In Situ Vaccine for Low-Grade Lymphoma: Combination of Intratumoral Flt3L and Poly-ICLC With Low-Dose Radiotherapy

NCT01976585 | Completed Phase 1 DMC

• 1 other identifier: GCO 13-1347
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Our recent trials combining local radiotherapy with intratumoral administration of TLR agonists - referred to as 'in situ vaccination' - for patients with low-grade lymphoma demonstrated safety, induction of anti-tumor CD8 T cell responses and partial and complete remissions of patients' non-irradiated sites of disease with complete remissions lasting from months to more than three years. This iteration of the in situ vaccine approach builds on our prior work in ways that should improve its efficacy, by adding Flt3L and changing the toll-like receptors (TLR) agonist to poly-ICLC -an optimal TLR agonist for the type of dendritic cells (DC) recruited by Flt3L. The vaccine is thus in 3 phases:

1. 1.intratumoral Flt3L administration recruits DC to the tumor
2. 2.low-dose radiotherapy to release tumor antigens
3. 3.intratumoral poly-ICLC administration activates tumor-antigen loaded DC

Conditions

Low-Grade B-cell Lymphoma

Keywords

Intratumoral injections; rhuFlt3L; Flt3L; CDX-301; Vaccine; Poly-ICLC; iNHL; TLR3; Low-Grade B-cell Lymphoma; Follicular; Marginal Zone; SLL; Small lymphocytic

Outcome Measures

Primary Outcomes (1)

• response rate

  Overall objective response rate at time of best response as defined by International Harmonization (Cheson) Criteria.

  week 12

Secondary Outcomes (12)

• safety profile

  week 1

• safety profile

  week 2

• safety profile

  week 4

• safety profile

  week 6

• safety profile

  week 8

Study Arms (1)

rhuFlt3L/CDX-301

EXPERIMENTAL

intratumoral injections on days 1-5 and 8-11. and Poly-ICLC intratumoral injection weekly, weeks 2-8

Drug: rhuFlt3L/CDX-301; Drug: Poly-ICLC

Interventions

rhuFlt3L/CDX-301 DRUG

rhuFlt3L/CDX-301 is a truncated, soluble, recombinant human fms-like tyrosine kinase-3 ligand (Flt3L), expressed in a Chinese hamster ovary cell. RhuFlt3L/CDX-301 is formulated as a sterile solution intended for single-use parenteral administration. Each vial contains 2.5 mg/mL rhuFlt3L/CDX-301 in a 1 mL of buffered solution composed of Sodium Phosphate and Sodium Chloride, with a pH of 7.

rhuFlt3L/CDX-301

Poly-ICLC DRUG

Poly-ICLC is supplied by Oncovir in single-dose vials containing 1 mL of 2 mg/mL opalescent white suspension. Each milliliter of Poly-ICLC for injection contains 2 mg/mL poly-IC, 1.5 mg/mL poly-L-lysine, and 5 mg/mL sodium carboxymethylcellulose in 0.9% sodium chloride solution and adjusted to pH 7.6-7.8 with sodium hydroxide.

Also known as: Hiltonol

rhuFlt3L/CDX-301

Eligibility Criteria

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

You may qualify if:

• Biopsy-confirmed low-grade B-cell lymphoma or cutaneous T cell lymphoma; specifically, follicular grade 1, 2, or 3A, marginal zone or small lymphocytic lymphoma, or mycosis fungoides of any initial stage. Patients in cohort A must be relapsed/refractory after at least one prior systemic therapy and patients in cohort B must have had no prior systemic therapy.
• Patients must have at least one site of disease that is accessible for intratumoral injection percutaneously (e.g. inguinal, axillary, cervical, or subcutaneous).
• Tumor specimens must be available for immunological studies, either from a previous biopsy or a new biopsy obtained before the initiation Day 1 of the study.
• Patients must have measurable disease other than the injection site or biopsy site, i.e. greater than 1.5 cm bi-dimensionally on standard computed tomography imaging.
• ECOG Performance Status of 1 or better (corresponds to Karnofsky Performance Status (KPS) of ≥ 70)
• Patients must be 18 years of age or older.
• Adequate bone marrow function: WBC ≥ 2,000/μL; platelet count ≥ 75,000/mm3; ANC ≥ 1000/μL.
• Adequate renal function: serum creatinine ≤ 2.0mg/dL.
• Adequate hepatic function: bilirubin ≤ 1.5 mg/dL; SGOT/SGPT \< 3 x upper limit of normal
• Required wash out periods for prior therapy (for cohort B):
• Topical therapy: 2 weeks
• Chemotherapy: 4 weeks
• Radiotherapy: 4 weeks
• Other investigational therapy: 4 weeks
• Rituximab: 12 weeks

You may not qualify if:

• Pre-existing autoimmune or antibody -mediated disease including: systemic lupus, erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia, history of uveitis. Patients with controlled thyroid disease, or the presence of auto-antibodies without clinical autoimmune disease, are permitted on study.
• Known history of human immunodeficiency virus (HIV).
• Patients with active infection.
• Known CNS metastases.
• Prior malignancy (active within 5 years of screening) except basal cell or completely excised non-invasive squamous cell carcinoma of the skin, or in situ squamous cell carcinoma of the cervix.
• History of allergic reactions to compounds of similar composition to either CDX-301 or poly-ICLC.
• Current anticoagulant therapy. (ASA ≤ 325 mg per day is allowed.).
• Significant cardiovascular disease (i.e. NYHA class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias).
• Pregnant or lactating.
• Any other medical history, including laboratory abnormalities, deemed by the investigator to be likely to interfere with their participation in the study, or to interfere with the interpretation of the results.

Sponsors & Collaborators

• Joshua Brody: lead
• Celldex Therapeutics: collaborator

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Related Publications (11)

• Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani RH, Kim YH, Hoppe RT, Knox SJ, Shin LK, Wapnir I, Tibshirani RJ, Levy R. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol. 2010 Oct 1;28(28):4324-32. doi: 10.1200/JCO.2010.28.9793. Epub 2010 Aug 9.

  PMID: 20697067 BACKGROUND

• Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, Morales A, Abdulla F, Xing L, Navi D, Tibshirani RJ, Advani RH, Lingala B, Shah S, Hoppe RT, Levy R. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study. Blood. 2012 Jan 12;119(2):355-63. doi: 10.1182/blood-2011-05-355222. Epub 2011 Nov 1.

  PMID: 22045986 BACKGROUND

• Li J, Song W, Czerwinski DK, Varghese B, Uematsu S, Akira S, Krieg AM, Levy R. Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J Immunol. 2007 Aug 15;179(4):2493-500. doi: 10.4049/jimmunol.179.4.2493.

  PMID: 17675511 BACKGROUND

• Link BK, Ballas ZK, Weisdorf D, Wooldridge JE, Bossler AD, Shannon M, Rasmussen WL, Krieg AM, Weiner GJ. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J Immunother. 2006 Sep-Oct;29(5):558-68. doi: 10.1097/01.cji.0000211304.60126.8f.

  PMID: 16971811 BACKGROUND

• Chen W, Chan AS, Dawson AJ, Liang X, Blazar BR, Miller JS. FLT3 ligand administration after hematopoietic cell transplantation increases circulating dendritic cell precursors that can be activated by CpG oligodeoxynucleotides to enhance T-cell and natural killer cell function. Biol Blood Marrow Transplant. 2005 Jan;11(1):23-34. doi: 10.1016/j.bbmt.2004.08.004.

  PMID: 15625541 BACKGROUND

• Zhang YL, Wei YJ, Deng YC, Wang YD, Liu CZ, Su L, Yang KG, Chen SS. Human Flt3 ligand from Pichia pastoris inhibits growth of lymphoma and colon adenocarcinoma in mice. J Exp Ther Oncol. 2006;5(3):161-6.

  PMID: 16528967 BACKGROUND

• Esche C, Subbotin VM, Maliszewski C, Lotze MT, Shurin MR. FLT3 ligand administration inhibits tumor growth in murine melanoma and lymphoma. Cancer Res. 1998 Feb 1;58(3):380-3.

  PMID: 9458075 BACKGROUND

• Giantonio BJ, Hochster H, Blum R, Wiernik PH, Hudes GR, Kirkwood J, Trump D, Oken MM. Toxicity and response evaluation of the interferon inducer poly ICLC administered at low dose in advanced renal carcinoma and relapsed or refractory lymphoma: a report of two clinical trials of the Eastern Cooperative Oncology Group. Invest New Drugs. 2001;19(1):89-92. doi: 10.1023/a:1006458232384.

  PMID: 11291838 BACKGROUND

• Black PL, Hartmann D, Pennington R, Phillips H, Schneider M, Tribble HR, Talmadge JE. Effect of tumor burden and route of administration on the immunotherapeutic properties of polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethyl cellulose [Poly(I,C)-LC]. Int J Immunopharmacol. 1992 Nov;14(8):1341-53. doi: 10.1016/0192-0561(92)90005-6.

  PMID: 1464467 BACKGROUND

• Storch E, Kirchner H, Schirrmacher V. Prolongation of survival of mice bearing the Eb and ESb lymphoma by treatment with interferon inducers alone or in combination with Corynebacterium parvum. Cancer Immunol Immunother. 1986;23(3):179-84. doi: 10.1007/BF00205647.

  PMID: 2431778 BACKGROUND

• Fresa KL, Korngold R, Murasko DM. Induction of natural killer cell activity of thoracic duct lymphocytes by polyinosinic-polycytidylic acid (poly(I:C)) or interferon. Cell Immunol. 1985 Apr 1;91(2):336-43. doi: 10.1016/0008-8749(85)90231-x.

  PMID: 2581698 BACKGROUND

MeSH Terms

Interventions

poly ICLC

Study Officials

• Joshua Brody, MD

  Icahn School of Medicine at Mount Sinai

  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 INVESTIGATOR
• PI Title: Director, Lymphoma Immunotherapy Program

Study Record Dates

• First Submitted: October 30, 2013
• First Posted: November 6, 2013
• Study Start: January 3, 2014
• Primary Completion: November 20, 2020
• Study Completion: November 20, 2020
• Last Updated: September 22, 2022

Record last verified: 2022-09

Locations

US (1)