Clinical Trials /

Talimogene Laherparepvec for the Treatment of Peritoneal Surface Malignancies

NCT03663712

Description:

The primary objective of this open-label, Phase I, trial is to evaluate the toxicity profile of intraperitoneal talimogene laherparepvec (TVEC) in patients with peritoneal surface dissemination from gastrointestinal or recurrent, platinum-resistant ovarian tumors. The secondary objectives are to evaluate the pharmacokinetic profile and viral shedding of TVEC by measuring viral load in serum and urine as well as viral load in peritoneal washings.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Ampulla of Vater Carcinoma
  • Esophageal Carcinoma
  • Gastrointestinal Stromal Tumor
  • Malignant Esophagogastric Neoplasm
  • Malignant Gastric Neoplasm
  • Malignant Intestinal Neoplasm
  • Malignant Small Intestinal Neoplasm
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Talimogene Laherparepvec for the Treatment of Peritoneal Surface Malignancies
  • Official Title: A Phase I Trial of Talimogene Laherparepvec for the Treatment of Peritoneal Surface Malignancies

Clinical Trial IDs

  • ORG STUDY ID: Pro00086917
  • NCT ID: NCT03663712

Conditions

  • Stage IV Peritoneal Surface Dissemination From Gastrointestinal or Recurrent, Platinum-resistant Ovarian Cancer That Cannot be Completely Resected

Interventions

DrugSynonymsArms
Talimogene Laherparepvec(T-VEC)Dose

Purpose

The primary objective of this open-label, Phase I, trial is to evaluate the toxicity profile of intraperitoneal talimogene laherparepvec (TVEC) in patients with peritoneal surface dissemination from gastrointestinal or recurrent, platinum-resistant ovarian tumors. The secondary objectives are to evaluate the pharmacokinetic profile and viral shedding of TVEC by measuring viral load in serum and urine as well as viral load in peritoneal washings.

Detailed Description

      This is a non-randomized, open-label Phase I trial in patients with Stage IV peritoneal
      surface dissemination from gastrointestinal or recurrent, platinum-resistant ovarian tumors
      enrolled at Duke Cancer Institute. All subjects will complete an extensive medical history,
      baseline physical examination and clinical assessment to ensure subject eligibility
      requirements within 4 weeks of starting study drug. All eligible patients must have a
      peritoneal catheter placed at least 2 weeks prior to the initiation of therapy. All patients
      will receive an initial loading dose of TVEC 4x106 Plaque Forming Units (PFU) on Cycle 1 Day
      1 to enable the formation of protective antibodies as described in the currently approved
      treatment protocol for the treatment of cutaneous melanoma. Three weeks after the initial
      loading dose, patients will receive TVEC at the dose level for the cohort for which they are
      enrolled every 2 weeks for up to 4 doses. The length of the first cycle is 5 weeks and
      subsequent cycles are 2 weeks in duration.

      The first portion of the study, the Dose Escalation cohort, will evaluate the toxicity
      profile of TVEC in patients with peritoneal surface dissemination from gastrointestinal or
      recurrent, platinum-resistant ovarian tumors. Using a standard '3+3' dose escalation design,
      there are up to three dose levels that may be explored. Dose escalation will be dependent on
      dose-limiting toxicity (DLT) within the cohorts.

      Once the MTD has been determined, an additional 6 subjects will be enrolled to the dose
      expansion cohort. All subjects will receive an initial loading dose of TVEC 4x106 PFU on
      Cycle 1 Day 1. Three weeks after the initial loading dose, patients will receive TVEC at the
      MTD every 2 weeks for up to 4 doses. The length of the first cycle is 5 weeks and the
      subsequent cycles are 2 weeks in duration. There are a total of four cycles.
    

Trial Arms

NameTypeDescriptionInterventions
DoseExperimentalDrug: Talimogene Laherparepvec There will be two parts to this phase I study: 1) Dose Escalation Cohort; 2.) Dose Expansion Cohort In the Dose Escalation Cohort, three subjects will be enrolled at the starting dose of 4x106 PFU, and the dosing will continue in the standard '3+3' dose escalation scheme. If the starting dose is tolerated, enrollment will continue at 4x107 and 4x108 PFU. Once the MTD is determined, six subjects will be enrolled to the Dose Expansion Cohort at the MTD. All subjects will be dosed with talimogene laherparepvec intraperitoneal (IP) once every 2 weeks for up to 4 doses (in addition to the initial seroconversion dose, which all patients will receive).
  • Talimogene Laherparepvec

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have stage IV peritoneal surface dissemination of gastrointestinal
             cancer that cannot be completely resected at the time of abdominal exploration, or
             recurrent, platinum-resistant ovarian cancer with peritoneal metastasese.
             Radiographically measurable disease is preferable, but for patients with previously
             documented gastrointestinal or ovarian cancer, for whom tumor markers (CEA or CA-125)
             have been useful markers of disease progression and/or response to treatment, a rising
             tumor marker (CEA or CA-125) could be substituted for radiographic imaging.

          2. Subjects must have had at least one prior round of systemic therapy or have refused or
             be ineligible for standard systemic therapy for their disease type.

          3. Age ≥ 18 years

          4. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-2

          5. Adequate marrow function as evidenced by:

               1. Absolute neutrophil count (ANC) ≥ 2,000/µL

               2. Platelets ≥ 100,000/µL

               3. Hemoglobin (Hgb) ≥ 9 g/dL

          6. Adequate renal function as evidenced by serum creatinine ≤ 1.5 x upper limit of normal
             (ULN), OR 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels
             > 1.5 x ULN.

          7. Adequate hepatic function as evidenced by:

               1. Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total
                  bilirubin level > 1.5 x ULN

               2. Aspartate aminotransferase (AST) ≤ 3 x ULN

               3. Alanine aminotransferase (ALT) ≤ 3 x ULN

               4. Alkaline phosphatase ≤ 3 x ULN

          8. INR or PT ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which
             case PT and PTT/aPTT must be within therapeutic range of intended use of
             anticoagulants (and may need to be held per institutional standards for placement of
             the Bard peritoneal catheter).

          9. Patients must be recovered from both acute and late effects of any prior surgery,
             radiotherapy or other antineoplastic therapy.

         10. Patients of reproductive potential (men and women) must agree to use medically
             accepted barrier methods of contraception (e.g., male or female condom) at the time of
             pregnancy test (women of childbearing potential only), during the course of the study
             and for 90 days after the last dose of study drug, even if oral contraceptives are
             also used. All subjects of reproductive potential must agree to use both a barrier
             method and a second method of birth control during the course of study and for 90 days
             after the last dose of study drug.

         11. Patients or their legal representatives must be able to read, understand and provide
             informed consent to participate in the trial.

        Exclusion Criteria:

          1. Prior chemotherapy, radiotherapy, biological cancer therapy, targeted therapy, or
             major surgery within 28 days prior to enrollment or has not recovered to CTCAE grade 1
             or better from adverse event due to cancer therapy administered more than 28 days
             prior to enrollment.

          2. Patients who received radiotherapy to more than 25% of their bone marrow.

          3. Currently receiving treatment with another investigational device or drug study, or <
             30 days since ending treatment with another investigational device or drug study(s).
             Other investigational procedures while participating in this study are excluded.

          4. Known active central nervous system (CNS) metastases. Subjects with previously treated
             brain metastases may participate provided they are stable (without evidence of
             progression by imaging for at least four weeks prior to the first dose of trial
             treatment and any neurologic symptoms have returned to baseline), have no evidence of
             new or enlarging brain metastases, and are not using steroids >10 mg/day of prednisone
             or equivalent. The exception does not include carcinomatous meningitis, which is
             excluded regardless of clinical stability.

          5. Metastatic disease in a site other than the peritoneal surfaces.

          6. History or evidence of active autoimmune disease that requires systemic treatment
             (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          7. Evidence of clinically significant immunosuppression such as the following:

               1. Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease.

               2. Concurrent opportunistic infection.

               3. Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid
                  doses >10mg/day of prednisone or equivalent within 7 days prior to enrollment.

          8. History of allogenic organ or hematopoietic transplant.

          9. Active herpes simplex virus (HSV) that requires intermittent or chronic systemic
             anti-herpetic therapy or prior complications of herpetic infection, e.g. herpetic
             keratitis or encephalitis.

         10. Requiring intermittent or chronic systemic (intravenous or oral) treatment with an
             antiherpetic drug (e.g., acyclovir), other than intermittent topical use.

         11. Prior treatment with talimogene laherparepvec or any other oncolytic virus.

         12. Subject has known sensitivity to talimogene laherparepvec or any of its components to
             be administered during dosing.

         13. Prior therapy with tumor vaccine.

         14. Receipt of a live vaccine within 28 days prior to enrollment.

         15. Known to have acute or chronic active hepatitis B or C infection (active, previously
             treated, or both).

         16. Known history of HIV infection.

         17. Active infection or fever ≥ 101.3°F within 3 days of the first scheduled day of
             protocol treatment.

         18. Peripheral neuropathy ≥ Grade 2.

         19. Bleeding disorders that would preclude intraperitoneal port placement.

         20. Refractory ascites that requires palliative paracentesis more frequently than once a
             month. Any other medical condition, including mental illness or substance abuse,
             deemed by the Investigator to be likely to interfere with a patient's ability to sign
             informed consent, cooperate and participate in the study or interferes with the
             interpretation of the results.

         21. History of other malignancy within the past 5 years.

         22. Female subjects who are pregnant or breast-feeding, or planning to become pregnant
             during study treatment or through 90 days after the last dose of talimogene
             laherparepvec.

         23. Subjects of childbearing potential who are unwilling to use acceptable method(s) of
             effective contraception during study treatment and through 90 days after the last dose
             of talimogene laherparepvec.

         24. Sexually active subjects and their partners unwilling to use male or female latex
             condom to avoid potential viral transmission during sexual contact while on treatment
             and within 90 days after treatment with talimogene laherpareapvec.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Most Tolerable Dose (MTD) for talimogene laherparepvec
Time Frame:MTD for the study will be determined at the completion of Phase I dose escalation cohort; estimated as 1 year
Safety Issue:
Description:The MTD across three dose levels will be determined and the safety analyses will be performed on the safety population

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dan Blazer III, M.D.

Last Updated

June 7, 2019