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
Pembrolizumab 200 mg will be administered every 3 weeks for up to one year or until disease
progression, whichever occurs first.
This is a Phase 2, non-randomized, open-label, uncontrolled, efficacy and safety trial.
Participants will receive 2 priming injections (0.5ml) of DPX-Survivac 3 weeks apart on Study
Days 7 and 28. In addition, up to 6 maintenance injections (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 participant is removed from the trial prior to the completion of at least 4 doses of
Pembrolizumab and 3 injections of DPX-Survivac, that particiapnt may be replaced to determine
the efficacy of treatment in a minimum of 16 participants.
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 DPX Survivac will have on the participants immune system. During all treatment cycles a
physical exam and questions about the participants general health will be performed.
Participants 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 again at
end of study or study withdrawal for all participants.
A follow-up tumour biopsy will be requested between study day 77-83 for participants 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.
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Male or female 18+ years of age on day of signing informed consent and of any racial
or ethnic group
A. histologically proven DLBCL with recurrence after first, second or tertiary
treatment regimens for DLBCL or,
B. evidence of transformed lymphoma with past history of indolent lymphoma with
current biopsy showing DLBCL) or,
C. 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)
4. Has had:
A. recurrence requiring therapy 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), CART therapy, or aggressive
second line combination therapy or,
B. partial response or measureable disease after first line therapy (who are not
candidates for ASCT) or after second or third line therapy without disease progression
C. recurrence any time after non-aggressive combination or single agent therapy with
or without Rituximab (i.e. CVP, CHL or, VP16) for first, second or third line disease
D. for subjects with transformed lymphoma, a treatment for indolent lymphoma within
the last 2 years
5. Have at least one measurable site of disease based on Cheson Criteria using standard
6. Be willing to provide tissue from a newly obtained (up to 3 months + 7 days prior to
Study 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.
7. Have a performance status of 0-1 on the ECOG Performance Scale.
8. Demonstrate adequate organ function as defined in Table 2, within 48 hours prior to
receiving the first dose of study medication (SD0). Patients with abnormal liver
enzymes of up to 5 times the upper limit of normal and/or reduced GFR of 50-100%
normal range can be considered for enrolment if the alteration is due to lymphoma.
9. 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.
10. A life expectancy > 6 months.
11. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 48 hours prior to receiving the first dose of study medication (SD0).
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
12. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.
13. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through to 120 days from the last dose of study
14. Ability to comply with protocol requirements.
The subject must be excluded from participating in the trial if the subject:
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 had previous allogeneic stem cell transplant
6. Has known active TB (Bacillus Tuberculosis)
7. Hypersensitivity to pembrolizumab or any of its excipients.
8. Has had a prior anti-cancer monoclonal antibody (mAb) within 21 days prior to SD0 or
who has not recovered (i.e., ≤ Grade 1) from adverse events due to agents administered
more than 21 days earlier.
9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 21 days prior to SD0. Subjects must have recovered from all acute toxicities
from prior treatments; peripheral neuropathy must be ≤ grade 2.
10. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include in situ cervical cancer, basal cell carcinoma of the skin or
squamous cell carcinoma of the skin that has undergone potentially curative therapy.
11. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. 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 for at least 35 days prior to trial treatment.
12. Progressive CNS lymphoma requiring treatment within 35 days prior to SD0.
13. Has history of active autoimmune disease that has required systemic treatment in the
past 2 years (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.
14. Has known history of, or any evidence of active, non-infectious pneumonitis.
15. Thyroiditis within the past 5 years.
16. Has an active infection requiring systemic therapy. 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.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. 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 after last
dose of study medication.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
22. 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 (Heptavir
23. Patients who have received prior survivin based vaccines.
24. Acute or chronic skin disorders that will interfere with subcutaneous injection of the
DPX-Survivac or subsequent assessment of potential skin reactions.
25. 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.
26. Allergies to any vaccine, that after discussion with the medical monitor are serious
enough to warrant exclusion from this study.
27. Received a live vaccine within 30 days of planned start of study therapy. 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