Clinical Trials /

Vaccination With Flt3L, Radiation, and Poly-ICLC

NCT03789097

Description:

This is a combination of 4 therapies, three of which are used to treat a single "target site" of your cancer (such as a lymph node or a single tumor), and the 4th is given directly into the blood stream (intravenous or "IV"). 1. Radiation: The target site --lymph node or tumor (the one what will be injected) --will get two small treatments of radiation. Radiation is often times used to shrink and kill tumors in patients with certain types of lymphoma, breast cancer and head and neck cancer, however, the dose of radiation that you will receive --one dose on day one of the clinical trial and one dose on day two --is 10 to 20 time less radiation that you would receive for treatment of these cancers. 2. Flt3L/CDX-301 is an immune cell growth factor, similar to white blood cell growth factors (Neupogen or Neulasta) or red blood cell growth factors (EPO or Epogen) that you may have received to help protect your blood cells previously. Flt3L causes your body to make more immune cells, specifically a type of immune cell called "dendritic cells". 3. Poly-ICLC is an immune cell activating factor. Its function is to turn on the immune cells that have been brought to the tumor by Flt3L. 4. Pembrolizumab is an antibody (a type of human protein) that is being tested to see if it will allow the body's immune system to kill your tumor cells. Pembrolizumab is approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with many different types of cancer including head and neck cancer. Pembrolizumab is not FDA approved to treat patients with non-Hodgkin's lymphoma or metastatic breast cancer, as it has not been effective at treating these cancers when used alone. While most people do not have immediate side effects when this medication is given, it has the ability to cause side effects for.

Related Conditions:
  • Breast Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vaccination With Flt3L, Radiation, and Poly-ICLC
  • Official Title: In Situ Vaccination With Flt3L, Radiation, and Poly-ICLC Combined With Pembrolizumab in Patients With Non-Hodgkin's Lymphoma, Metastatic Breast Cancer, and Head and Neck Squamous Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: GCO 19-0477
  • SECONDARY ID: GCO 18-2394
  • NCT ID: NCT03789097

Conditions

  • Non-Hodgkin's Lymphoma
  • Metastatic Breast Cancer
  • Head and Neck Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaCombination therapy
Flt3LCDX-301, Recombinant Human Flt3 LigandCombination therapy
Poly ICLCHiltonolCombination therapy

Purpose

This is a combination of 4 therapies, three of which are used to treat a single "target site" of your cancer (such as a lymph node or a single tumor), and the 4th is given directly into the blood stream (intravenous or "IV"). 1. Radiation: The target site --lymph node or tumor (the one what will be injected) --will get two small treatments of radiation. Radiation is often times used to shrink and kill tumors in patients with certain types of lymphoma, breast cancer and head and neck cancer, however, the dose of radiation that you will receive --one dose on day one of the clinical trial and one dose on day two --is 10 to 20 time less radiation that you would receive for treatment of these cancers. 2. Flt3L/CDX-301 is an immune cell growth factor, similar to white blood cell growth factors (Neupogen or Neulasta) or red blood cell growth factors (EPO or Epogen) that you may have received to help protect your blood cells previously. Flt3L causes your body to make more immune cells, specifically a type of immune cell called "dendritic cells". 3. Poly-ICLC is an immune cell activating factor. Its function is to turn on the immune cells that have been brought to the tumor by Flt3L. 4. Pembrolizumab is an antibody (a type of human protein) that is being tested to see if it will allow the body's immune system to kill your tumor cells. Pembrolizumab is approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with many different types of cancer including head and neck cancer. Pembrolizumab is not FDA approved to treat patients with non-Hodgkin's lymphoma or metastatic breast cancer, as it has not been effective at treating these cancers when used alone. While most people do not have immediate side effects when this medication is given, it has the ability to cause side effects for.

Detailed Description

      Phase 1 and Phase 2 will occur sequentially:

      Phase 1 is the preliminary safety assessment portion of the study, which will follow a
      modified 3 + 3 design to assess toxicity. The trial would be held for review should there be
      more than 1 dose-limiting toxicity (DLT) observed within the first 3-6 patients. The toxicity
      of the in situ vaccine without pembrolizumab (ongoing and previous trials) has been minimal,
      limited to transient febrile response to the intratumoral Toll-like receptor (TLR) ligand
      poly-ICLC, typically resolving with oral acetaminophen. As such, the primary objective of
      Phase 1 is to assess the safety of the addition of pembrolizumab to this in situ vaccine
      protocol. In Phase 1, patients will only be enrolled at the lead institution (Mount Sinai).
      After enrollment of the initial 3 patients, enrollment will pause until all three patients
      have completed cycle 1 of pembrolizumab (DLT evaluation window is 63 days from initiation of
      in situ vaccine). During the pause, new patients may be consented and screened, but not
      initiated on therapy. If 1 or no DLTs are observed in the first 3 patients, an additional 3
      patients will be enrolled. The regimen will be considered safe (in order to progress to Phase
      2) if no more than 1 out of 6 patients experience a DLT. If two or more DLTs are observed at
      any point in Phase 1 then accrual will be stopped for protocol review by Data Safety
      Monitoring Board, PIs and sponsor for possibility of protocol amendment.

      Phase 2 will follow a Simon's two-stage design. This Phase will proceed only if toxicity is
      acceptable as determined in Phase 1.

      Phase 1/2 design: Patients will be enrolled concurrently into three independent cohorts, with
      patients from Phase 1 evaluated within their subsequent disease-specific cohorts. iNHL, MBC
      and HNSCC often have peripherally accessible tumors amenable to intratumoral injection, and
      have all had relatively modest responses to single-agent checkpoint blockade, so are good
      candidates for this novel combination. Patients will be enrolled regardless of the PD-L1
      staining of their tumor. We will also enroll patients previously exposed to PD-1/PD-L1
      targeted therapies either on a clinical trial or as standard of care (as for HNSCC).

      Cohort A: iNHL including but not limited to chronic lymphocytic leukemia (CLL/SLL),
      follicular lymphoma (FL), and marginal zone lymphoma (MZL). This cohort excludes patients
      with diffuse large B cell lymphoma (DLBCL) and any other lymphoma determined to be
      progressing rapidly by investigator (PI or site PI).

      Cohort B: MBC with peripherally palpable disease amenable to intratumoral injection.

      Cohort C: HNSCC with peripherally palpable disease amenable to intratumoral injection.

      Stage 1: Seven patients will be evaluated in Stage 1 of Phase 2 in each disease-specific
      cohort, inclusive of patients enrolled in Phase 1. If no patient in a cohort achieves a
      response, the study in that cohort will close due to a lack of efficacy. The first seven
      patients in each histology will only be enrolled at Mount Sinai.

      Stage 2: If one or more responses are seen in Stage 1, enrollment of an additional 12
      patients for Cohorts A and B or 11 patients for Cohort C will proceed. These cohorts may be
      also be enrolled at collaborator sites (to be determined).

        -  Cohorts A or B: If at least three out of the 19 patients achieve a response, the
           intervention will be considered promising and worthy of further investigation.

        -  Cohort C: If at least four out of the 18 patients achieve a response, the intervention
           will be considered promising and worthy of further investigation.
    

Trial Arms

NameTypeDescriptionInterventions
Combination therapyExperimentalVaccination with Flt3L, Radiation, and Poly ICLC combined with Pembrolizumab
  • Pembrolizumab
  • Flt3L
  • Poly ICLC

Eligibility Criteria

        Inclusion Criteria:

          -  Have pathologically confirmed iNHL, MBC or HNSCC

          -  Lymphoma subtypes that may be enrolled include small lymphocytic lymphoma

        Exclusion Criteria:

          -  Is currently participating and receiving an investigational therapy (not standard
             therapies) or has participated in a study of an investigational agent and received
             study therapy or used an investigational device within 28 days of the first dose of
             treatment.

          -  Any patients that require immediate treatment or cytoreduction are excluded. Note:
             This is applicable for iNHL, MBC, and HNSCC populations.

          -  Any patient with transformed lymphoma, or patients with grade 3A follicular lymphoma
             are excluded.

          -  MZL patients with gastric MALT lymphomas with disease localized to the stomach are
             excluded, and any patient with disease in a site where injection is determined to be
             high risk.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent
             to ≤ 10mg prednisone will not be excluded.

          -  Hypersensitivity to pembrolizumab, poly-ICLC, Flt3L or any of their excipients.

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 28 days prior to study
             D22 (First dose of pembrolizumab) or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from AEs due to agents administered more than 28 days before initiation of
             in situ vaccine protocol.

          -  Has had prior chemotherapy, targeted small molecule therapy, or RT therapy within 14
             days prior to study D0 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
             AEs due to a previously administered agent. Note: Patients with chronic ≤ Grade 2 AEs
             such as neuropathy are an exception to this criterion and may qualify for the study.

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

          -  If patient received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          -  Has known active central nervous system metastases, leptomeningeal disease and/or
             lymphomatous meningitis. Patients with previously treated brain metastases may
             participate provided they are stable (without evidence of progression by imaging for
             at least 28 days prior to the first dose of trial treatment and any neurologic
             symptoms have returned to baseline), have no evidence of new or enlarging brain
             metastases, and are not using steroids for at least 7 days prior to trial treatment.
             This exception does not include leptomeningeal disease or lymphomatous meningitis,
             which are excluded regardless of clinical stability.

          -  Has active autoimmune disease that has required systemic treatment in the past 1 year
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             systemic treatment. Patients on chronic steroids (more than 4 weeks at stable dose)
             equivalent to ≤ 10mg prednisone will not be excluded.

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Has an active infection requiring systemic therapy at time of enrollment in trial.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical or anal
             cancer, prostate cancer on stable dose of hormonal therapy without rising PSA.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the patient's
             participation for the full duration of the trial, or is not in the best interest of
             the patient to participate, in the opinion of the treating Investigator.

          -  Has known psychiatric or substance abuse disorders that investigator believes would
             interfere with cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment (roughly two and a half years
             after enrollment).

          -  HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART)
             regimen.

          -  Has known active Hepatitis B (e.g., HBV detected by PCR) or active Hepatitis C (e.g.,
             HCV RNA [qualitative] is detected).

          -  History of allogeneic hematopoietic cell transplantation or solid organ
             transplantation.

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity (DLT)
Time Frame:63 days
Safety Issue:
Description:DLTs recorded and graded according to NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03, within DLT evaluation window of 63 days (end of cycle 1 of pembrolizumab) from initiation of in situ vaccine.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:6 months
Safety Issue:
Description:Overall response rate (ORR) as defined as best response achieved within the first 6 months from initiation of trial. ORR is defined as complete remission (CR) or partial remission (PR) in patients as defined by RECIST v1.1 for MBC and HNSCC or as per the RECIL Criteria for patients with lymphoma, determined by Positron emission tomography-computed tomography (PET/CT) or computed tomography (CT) imaging which occurs at 3 month intervals, with the first imaging 3 months following initiation of Flt3L (D0) +/- 2 weeks.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Icahn School of Medicine at Mount Sinai

Trial Keywords

  • Radiation
  • Poly-ICLC
  • Pembrolizumab
  • Lymphoma
  • Breast Cancer
  • Carcinoma

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