pexa-Vec administration.
- Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade greater than or equal to 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Patients with Grade greater than or equal to 2 neuropathy will be evaluated on a case-by-case basis
- Patients with known brain metastases will be excluded from this clinical trial becau
Data sourced from ClinicalTrials.gov (NCT03206073). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.