Personalized Tumor Vaccine Strategy and PD-1 Blockade in Patients With Follicular Lymphoma

Follicular Lymphoma Clinical Trial

Official title:

Pilot Study of a Personalized Tumor Vaccine Strategy and PD-1 Blockade in Patients With Follicular Lymphoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03121677
• Other study ID #: 201804151
• Status: Terminated
• Phase: Phase 1
• Start date: October 16, 2018
• Est. completion date: August 7, 2023

Study information

• Verified date: August 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Follicular lymphoma (FL) has a number of effective standard of care therapies; however, FL is not currently considered curable. Therefore, designing well tolerated therapies without cumulative and long-term toxicity is critical. This is a pilot safety and feasibility study that combines a personalized tumor vaccine with nivolumab for the treatment of FL. Patients who demonstrate progression on this study may be treated with rituximab (or another monoclonal antibody against CD20) in addition to vaccine therapy with nivolumab at the discretion of treating physician if clinically indicated.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: August 7, 2023
• Est. primary completion date: September 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed follicular lymphoma, grade 1-3a
• Patients who have relapsed after at least 1 prior anti-lymphoma therapy that include anti-CD20 monoclonal antibody and an alkylator chemotherapy agent, or at least 2 prior anti-lymphoma therapies that include anti-CD20 monoclonal antibody, may be included
• Anti-CD20 mAb-naïve or anti CD20 mAb-sensitive (defined as progression of FL = 6 months following prior anti-CD20 mAb containing therapy).
• Presence of measurable disease according to the 2014 Lugano Classification
• Disease course appropriate for therapy initiation approximately 4-5 months from enrollment per treating physician.
• Tumor site amenable to a) excisional biopsy or b) approximately 12 core biopsies from lymph node or extranodal site(s) or other site of lymphoma or c) other surgical procedure to provide adequate lymphoma sample for TSMA sequencing and screening.
• At least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status = 1
• Normal bone marrow and organ function as defined below:
• Absolute neutrophil count = 1,000/mcl
• Platelets = 100,000/mcl
• Total bilirubin = 1.5 x ULN
• AST, ALT = 3.0 x ULN
• Creatinine clearance = 50 mL/min (calculated by the Cockcroft-Gault or via 24-hour urine collection)
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Known current or previous histologic transformation from indolent non-Hodgkin lymphoma to diffuse large B-cell lymphoma or other aggressive lymphoma histology.
• Any anti-lymphoma treatment within 6 months' treatment initiation.
• Prior therapy with anti-PD-1, PD-L1, or PD-L2 agent.
• Diagnosis of a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Live vaccine within 30 days prior to treatment initiation.
• Prior organ allograft or allogeneic transplantation.
• Known central nervous system (CNS) involvement with lymphoma.
• Tested positive for hepatitis B surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• Known history of HIV or AIDS.
• History of concurrent malignancy requiring active therapy or prior history of another malignancy within 5 years
• Active, known, or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in absence of an external trigger.
• Currently receiving any other investigational agents.
• A history of allergic reactions or significant toxicity attributed to compounds of similar chemical or biologic composition to anti-CD20 mAbs, anti-PD-1 mAbs, or TLR agonists.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Women who are pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of nivolumab.

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

Biological:
• Personalized tumor vaccine
Cycle 12 vaccine administration is optional The peptides comprising the vaccine are reconstituted in up to 4 pools with 5 peptides per pool (A, B, C, and D) . At each vaccination time point, each of the up to four pools will be administered to one of the four limbs (A - Right Arm, B - Left Arm, C - Right Leg, D - Left Leg) by subcutaneous injection.

Drug:
• Poly ICLC
-The personalized tumor vaccine will be co-administered with poly-ICLC.

Biological:
• Nivolumab
-Nivolumab will be administered at a dose of 240 mg intravenously

Procedure:
• Peripheral blood draws
-Time of biopsy, during the pre-treatment check (any time before cycle 1 day 1), Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, Cycle 12 Day 1, Time of response, and Time of progression or relapse
• Leukapheresis
Prior to the initiation of treatment and up to five days prior to treatment on cycle 6 day 1, patients will undergo apheresis according to standard institutional procedures for non-mobilized collection. Peripheral blood leukocytes will be cryopreserved for later assessment for the presence of T-cells that recognize tumor specific mutant antigens and immunophenotype, and the presence of other lymphocytes or regulatory populations.

Biological:
• Rituximab
-Other anti-CD20 mAb treatment can be used

Procedure:
• Biopsy
-Biopsies on lymph node or extranodal site(s) are to be obtained at: screening (only after the patient is deemed eligible; during cycle 2 (after treatment on C2D15 and prior to treatment on C3D1); disease relapse or progression (if this occurs)

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility and safety of vaccine in combination with nivolumab +/1 anti-CD20 monoclonal antibody therapy as measured by the number of participants whose personal vaccines can be manufactured and delivered without unacceptable toxicity	-Unacceptable toxicity will be described as inability to receive further therapy due to toxicities of therapy as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or the occurrence of other toxicities deemed to be at sufficiently high risk to patients by the principal investigator	Through 6 months following the first treatment of the last patient enrolled (approximately 54 months)
Secondary	Overall response rate (ORR)	ORR = number of participants with complete response + number of participants with partial response; Overall response rates will be compared between participants who received anti-CD20 mAb treatment (rituximab) versus those participants who did not receive anti-CD20 mAb treatment	Through 5 years after completion of treatment (approximately 111 months)
Secondary	Complete response (CR) rate	CR rates will be compared between participants who received anti-CD20 mAb treatment (rituximab) versus those participants who did not receive anti-CD20 mAb treatment; CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.; London Deauville score of 1 and 2 in lymph nodes and extra lymphatic sites is considered to represent complete metabolic response. A London Deauville score 3 in the post treatment PET scan may be considered to represent complete metabolic response especially if it is not higher than the surrounding normal physiologic uptake.; No evidence of FDG avid disease in the bone marrow; No new lesions; If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy.	Through 5 years after completion of treatment (approximately 111 months)
Secondary	Duration of response	Duration of responses will be compared between participants who received anti-CD20 mAb treatment (rituximab) versus those participants who did not receive anti-CD20 mAb treatment; Duration of response = time from first vaccine dose to first evidence of disease progression in participants with at least one response of CR, PR, or SD	Through 5 years after completion of treatment (approximately 111 months)
Secondary	Progression-free survival (PFS)	PFS will be compared between participants who received anti-CD20 mAb treatment (rituximab) versus those participants who did not receive anti-CD20 mAb treatment; PFS: time from first CR, PR, or SD response to disease progression, death, or last follow-up; PD: London Deauville score of 4 or 5 in individual target nodes/masses with an increase in intensity of uptake from the baseline and/or new FDG avid foci consistent with lymphoma at interim or end of treatment assessment; New FDG avid foci of extranodal disease consistent with lymphoma. If there is concern regarding the etiology of the new lesions, biopsy or interval scan may be considered.; New or recurrent FDG avid foci in the bone marrow	Through 5 years after completion of treatment (approximately 111 months)
Secondary	Overall survival (OS)	OS will be compared between participants who received anti-CD20 mAb treatment (rituximab) versus those participants who did not receive anti-CD20 mAb treatment; OS: time from first vaccine dose to death or last follow-up	Through 5 years after completion of treatment (approximately 111 months)
Secondary	Partial response (PR) rate	Partial response rates will be compared between participants who received anti-CD20 mAb treatment (rituximab) versus those participants who did not receive anti-CD20 mAb treatment; PR: London Deauville score of 4 or 5 in lymph nodes and extra lymphatic sites with reduced uptake compared with the baseline and residual mass(es) of any size on interim scan; Residual bone marrow uptake higher than the uptake in the normal marrow but reduced when compared with baseline If there are persistent focal changes in the marrow in the context of a nodal response consideration should be given to further evaluation with MRI or biopsy or an interval scan; No new lesions	Through 5 years after completion of treatment (approximately 111 months)

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine