Clinical Trials /

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

NCT03206073

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 170092
  • SECONDARY ID: 17-C-0092
  • NCT ID: NCT03206073

Conditions

  • Colorectal Cancer
  • Colorectal Carcinoma
  • Colorectal Adenocarcinoma
  • Refractory Cancer
  • Colorectal Neoplasms

Interventions

DrugSynonymsArms
Durvalumab2/Arm A2
Tremelimumab3/Arm B1
Pexa-Vec1/Arm A1

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm A1ExperimentalPexa-Vec escalation dose levels + Durvalumab
  • Durvalumab
  • Pexa-Vec
2/Arm A2ExperimentalMTD of Pexa-Vec after the MTD is established +Durvalumab
  • Durvalumab
  • Pexa-Vec
3/Arm B1ExperimentalPexa-Vec escalation dose levels + Durvalumab +Tremelimumab
  • Durvalumab
  • Tremelimumab
  • Pexa-Vec
4/Arm B2ExperimentalMTD of Pexa-Vec after the MTD is established+Durvalumab + Tremelimumab
  • Durvalumab
  • Tremelimumab
  • Pexa-Vec

Eligibility Criteria

        -  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
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:safety, tolerability and feasibility of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition
Time Frame:30 days after last treatment
Safety Issue:
Description:List of adverse event frequency

Secondary Outcome Measures

Measure:progression-free survival
Time Frame:5 month
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment
Measure:overall progression-free survival
Time Frame:at progression
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment
Measure:overall survival
Time Frame:death
Safety Issue:
Description:Median amount of time subject survives after therapy
Measure:response rate
Time Frame:every 2 months until disease progression or intolerable toxicity
Safety Issue:
Description:Changes in tumor size and occurrence of metastases

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

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

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