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Low-Grade B-cell LymphomaPhase 1/2NCT01976585

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

A Phase 1/2 study testing rhuFlt3L/CDX-301 and Poly-ICLC in people with Low-Grade B-cell Lymphoma, run by Joshua Brody at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Low-Grade B-cell Lymphoma
What is being tested?
rhuFlt3L/CDX-301 and Poly-ICLC
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
21 participants
Where
1 siteUnited States
Study dates
3 Jan 2014to 20 Nov 2020
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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
  • Patients of reproductive potential and their partners must agree to use an effective (> 90% reliability) form of contraception during the study and for 4 weeks following the last study drug administration.
  • Women of reproductive potential must have negative urine pregnancy test.
  • Life expectancy greater than 4 months.
  • Able to comply with the treatment schedule.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Icahn School of Medicine at Mount Sinai

    New York, New York, 10029

Other trials in United States

About this study

Official title: A Phase I/II Study of Intratumoral Injection of rhuFlt3L/CDX-301 and Poly-ICLC in Combination With Low-Dose Radiotherapy in Low-Grade B-cell Lymphomas

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

Lymphomas comprise the 5th most common cancer in the U.S. with approximately 80,000 new cases diagnosed in the U.S. each year. Low-grade B-cell lymphomas are the most prevalent subtype amongst these and are considered incurable with standard therapies. Chemotherapy and monoclonal antibody therapy induce temporary remissions, though disease generally recurs, becomes progressively more resistant to therapy and ultimately therapy-resistant. Standard therapies prolong survival, though there is no standard of care regarding when to initiate therapy (versus observation) or the optimal sequence of different therapies. Novel therapies are needed with distinct mechanisms and with greater tolerability profiles. Immunotherapy has a long precedent of being able to cure low-grade lymphomas with allogeneic transplant being curative in a proportion of chemo-refractory patients, though the morbidity of this procedure reduces its broader utilization.

Previously, we completed four trials combining local radiotherapy (a standard of care for these diseases) with intratumoral administration of TLR agonists - an approach we refer to as 'in situ vaccination' for patients with previously untreated or relapsed/refractory low-grade lymphoma. We demonstrated safety, induction of anti-tumor CD8 T cell responses and partial and complete remissions of patients' non-irradiated sites of disease.1, 2 The most recent trials compared previously untreated versus relapsed/refractory patients receiving the same therapy and observed superior responses in the former group, presumably due to immunosuppressive effects of prior treatments in the latter group. The in situ vaccine is premised on pre-clinical data showing this approach to be superior to systemic TLR agonist delivery3 and our clinical results reproduce this finding; in situ vaccination yields superior response rates as compared to trials of systemic TLR agonist therapy for lymphoma.4

This iteration of the in situ vaccine approach builds on our prior work in ways that should improve its efficacy, by making two changes to the prior approach:

  1. intratumoral administration of rhuFlt3L/CDX-301 to recruit dendritic cells to the tumor site
  2. intratumoral administration of poly-ICLC. Flt3L has been safely administered to patients with lymphoma5 and -pre-clinically- has been shown to induce tumor leukocyte infiltration and regression of lymphoma tumors.6, 7 A total of 36 healthy volunteers and 294 cancer patients were treated including only industry-sponsored studies with the prior formulation of this agent (AMG 949) with excellent tolerability and 30 healthy volunteers were recently treated with the current formulation (CDX-301), again with excellent tolerability.

Poly-ICLC has been safely administered to patients with lymphoma8 and -pre-clinically- has been shown to induce natural killer (NK) cell cytolytic activity and regression of lymphoma tumors.9-11 Over 600 healthy volunteers and cancer patients in 17 trials have been treated with comparable doses of poly-ICLC as that used here with excellent tolerability.

Being tested
rhuFlt3L/CDX-301, Poly-ICLC
Keywords
Intratumoral injections, rhuFlt3L, Flt3L, CDX-301, Vaccine, Poly-ICLC, iNHL, TLR3, Low-Grade B-cell Lymphoma, Follicular, Marginal Zone, SLL, Small lymphocytic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rhuFlt3L/CDX-301Drug

    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.

  • Poly-ICLCDrug

    Also called Hiltonol

    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.

Study groups in NCT01976585
Study groupRoleWhat they receive
rhuFlt3L/CDX-301Experimentalintratumoral injections on days 1-5 and 8-11. and Poly-ICLC intratumoral injection weekly, weeks 2-8
Receives: Drug: rhuFlt3L/CDX-301; Drug: Poly-ICLC

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. response rate

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

    Measured: week 12

Secondary outcomes (12)

  1. safety profile

    Patient reported and clinical observation of adverse events, including changes in physical examination, peripheral blood hematology and serum chemistry

    Measured: week 1

  2. safety profile

    Patient reported and clinical observation of adverse events, including changes in physical examination, peripheral blood hematology and serum chemistry

    Measured: week 2

  3. safety profile

    Patient reported and clinical observation of adverse events, including changes in physical examination, peripheral blood hematology and serum chemistry

    Measured: week 4

  4. safety profile

    Patient reported and clinical observation of adverse events, including changes in physical examination, peripheral blood hematology and serum chemistry

    Measured: week 6

  5. safety profile

    Patient reported and clinical observation of adverse events, including changes in physical examination, peripheral blood hematology and serum chemistry

    Measured: week 8

  6. safety profile

    Patient reported and clinical observation of adverse events, including changes in physical examination, peripheral blood hematology and serum chemistry

    Measured: week 12

  7. tumor-specific immune response

    Pre- to post-treatment induction of systemic (peripheral blood) tumor-specific immune response.

    Measured: baseline

  8. tumor-specific immune response

    Pre- to post-treatment induction of systemic (peripheral blood) tumor-specific immune response.

    Measured: week 2

  9. tumor-specific immune response

    Pre- to post-treatment induction of systemic (peripheral blood) tumor-specific immune response.

    Measured: week 4

  10. tumor-specific immune response

    Pre- to post-treatment induction of systemic (peripheral blood) tumor-specific immune response.

    Measured: week 6

  11. tumor-specific immune response

    Pre- to post-treatment induction of systemic (peripheral blood) tumor-specific immune response.

    Measured: week 8

  12. tumor-specific immune response

    Pre- to post-treatment induction of systemic (peripheral blood) tumor-specific immune response.

    Measured: week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Nov 2013 (estimated)
  2. Study start3 Jan 2014
  3. Primary completion20 Nov 2020
  4. Study completion20 Nov 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
21 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01976585
Sponsor's protocol ID
GCO 13-1347
Status last verified
Sep 2022
First submitted
30 Oct 2013
Last updated
22 Sep 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 20697067

  • 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.

    PubMed 22045986

  • 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.

    PubMed 17675511

  • 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.

    PubMed 16971811

  • 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.

    PubMed 15625541

  • 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.

    PubMed 16528967

  • 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.

    PubMed 9458075

  • 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.

    PubMed 11291838

  • 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.

    PubMed 1464467

  • 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.

    PubMed 2431778

  • 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.

    PubMed 2581698

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing rhuFlt3L/CDX-301 and Poly-ICLC in people with Low-Grade B-cell Lymphoma, run by Joshua Brody at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

response rate (time frame: week 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01976585, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2022.

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