Clinical Trials /

DPX-Survivac and Checkpoint Inhibitor in DLBCL

NCT03349450

Description:

This is a Phase 2 non-randomized, open label, uncontrolled, efficacy and safety study. Study participants will receive two priming doses of 0.5mL of DPX-Survivac 21 days apart and up to six 0.1ml maintenance injections every two months with low dose metronomic oral cyclophosphamide (50 mg BID) for one year or until disease progression, whichever occurs first. Pembrolizumab 200 mg will be administered every 3 weeks for up to one year or until disease progression, whichever occurs first.

Related Conditions:
  • Burkitt Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Double-Hit Lymphoma
  • Transformed Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: DPX-Survivac and Checkpoint Inhibitor in DLBCL
  • Official Title: Phase 2 Study of an Immunotherapeutic Vaccine, DPX-Survivac With Low Dose Cyclophosphamide Administered With Pembrolizumab in Patients With Persistent or Recurrent/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: 0891
  • NCT ID: NCT03349450

Conditions

  • Adult Diffuse Large Cell Lymphoma
  • Recurrent
  • Adult Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
DPX-SurvivacSingle Arm-Investigational
PembrolizumabSingle Arm-Investigational
Cyclophosphamide 50mgSingle Arm-Investigational

Purpose

This is a Phase 2 non-randomized, open label, uncontrolled, efficacy and safety study. Study participants will receive two priming doses of 0.5mL of DPX-Survivac 21 days apart and up to six 0.1ml booster vaccinations every two months with low dose metronomic oral cyclophosphamide (50 mg BID) for one year or until disease progression, whichever occurs first. Pembrolizumab 200 mg will be administered every 3 weeks for up to one year or until disease progression, whichever occurs first.

Detailed Description

      This is a Phase 2, non-randomized, open-label, uncontrolled, efficacy and safety trial.

      Participants will receive 2 priming injections (0.5ml) of the DPX-Survivac vaccine 3 weeks
      apart on Study Days 7 and 28. In addition, up to 6 booster vaccinations (0.1ml) over the
      course of the study occurring on Study Days 84, 140, 196, 252, 308, and 364. All injections
      will be given under the skin of the upper thigh.

      Participants will receive metronomic oral cyclophosphamide (50mg BID; 7 days on / 7 days off)
      for study period.

      Pembrolizumab 200mg will be administered intravenously every 3 weeks, commencing on study day
      7, to a total of 18 infusions.

      If a subject is removed from the trial prior to the completion of at least 4 doses of
      Pembrolizumab and 3 vaccinations of DPX-Survivac, that subject may be replaced to determine
      the efficacy of treatment in a minimum of 16 subjects.

      DPX-Survivac injection sites will be evaluated throughout the study and if evidence of
      significant reaction, an Injection site reaction biopsy will be sought.

      During the course of the study, blood will be drawn to evaluate immune cells and the effect
      that the vaccinations have on the participants immune system. During all treatment cycles a
      physical exam and questions about the participants general health will be performed.

      Participant will undergo "re-staging" to assess the status of their disease at approximately
      study day 70 (if there is evidence of Grade 2 or greater injection site reaction or
      ulceration evident on study day 49) or routinely at approximately study day 91 and repeated
      at end of study or study withdrawal for all participants.

      A follow-up tumour biopsy will be requested between study day 77-83 for subjects with any
      grade 2 or greater Injection site reaction or ulceration on SD49 or between SD98 and SD104 if
      no evidence of injection site reaction or ulceration.

      Upon completion of study, participants will be monitored every 2 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Single Arm-InvestigationalExperimentalDPX-Survivac Priming dose of 0.5ml. DPX-Survivac Booster dose of 0.1ml. Pembrolizumab 200mg Intravenously. Cyclophosphamide 50mg Twice daily orally.
  • Cyclophosphamide 50mg

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects with histologically proven recurrent DLBCL. Subjects may have recurrence
             after primary, secondary or tertiary treatment regimens for DLBCL.

          2. Subjects with recurrence at least 90 days post aggressive first line combination
             chemotherapy (e.g. RCHOP, Hyper-CVAD or other aggressive "curative" combination),
             autologous stem cell transplantation (ASCT), or aggressive second line combination
             therapy are eligible.

          3. Patients with partial response or measurable disease after first line therapy (who are
             not candidates for ASCT) or after second or third line therapy without disease
             progression may also be eligible.

          4. Patients with recurrence any time after non-aggressive combination or single agent
             therapy with or without Rituximab (ie. CVP, CHL or, VP16) for first, second or third
             line disease are eligible.

          5. Patients may have evidence of transformed lymphoma with past history of indolent
             lymphoma provided current biopsy shows DLBCL.

          6. Patients with double hit or high grade lymphomas including Burkitts lymphoma and High
             Grade B-Cell lymphoma unclassifiable (with features intermediate between Burkitts and
             diffuse large B cell lymphoma are eligible.

          7. Be willing and able to provide written informed consent/assent for the trial.

          8. Male or female ≥ 18 years of age on day of signing informed consent

          9. Have at least one measurable site of disease based on Cheson Criteria using standard
             CT imaging.

         10. Be willing to provide tissue from a newly obtained (up to 3 month prior to Day 0)
             biopsy of a tumour lesion. If this is not available, the patient must be willing to
             undergo a core biopsy prior to starting treatment. They must also be willing to
             provide an on-treatment biopsy.

         11. Have a performance status of 0-1 on the ECOG Performance Scale.

         12. Demonstrate adequate organ function confirmed 48 hours prior to enrollment.

         13. Previous localized surgery, radiotherapy, chemotherapy, and immunotherapy more than 21
             days prior to SD0. Cyclophosphamide, up to 100 mg/day, may be administered until SD-1
             for subjects already receiving as a single agent therapy.

         14. Subjects must have evidence of survivin expression in pre-treatment tumour sample (>
             10% of tumour cells stained).

         15. A life expectancy > 6 months.

         16. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication

         17. Ability to comply with protocol requirements

        Exclusion Criteria:

          1. Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 21 days of the first dose of treatment (SD0).

          2. Patients eligible for possible curative therapies such as ASCT.

          3. LDH greater than 5 times the upper limit of normal.

          4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 35 days prior to the first dose of
             trial treatment (SD0), except that used as pre-medication for chemotherapy or
             contrast-enhanced studies are eligible. Subjects may be on physiologic doses of
             replacement prednisone or equivalent doses of corticosteroid (<10 mg daily).

          5. Has a known history of active TB (Bacillus Tuberculosis)

          6. Hypersensitivity to Pembrolizumab or any of its excipients.

          7. Has had a prior anti-cancer monoclonal antibody (mAb) within 21 days prior to study
             Day 0 or who has not recovered (i.e., ≤ Grade 1) from adverse events due to agents
             administered more than 21 days earlier.

          8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 21 days prior to study Day 0

          9. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

         10. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis.

         11. Progressive CNS lymphoma requiring treatment within 35 days prior to SD0.

         12. Has history of active autoimmune disease that has required systemic treatment in the
             past 2 years. Replacement therapy (eg., thyroxine, insulin, or physiologic
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
             not considered a form of systemic treatment.

         13. Has known history of, or any evidence of active, non-infectious pneumonitis.

         14. Thyroiditis within the past 5 years.

         15. Has an active infection requiring systemic therapy. Note: Subjects completing a course
             of antibiotic for acute infection 7 days prior to SD0 and who do not experience a
             recurrence of symptoms or fever are eligible.

         16. Presence of a serious acute infection or chronic infection

         17. Other serious intercurrent chronic or acute illness

         18. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with screening visit to 120 days post
             completion of study

         19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         21. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected). Evidence of Hepatitis B surface antigen without
             transaminitis is allowed provided patient is treated with anti-viral therapy (Heptovir
             or Tenofovir)

         22. Patients who have received prior survivin based vaccines.

         23. Acute or chronic skin disorders that will interfere with subcutaneous injection of the
             vaccine or subsequent assessment of potential skin reactions.

         24. Serious intercurrent chronic or acute illness, such as cardiac disease (New York Heart
             Association class III or IV), hepatic disease, or other illness considered by the
             investigator as an unwarranted high risk for an investigational product.

         25. Allergies to any vaccine, that after discussion with the medical monitor are serious
             enough to warrant exclusion from this study.

         26. Received a live vaccine within 30 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To document the objective response rate using modified Cheson criteria to treatment with DPX-Survivac and low dose cyclophosphamide administered together with Pembrolizumab in patients with recurrent, survivin-expressing B cell lymphomas
Time Frame:1 Year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To document changes in tumour volume using waterfall analyses
Time Frame:1 Year
Safety Issue:
Description:Tumor volume measurements will be obtained at multiple time points by adding the volumes of the perpendicular measurements for up to 6 target lesions
Measure:To document the toxicity profile
Time Frame:1 Year
Safety Issue:
Description:Number of participants with abnormal laboratory values and/or adverse events related to treatment will be assessed.
Measure:To document duration of response using modified Cheson criteria.
Time Frame:2 Years
Safety Issue:
Description:
Measure:To document duration of response using immune related response criteria
Time Frame:2 Years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sunnybrook Health Sciences Centre

Trial Keywords

  • Lymphoma
  • DLBCL
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse
  • Neoplasms by Histologic Type
  • Neoplasms
  • Lymphoproliferative Disorders
  • Lymphatic Diseases
  • Immunoproliferative Disorders
  • Immune System Diseases
  • Lymphoma, Non-Hodgkin
  • Cyclophosphamide
  • Pembrolizumab
  • Immunosuppressive Agents
  • Immunologic Factors
  • Physiological Effects of Drugs
  • Antirheumatic Agents
  • Antineoplastic Agents, Alkylating
  • Alkylating Agents
  • Molecular Mechanisms of Pharmacological Action
  • Antineoplastic Agents
  • Myeloablative Agonists
  • Canada
  • Ontario
  • Diffuse Large B Cell Lymphoma
  • refractory
  • relapsed
  • checkpoint inhibitor
  • vaccine
  • DPX-Survivac
  • Survivin
  • Immunotherapy
  • Transformed Lymphoma
  • Double Hit
  • Large Cell Lymphoma
  • Keytruda

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