DPX-Survivac and Checkpoint Inhibitor in DLBCL

Refractory Diffuse Large B-Cell Lymphoma Clinical Trial

— SPiReL  

Official title:

Phase 2 Study of an Immunotherapeutic Vaccine, DPX-Survivac With Low Dose Cyclophosphamide Administered With a Pembrolizumab in Patients With Persistent or Recurrent/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03273582
• Other study ID #: 0891
• Status: Not yet recruiting
• Phase: Phase 2
• First received: August 25, 2017
• Last updated: August 31, 2017
• Start date: November 2017
• Est. completion date: May 2021

Study information

• Verified date: August 2017
• Source: Sunnybrook Health Sciences Centre
• Contact: Neil L Berinstein, MD
• Phone: 4164805248
• Email: Neil.Berinstein[@]sunnybrook.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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, we will also be drawing blood 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 25
• Est. completion date: May 2021
• Est. primary completion date: May 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subjects with histologically proven recurrent DLBCL. Subjects may have recurrence after primary, secondary or tertiary treatment regimens for DLBCL. 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. Patients with 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 may also be eligible. 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. Patients may have evidence of transformed lymphoma with past history of indolent lymphoma provided current biopsy shows DLBCL. 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.

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

3. Male or female = 18 years of age on day of signing informed consent and of any racial or ethnic group

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

5. 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.

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

7. Demonstrate adequate organ function as defined in Table 2. Adequate organ function should be confirmed 48 hours prior to enrollment. 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.

8. 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.

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

10. A life expectancy > 6 months.

11. 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 (day 0). 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 (Reference Section 6.1.8). 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 study visit.

14. 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. Subjects must have recovered from all acute toxicities from prior treatments; peripheral neuropathy must be = grade 2.

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. 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.

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 (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 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. 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.

17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

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

Related Conditions & MeSH terms

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

Intervention

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.
• 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, until study day 377

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre	ImmunoVaccine Technologies, Inc., Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Standard radiologic criteria (Cheson) will be used to assess overall, complete and partial clinical responses as well as stable disease at multiple time points post treatment.	1 Year
Secondary	To document changes in tumour volume using waterfall analyses	Tumor volume measurements will be obtained at multiple time points by adding the volumes of the perpendicular measurements for up to 6 target lesions	1 Year
Secondary	To document the toxicity profile	Safety will be assessed through patient reported and investigator observed AE's as well as changes in laboratory parameters.	1 Year
Secondary	To document the changes in circulating T cell immune responses to survivin using complimentary methodologies	Survivin-peptide specific T cell immune response will be measured by methods such as ELISpot assay to enumerate T cells that produce molecules associated with anti-tumour immune responses such as IFN-? and/or Granzyme-B. Additional immunological assays such as MHC-peptide multimer staining for survivin-specific CD8+ T cells, or multi-parametric flow cytometry for antigen-activated T cells and their phenotypes may also be performed for select subjects.	1 Year
Secondary	To document changes in T cell subset infiltration in tumor biopsies on treatment compared to pretreatment tumor biopsies.	Immune subsets included CD3, CD4,CD8, CD68, CD4FoxP3, polymorphoculear immune cell will be quantitated multiplex immunohistochemistry and nanostring gene expression analyses. State of activation and immune inhibitory pathways will be quantitated by nano string gene expression analysis	1 Year
Secondary	To document changes in T cell activation and gene expression using nano string technologies in tumor biopsies on treatment compared to pretreatment tumor biopsies.	State of immune activation and immune inhibitory pathways will be quantitated by nano string gene expression analysis	1 year
Secondary	To document duration of response using modified Cheson criteria.	Standard Chasten criteria will be used to document duration of response	2 Year
Secondary	To document duration of response using immune related response criteria	Immune related response criteria will be used to document duration of response	2 year
Secondary	To assess potential biomarkers of immune and clinical response from pre-treatment and on-treatment tumour biopsies.	The quantity of CD3, CD4, CD8, CD68, FoxP3, Pmns, and PDL1+ cells in the initial tumor biopsy will be correlated with objective clinical response rate, Cheson duration of response, Immune response duration of response and increases in survivin specific T cell subsets in the peripheral blood	2 Year