Flt3L, Radiation Therapy, Poly-ICLC, and Pembrolizumab in Treating Patients with Refractory Indolent Non-Hodgkin's Lymphoma, Metastatic Breast Cancer, or Head and Neck Cancer

Status: Active

Description

This phase I / II trial studies the side effects of Flt3L, radiation therapy, poly-ICLC, and pembrolizumab and how well they work in treating patients with indolent non-Hodgkin's lymphoma, breast cancer that has spread to other places in the body, and head and neck cancer that do not respond to treatment. Flt3L causes the body to make more immune cells, specifically a type of immune cell called "dendritic cells". Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Poly-ICLC turns on the immune cells that have been brought to the tumor by Flt3L. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving Flt3L, radiation therapy, poly-ICLC, and pembrolizumab may work better in treating patients compared to Flt3L, radiation therapy, and poly-ICLC alone.

Eligibility Criteria

Inclusion Criteria

  • Have pathologically confirmed iNHL, MBC or HNSCC
  • Lymphoma subtypes that may be enrolled include small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL), follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma
  • All patients have had to have failed at least first line therapy (meaning progressive disease on or following at a minimum one line of therapy)
  • Patients with MBC may be enrolled regardless of hormone receptor or Her2 status on immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH). MBC can include stage 3 disease (such as inflammatory breast cancer) which is deemed unresectable, and only upon progression on or following at least one standard therapy
  • HNSCC patients must have disease that is determined by one of our surgical oncologists to be unresectable, and must have progressed on at least one line of standard therapy
  • Be willing and able to provide written informed consent/assent for the trial
  • Have a performance status of 0, or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days of treatment initiation)
  • Platelets >= 100,000/mcL (within 28 days of treatment initiation)
  • Hemoglobin >= 9 g/dL (within 28 days of treatment initiation)
  • Patients with cytopenias attributable to bone marrow lymphomatous bone marrow involvement per current bone marrow biopsy may be enrolled if other inclusion criteria are me
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for patient with creatinine levels > 1.5 x institutional ULN (within 28 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 ULN (within 28 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for patients with liver metastases (within 28 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (within 28 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants (within 28 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 28 days of treatment initiation)
  • If laboratory criteria are not met due to what the investigator determines to be a biologic cause (e.g. Gilbert’s syndrome causing elevated bilirubin or excessive muscle mass affecting creatinine) or drug-related cause (e.g. elevating in transaminases due to highly active antiretroviral therapy [HAART] therapy, elevated international normalized ratio [INR] due to anticoagulation) then the lab values will not be used to exclude patient from this trial. This determination will be made by site-principal investigator (PI) in conjunction with primary PI
  • Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of pembrolizumab. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female patients of childbearing potential must be willing to use an adequate method of contraception. Contraception should be used for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient
  • Male patients of childbearing potential must agree to use an adequate method of contraception. Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy

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
  • Marginal zone lymphoma (MZL) patients with gastric mucosa-associated lymphoid tissue (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 =< 10 mg 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 day (D) 22 (first dose of pembrolizumab) or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events (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-central nervous system (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 =< 10 mg 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 prostate-specific antigen (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)
  • Human immunodeficiency virus (HIV) positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen
  • Has known active hepatitis B (e.g., hepatitis B virus [HBV] detected by polymerase chain reaction [PCR]) or active hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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–Guerin (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

Locations & Contacts

New York

New York
Icahn School of Medicine at Mount Sinai
Status: Active
Contact: Joshua Brody
Phone: 646-543-2859
Email: joshua.brody@mountsinai.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To evaluate the safety of in situ vaccine with pembrolizumab in patients with indolent non-Hodgkin’s lymphoma (iNHL), metastatic breast cancer (MBC) and head and neck squamous cell carcinoma (HNSCC). (Phase I)

II. Within each disease-specific cohort assess patients for regression of disease in response to in situ vaccine and pembrolizumab in patients with iNHL, MBC and HNSCC. (Phase II)

SECONDARY OBJECTIVES:

I. Overall response rate (ORR) at 12 and 24 months of evaluation from initiation of trial. (Phase II)

II. ORR as per immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. (Phase II)

III. Progression free survival (PFS) defined as the duration of time from initial recombinant Flt3 ligand (Flt3L) administration to any progression per by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and iRECIST criteria for MBC (Cohort B) and HNSCC (Cohort C) or as per the Response Evaluation Criteria in Lymphoma (RECIL) criteria for iHNL (Cohort A) patients, or death from any cause, whichever occurs first. (Phase II)

IV. Overall Survival (OS) defined as the duration of time from initial Flt3L administration until death from any cause. (Phase II)

V. Adverse events (AEs) measured using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. (Phase II)

OUTLINE:

Patients receive recombinant Flt3 ligand intratumorally (IT) daily on days 0-4 and 7-10, and undergo radiation therapy (RT) on days 1 and 2. Patients also receive poly-ICLC IT on days 11, 15, 18, 22, 29, 35, 43, and 50, and pembrolizumab intravenously (IV) over 30 minutes on day 22. Treatment with pembrolizumab repeats every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 60 days, then every 3-6 months for at least 2 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Joshua Brody

Trial IDs

Primary ID 19-0477
Secondary IDs NCI-2019-02152
Clinicaltrials.gov ID NCT03789097