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DPX-Survivac and Checkpoint Inhibitor in DLBCL (SPiReL)

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ClinicalTrials.gov Identifier: NCT03349450
Recruitment Status : Recruiting
First Posted : November 21, 2017
Last Update Posted : March 29, 2018
Sponsor:
Collaborators:
ImmunoVaccine Technologies, Inc. (IMV Inc.)
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Adult Diffuse Large Cell Lymphoma Recurrent Adult Refractory Diffuse Large B-Cell Lymphoma Biological: DPX-Survivac Biological: Pembrolizumab Drug: Cyclophosphamide 50mg Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 13, 2018
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2021


Arm Intervention/treatment
Experimental: Single Arm-Investigational

DPX-Survivac Priming dose of 0.5ml. DPX-Survivac Booster dose of 0.1ml.

Pembrolizumab 200mg Intravenously.

Cyclophosphamide 50mg Twice daily orally.

Biological: DPX-Survivac
DPX-Survivac Priming dose of 0.5ml on Study days 7 and 28. DPX-Survivac Booster dose of 0.1ml on Study days 84, 140, 196, 252, 308, and 364.

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

Drug: Cyclophosphamide 50mg
Cyclophosphamide 50mg twice daily by mouth, administered 7 days on / 7 days off, stating at study day 0, until study day 384




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. To document changes in tumour volume using waterfall analyses [ Time Frame: 1 Year ]
    Tumor volume measurements will be obtained at multiple time points by adding the volumes of the perpendicular measurements for up to 6 target lesions

  2. To document the toxicity profile [ Time Frame: 1 Year ]
    Number of participants with abnormal laboratory values and/or adverse events related to treatment will be assessed.

  3. To document duration of response using modified Cheson criteria. [ Time Frame: 2 Years ]
  4. To document duration of response using immune related response criteria [ Time Frame: 2 Years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03349450


Contacts
Contact: Neil L Berinstein, MD 4164805248 Neil.Berinstein@sunnybrook.ca

Locations
Canada, Alberta
Tom Baker Cancer Centre - Alberta Health Services Not yet recruiting
Calgary, Alberta, Canada
Contact: Douglas Stewart, MD       Douglas.Stewart@albertahealthservices.ca   
Canada, Ontario
Ottawa Hospital Research Institute Not yet recruiting
Ottawa, Ontario, Canada
Contact: Richard Van der Jagt, MD       RVANDERJAGT@toh.ca   
Sunnybrook Health Sciences Centre, Odette Cancer Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Contact: Neil Berinstein    416-480-5248    neil.berinstein@sunnybrook.ca   
Contact: Lindsay McCaw    416-480-5000 ext 7937    lindsay.mccaw@sunnybrook.ca   
Principal Investigator: Neil L Berinstein, MD, FRCP(C)         
Canada, Quebec
McGill Not yet recruiting
Montréal, Quebec, Canada
Contact: Pierre Laneuville, MD       pierre.laneuville@mcgill.ca   
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
ImmunoVaccine Technologies, Inc. (IMV Inc.)
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Neil L Berinstein, MD Sunnybrook Research Institute

Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT03349450     History of Changes
Other Study ID Numbers: 0891
First Posted: November 21, 2017    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sunnybrook Health Sciences Centre:
DLBCL
Diffuse Large B Cell Lymphoma
Lymphoma
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
refractory
relapsed
checkpoint inhibitor
vaccine
DPX-Survivac

Additional relevant MeSH terms:
Lymphoma
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
Antineoplastic Agents, Alkylating
Pembrolizumab
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Alkylating Agents
Myeloablative Agonists