A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination With Immune Checkpoint Inhibition in Refractory Colorectal Cancer

NCT03206073 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 17009217-C-0092
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Colorectal Cancer; Colorectal Carcinoma; Colorectal Adenocarcinoma; Refractory Cancer; Colorectal Neoplasms

Keywords

Oncolytic Vaccinia Virus; Tumor Cell Death; Viral Therapy; Anti-Tumor Immunity

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Grade 1-5 Adverse Events

  Number of participants with Grade 1-5 Adverse events. Grade 1 is mild, Grade 2 is moderate, Grade 3 severe or medically significant, Grade 4 is life-threatening consequences, and Grade 5 is death related to adverse event.

  30 days after last treatment

Secondary Outcomes (4)

• Percentage of Participants With 5 Month Progression-free Survival

  5 months

• Overall Progression-free Survival

  At progression, approximately 9 months

• Overall Survival

  Death, an average of 9 months

• Number of Participants With Response

  Every 2 months until disease progression or intolerable toxicity, approximately 12 months

Other Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.3)

  Date treatment consent signed to date off study, approximately 20 months and 3 days for 1/Arm A1, 30 months and 27 days for 2/Arm A2, 14 months for 3/Arm B1, and 13 months and 21 days for 4/Arm B2.

Study Arms (4)

1/Arm A1 Pexa-Vec + Durvalumab

EXPERIMENTAL

Pexa-Vec escalation dose levels + Durvalumab

Drug: Durvalumab; Biological: Pexa-Vec

2/Arm A2 Pexa-Vec +Durvalumab

EXPERIMENTAL

Maximum tolerated dose (MTD) of Pexa-Vec after the MTD is established +Durvalumab

Drug: Durvalumab; Biological: Pexa-Vec

3/Arm B1 Pexa-Vec + Durvalumab +Tremelimumab

EXPERIMENTAL

Pexa-Vec escalation dose levels + Durvalumab +Tremelimumab

Drug: Durvalumab; Drug: Tremelimumab; Biological: Pexa-Vec

4/Arm B2

EXPERIMENTAL

MTD of Pexa-Vec after the MTD is established+Durvalumab + Tremelimumab

Drug: Durvalumab; Drug: Tremelimumab; Biological: Pexa-Vec

Interventions

Durvalumab DRUG

1500 mg of durvalumab via intravenous (IV) infusion on Day 1 of each cycle until patients meet off treatment criteria

Also known as: MEDI-4736

1/Arm A1 Pexa-Vec + Durvalumab; 2/Arm A2 Pexa-Vec +Durvalumab; 3/Arm B1 Pexa-Vec + Durvalumab +Tremelimumab; 4/Arm B2

Tremelimumab DRUG

300 mg of tremelimumab via intravenous (IV) infusion on Day 1 of cycle 1

Also known as: CP-675,206

3/Arm B1 Pexa-Vec + Durvalumab +Tremelimumab; 4/Arm B2

Pexa-Vec BIOLOGICAL

3 x 10E\^8 plaque-forming unit (pfu) (Dose Level (DL) 1) via intravenous (IV) infusion for 4 doses: Day 12, Day 2, Day 16 of Cycle 1 and Day 2 of Cycle 2.

Also known as: Pexa-Vec, INN pexastimogene devacirepvec

1/Arm A1 Pexa-Vec + Durvalumab; 3/Arm B1 Pexa-Vec + Durvalumab +Tremelimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must have acceptable organ and marrow function as defined below:
• Leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,500/mcL
• Platelets greater than or equal to 100,000/mcL
• total bilirubin less than or equal to 1.5X institution upper limit of normal
• Hemoglobin (Hb) \> 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 \<1.5X institution upper limit of normal, OR

You may not qualify if:

• 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.
• 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 because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Uncontrolled intercurrent illness including, but not limited to, hypertension (systolic blood pressure (BP) \> 160, diastolic BP \> 100), ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes or psychiatric illness/social situations that would limit compliance with study requirements. For patients with a history of cardiovascular disease, cardiology consultation. Echocardiogram, troponin and creatinine clearance must be obtained prior to enrollment. NOTE: Patients with active cardiac disease (e.g. myocarditis and myocardial infarction) within 12 months of study entry are excluded from study participation.
• Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and the investigational agent. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that Durvalumab or Tremelimumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events.
• Known significant immunodeficiency due to underlying illness (e.g. HIV/Acquired immunodeficiency syndrome (AIDS) and/or immune-suppressive medication including high-dose corticosteroids (defined as greater than or equal to 20 mg/day prednisone or equivalent which is ongoing at the time of enrollment and/or was taken for more than 4 weeks within the preceding 2 months of enrollment)
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Rajani KR, Vile RG. Harnessing the Power of Onco-Immunotherapy with Checkpoint Inhibitors. Viruses. 2015 Nov 13;7(11):5889-901. doi: 10.3390/v7112914.

  PMID: 26580645 BACKGROUND

• Kohlhapp FJ, Kaufman HL. Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy. Clin Cancer Res. 2016 Mar 1;22(5):1048-54. doi: 10.1158/1078-0432.CCR-15-2667. Epub 2015 Dec 30.

  PMID: 26719429 BACKGROUND

• Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013 Mar;19(3):329-36. doi: 10.1038/nm.3089. Epub 2013 Feb 10.

  PMID: 23396206 BACKGROUND

• Monge C, Xie C, Myojin Y, Coffman K, Hrones DM, Wang S, Hernandez JM, Wood BJ, Levy EB, Juburi I, Hewitt SM, Kleiner DE, Steinberg SM, Figg WD, Redd B, Homan P, Cam M, Ruf B, Duffy AG, Greten TF. Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer. J Immunother Cancer. 2023 Feb;11(2):e005640. doi: 10.1136/jitc-2022-005640.

  PMID: 36754451 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Colorectal Neoplasms; Neoplasms

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Results Point of Contact

• Title: Dr. Tim F. Greten
• Organization: National Cancer Institute

tim.greten@nih.gov

240-760-6114

Study Officials

• Tim F Greten, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 30, 2017
• First Posted: July 2, 2017
• Study Start: December 7, 2017
• Primary Completion: September 24, 2020
• Study Completion: June 30, 2022
• Last Updated: October 24, 2023
• Results First Posted: October 26, 2021

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.

Locations

US (1)