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

Study Overview
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Brief Summary
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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.

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

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Biological: Personalized tumor vaccine
* Drug: Poly ICLC
* Biological: Nivolumab
* Procedure: Peripheral blood draws
* Procedure: Leukapheresis
* Biological: Rituximab
* Procedure: Biopsy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: For the first three patients treated on study therapy, treatment of each subsequent patient will not be allowed until the prior patient has completed Cycle 1. If no unexpected adverse events attributed to the combination therapy are observed, after the third patient completes Cycle 1, treatment initiation may occur without restrictions for the remaining patients.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab<br>All cycles are 4 weeks (wks), with nivolumab every 2 wks during Cycles 1-6 & every 4 wks during Cycles 7-12 & vaccine on Cycle 1 Days 1, 4, 8, 15; Cycle 2 Day 1; and then on Day 1 of Cycles 4, 6, 8, 10, 12 After 2 cycles, restaging will be performed, & patients with CR, PR, or SD will continue on nivolumab + vaccine. Patients with evidence of PD may initiate anti-CD20 mAb therapy (drug to be determined by the treating physician) weekly for 4 wks during Cycle 3, followed by a dose on Day 1 of every other cycle (Cycles 6, 8, 10, and 12). After 6 cycles, restaging will be performed again, and patients with CR, PR, or SD will continue nivolumab + vaccine. Patients with PD at that time point (but not treated with anti-CD20 mAb therapy thus far on this protocol) will initiate anti-CD20 mAb (drug to be determined by the treating physician) therapy weekly for 4 wks during Cycle 7, followed by a dose Day 1 of Cycles 10 & 12 & 2 additional doses 8 wks apart. | Biological: Personalized tumor vaccine<br>* 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.<br>Drug: Poly ICLC<br>* -The personalized tumor vaccine will be co-administered with poly-ICLC.<br>* Other names: poly-ICLC;Biological: Nivolumab<br>* -Nivolumab will be administered at a dose of 240 mg intravenously<br>* Other names: Opdivo;Procedure: Peripheral blood draws<br>* -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<br>Procedure: Leukapheresis<br>* 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.<br>Biological: Rituximab<br>* -Other anti-CD20 mAb treatment can be used<br>* Other names: Rituxan;Procedure: Biopsy<br>* -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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) |