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

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ClinicalTrials.gov Identifier: NCT03206073
Recruitment Status : Recruiting
First Posted : July 2, 2017
Last Update Posted : September 24, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE June 30, 2017
First Posted Date  ICMJE July 2, 2017
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE December 7, 2017
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 24, 2018)
safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition [ Time Frame: 30 days after last treatment ]
List of adverse event frequency
Original Primary Outcome Measures  ICMJE
 (submitted: June 30, 2017)
List of adverse event frequency [ Time Frame: 30 days after last treatment ]
Change History Complete list of historical versions of study NCT03206073 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2018)
  • progression-free survival [ Time Frame: 5 month ]
    Median amount of time subject survives without disease progression after treatment
  • overall progression-free survival [ Time Frame: at progression ]
    Median amount of time subject survives without disease progression after treatment
  • overall survival [ Time Frame: death ]
    Median amount of time subject survives after therapy
  • response rate [ Time Frame: every 2 months until disease progression or intolerable toxicity ]
    Changes in tumor size and occurrence of metastases
Original Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2017)
  • Median amount of time subject survives without disease progression after treatment [ Time Frame: 5 month ]
  • Median amount of time subject survives without disease progression after treatment [ Time Frame: at progression ]
  • Median amount of time subject survives after therapy [ Time Frame: death ]
  • Changes in tumor size and occurrence of metastases [ Time Frame: every 2 months until disease progression or intolerable toxicity ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination With Immune Checkpoint Inhibition in Refractory Colorectal Cancer
Official Title  ICMJE A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination With Immune Checkpoint Inhibition in Refractory Colorectal Cancer
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 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 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 KRAS wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumabbased 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-PD1/PDL1 therapy.
  • Patients must have at least one focus of metastatic disease that is amenable to pre- and ontreatment 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.

Detailed Description

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 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 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 KRAS wild type tumor must have progressed, been intolerant of or refused cetuximab or panitumumabbased 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-PD1/PDL1 therapy.
  • Patients must have at least one focus of metastatic disease that is amenable to pre- and ontreatment 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.
  • Patients will receive Pexa-Vec, administered IV every 2 weeks for 4 doses, in 4 separate arms A1, A2, B1, and B2. The first administration will be on Day (minus) 12, followed by administration on Days 2, 16 and 30 (i.e. 4 doses in total).

    • Arms A1 and A2: In addition to the oncolytic virus patients will also receive durvalumab at a flat dose of 1500 mg beginning on Day 1 followed by q28days until off-treatment criteria are met.
    • Arms B1 and B2: In addition to the oncolytic virus patients will also receive tremelimumab 300 mg and durvalumab 1500 mg on Day 1 followed by q28days subsequent continuation of the durvalumab alone until off-treatment criteria are met.
  • All patients will undergo a baseline tumor biopsy and a post treatment biopsy.
  • Accrual ceiling will be set at 35 to allow for patients replaceable for reasons other than toxicity.
  • Patients will be restaged every 8 weeks +/- 3 days
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Colorectal Cancer
  • Colorectal Carcinoma
  • Colorectal Adenocarcinoma
  • Refractory Cancer
  • Colorectal Neoplasms
Intervention  ICMJE
  • Drug: Durvalumab
    1500 mg of durvalumab via IV infusion on Day 1 of each cycle until patients meet off treatment criteria
  • Drug: Tremelimumab
    300 mg of tremelimumab via IV infusion on Day 1 of cycle 1
  • Biological: Pexa-Vec
    3 x 10E8 pfu (DL 1) or 1 x 10E9 pfu (DL 2) via IV infusion for 4 doses: Day 12, Day 2, Day 16 of Cycle 1 and Day 2 of Cycle 2.
Study Arms  ICMJE
  • Experimental: 1/Arm A1
    Pexa-Vec escalation dose levels + Durvalumab
    Interventions:
    • Drug: Durvalumab
    • Biological: Pexa-Vec
  • Experimental: 2/Arm A2
    MTD of Pexa-Vec after the MTD is established +Durvalumab
    Interventions:
    • Drug: Durvalumab
    • Biological: Pexa-Vec
  • Experimental: 3/Arm B1
    Pexa-Vec escalation dose levels + Durvalumab +Tremelimumab
    Interventions:
    • Drug: Durvalumab
    • Drug: Tremelimumab
    • Biological: Pexa-Vec
  • Experimental: 4/Arm B2
    MTD of Pexa-Vec after the MTD is established+Durvalumab + Tremelimumab
    Interventions:
    • Drug: Durvalumab
    • Drug: Tremelimumab
    • Biological: Pexa-Vec
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 30, 2017)
35
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the Laboratory of Pathology of the 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 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-PD1/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 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.
  • 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
    • Hb > 9g/dl
    • AST (SGOT)/ALT (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 ULN
    • Creatinine <1.5X institution upper limit of normal, OR
    • creatinine clearance greater than or equal to 45 mL/min/1.73 m(2), as calculated below, for patients with creatinine levels above institutional normal
  • Patient must be able to understand and willing to sign a written informed consent document
  • The effects of Pexa-Vec, durvalumab and tremelimumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and up to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
    • Women greater than or equal to 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >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 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 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 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 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.
  • 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/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)
  • History of chronic autoimmune disease (e.g. systemic lupus erythematosus or Wegener s granulomatosis, Addison s disease, multiple sclerosis, Graves disease, Hashimoto s thyroiditis, hypophysitis, etc.) with symptomatic disease within the 3 years before enrollment. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion. In addition, a past history of certain autoimmunity e.g. rheumatoid arthritis or thyroiditis may be allowed per PI discretion provided it has been quiescent for a minimum of three years. The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included
    5. Patients with celiac disease controlled by diet alone
    6. Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea.
  • History of active primary immunodeficiency
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing (if clinically indicated), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
    • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:

Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.

  • Female patients who are breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Pexa-Vec, breastfeeding should be discontinued if the mother is treated with Pexa-Vec. These potential risks may also apply to other agents used in this study.
  • Known allergy or hypersensitivity to IP
  • Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  • History of sarcoidosis syndrome
  • Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia s Correction
  • Patients with a history of Interstitial lung disease or pneumonitis
  • Subjects with uncontrolled seizures
  • History of leptomeningeal carcinomatosis
  • History of hypersensitivity reaction to human or mouse antibody products.
  • Patients with unhealed surgical wounds for more than 30 days
  • Ongoing severe inflammatory skin condition (as determined by the Investigator) requiring medical treatment
  • History of severe eczema (as determined by the Investigator) requiring medical treatment
  • Patients with tumor(s) invading a major vascular structure (e.g. carotid artery) or other key anatomical structure (e.g. pulmonary airway) in the event of post treatment tumor swelling and/or necrosis (hepatic and portal vein involvement allowed)
  • Patients with liver tumors in a location that would potentially result in significant clinical adverse effects in the opinion of investigator if post-treatment tumor swelling were to occur, including at the site of the common bile duct
  • Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions. Mild ascites that does not preclude safe tumor biopsy as protocol specified is allowed at the discretion of the treating physician.
  • Medical conditions, per the investigator s judgment, that predispose the patient to untoward medical risk in the event of volume loading (e.g. intravenous [IV] fluid bolus infusion), tachycardia, or hypotension during or following treatment with Pexa-Vec
  • Any prior or planned organ transplant (e.g. liver transplant)
  • Patients who experienced a severe systemic reaction or side-effect as a result of a previous vaccination with vaccinia
  • Pulse oximetry O2 saturation <90% at rest on room air
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Donna M Hrones, C.R.N.P. (240) 858-3155 donna.mabry@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03206073
Other Study ID Numbers  ICMJE 170092
17-C-0092
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Tim F Greten, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 20, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP