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

NCT03121677 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: 201804151
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Follicular Lymphoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Overall response rate (ORR)

  Through 5 years after completion of treatment (approximately 111 months)

• Complete response (CR) rate

  Through 5 years after completion of treatment (approximately 111 months)

• Duration of response

  Through 5 years after completion of treatment (approximately 111 months)

• Progression-free survival (PFS)

  Through 5 years after completion of treatment (approximately 111 months)

• Overall survival (OS)

  Through 5 years after completion of treatment (approximately 111 months)

Study Arms (1)

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

EXPERIMENTAL

* 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; Drug: Poly ICLC; Biological: Nivolumab; Procedure: Peripheral blood draws; Procedure: Leukapheresis; Biological: Rituximab; Procedure: Biopsy

Interventions

Personalized tumor vaccine BIOLOGICAL

* 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.

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Poly ICLC DRUG

-The personalized tumor vaccine will be co-administered with poly-ICLC.

Also known as: poly-ICLC

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Nivolumab BIOLOGICAL

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

Also known as: Opdivo

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Peripheral blood draws PROCEDURE

-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

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Leukapheresis PROCEDURE

* 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.

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Rituximab BIOLOGICAL

-Other anti-CD20 mAb treatment can be used

Also known as: Rituxan

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Biopsy PROCEDURE

-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)

Nivolumab/Poly-ICLC/Vaccine/+/- Rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Ramirez CA, Becker-Hapak M, Singhal K, Russler-Germain DA, Frenkel F, Barnell EK, McClain ED, Desai S, Schappe T, Onyeador OC, Kudryashova O, Belousov V, Bagaev A, Ocheredko E, Kiwala S, Hundal J, Skidmore ZL, Watkins MP, Mooney TB, Walker JR, Krysiak K, Gomez F, Fronick CC, Fulton RS, Schreiber RD, Mehta-Shah N, Cashen AF, Kahl BS, Ataullakhanov R, Bartlett NL, Griffith M, Griffith OL, Fehniger TA. Neoantigen landscape supports feasibility of personalized cancer vaccine for follicular lymphoma. Blood Adv. 2024 Aug 13;8(15):4035-4049. doi: 10.1182/bloodadvances.2022007792.

  PMID: 38713894 DERIVED

Related Links

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

MeSH Terms

Conditions

Lymphoma, Follicular

Interventions

poly ICLC; Nivolumab; Leukapheresis; Rituximab; Biopsy

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Antibodies, Monoclonal, Murine-Derived; Cytodiagnosis; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Study Officials

• Nancy Bartlett, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 17, 2017
• First Posted: April 20, 2017
• Study Start: October 16, 2018
• Primary Completion: September 24, 2020
• Study Completion: August 7, 2023
• Last Updated: August 14, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)