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Ibrutinib and Pembrolizumab in Treating Patients with Relapsed or Refractory Mantle Cell Lymphoma

Trial Status: Active

This phase I / IIa trial studies the side effects of ibrutinib and pembrolizumab and how well they work in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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 ibrutinib and pembrolizumab may work better in treating patients with mantle cell lymphoma.

Inclusion Criteria

  • Subjects must have relapsed/refractory MCL
  • Be willing and able to provide written informed consent/assent for the trial
  • Have measurable disease based on the Lugano classification
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen or leukemic blood sample, only upon written agreement from the study principal investigator (PI)
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,000 /mcL (within 28 days of treatment initiation)
  • Platelets >= 25,000/mcL (within 28 days of treatment initiation)
  • Hemoglobin >= 8 g/dL (within 28 days of treatment initiation)
  • Serum creatinine =< 2.0 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]) >= 60 mL/min for subject with creatinine levels > 2.0 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 subjects 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 subjects 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 (within 28 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN (within 28 days of treatment initiation)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception, 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 subject
  • Male subjects of childbearing potential must agree to use an adequate method of 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 study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • 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
  • Has a known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to ibrutinib or pembrolizumab or any of their excipients
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • 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 cancer
  • Has known active central nervous system (CNS) metastases and/or lymphomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks 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 lymphomatous meningitis which is 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
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that 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
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has previously received a btk inhibitor and had progressive disease during therapy; patients who have previously discontinued btk inhibitor therapy because of intolerance may be considered for eligibility per the assessment of the PI and treating physician if there is reason that the patient may better tolerate btk inhibitor therapy at enrollment versus previously
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

New York

New York
Icahn School of Medicine at Mount Sinai
Status: ACTIVE
Contact: Joshua Brody
Phone: 646-543-2859

PRIMARY OBJECTIVES:

I. Assess the safety of fixed dose or, as needed, de-escalated ibrutinib/pembrolizumab in patients with mantle cell lymphoma (MCL) to determine recommended phase 2 dosing of ibrutinib. (Phase I)

II. Assess complete response (CR) rate of combination ibrutinib/pembrolizumab therapy, in comparison to historical data of ibrutinib monotherapy, in patients with MCL. (Phase IIa)

SECONDARY OBJECTIVE:

I. Assess duration of response, overall response rate, and duration of stable disease, compared to historical data of single agent ibrutinib, in patients with MCL. (Phase IIa)

EXPLORATORY OBJECTIVES:

I. Assess progression-free survival rate at 1 year and overall survival at 1 year of combination ibrutinib/pembrolizumab therapy, in comparison to historical data of ibrutinib monotherapy, in patients with MCL.

II. Assess TH2:TH1 skewing and checkpoint/costimulatory molecule expression (e.g. PD-1, CTLA-4, ICOS, OX40, GITR, CD137, BTLA, LAG3, ICOS, TIM3, TIGIT) across the immune cell repertoire as well as checkpoint/costimulatory molecule ligands (e.g. PD-L1, PD-L2, CD80, CD86) of patients during the 4 week lead-in of ibrutinib and then during pembrolizumab therapy, using mass cytometry.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Joshua Brody

  • Primary ID 17-0554
  • Secondary IDs NCI-2017-01538
  • Clinicaltrials.gov ID NCT03153202