ERK 1/2 Signaling in Ibrutinib Resistant B-cell Malignancies

Inclusion Criteria:

* Participants must meet one of the following criteria:

  * Clinicopathological diagnosis of Waldenstrom's macroglobulinemia (WM) meeting criteria for treatment using consensus panel guidelines from the Second International Workshop on Waldenstrom's Macroglobulinemia31 or have high risk disease with a serum IgM level of 6,000 mg or higher.32
  * Confirmed diagnosis of chronic lymphocytic leukemia (CLL) per International Workshop on CLL 2018 criteria.33
  * Histologically or cytologically confirmed diagnosis of mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL).
* Participants must have a BTKCys481 and/or PLCγ2 mutation. Genomic alterations must have been confirmed via sequencing performed at NeoGenomics Laboratories.
* All participants must have experienced disease progression while actively receiving ibrutinib monotherapy based on National Comprehensive Cancer Network (NCCN) guidelines.
* All participants must be actively receiving ibrutinib monotherapy at the time of study entry. Participants with a gap in treatment or who received anti-cancer treatments other than ibrutinib immediately prior to study entry are not eligible.
* Participants must have been on a stable dose of ibrutinib monotherapy for a minimum of 3 weeks prior to cycle 1 day 1.
* Age ≥ 18 years.
* ECOG performance status ≤ 1 (see Appendix A)
* Participants must have measurable disease:

  * Participants with WM: presence of serum immunoglobulin M (IgM) with a minimum IgM level of \> 2 × institutional upper limit of normal.
  * Participants with CLL:

    * Palpable or CT measurable lymphadenopathy ≥ 1.5 cm, AND/OR
    * Lymphocytosis ≥ 5,000/μL, AND/OR
    * Bone marrow involvement of ≥ 30%
  * Participants with MCL or MZL: at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) with conventional imaging or \> 10 mm with spiral CT scan. If the patient has been previously irradiated, there must be evidence of progression in the lesion since the radiation.
* Participants must have adequate organ and marrow function as defined below:

  * Absolute Neutrophil Count ≥ 750/mcL
  * Platelet Count ≥ 50,000/mcL
  * Total Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN), OR
  * Total Bilirubin ≤ 2 × institutional ULN if elevation is attributable to Gilbert's syndrome
  * AST (SGOT) / ALT(SGPT) ≤ 2.5 × institutional ULN, OR
  * AST (SGOT) / ALT (SGPT) ≤ 5 × institutional ULN if elevation is a result of infiltration by neoplastic disease
  * Creatinine ≤ 1.5 × institutional ULN, OR
  * Creatinine Clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above 1.5 × institutional normal (calculated via the Cockcroft-Gault equation)
* The effects of ibrutinib or LY3214996 on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib or LY3214996 administration.
* Ability to understand and the willingness to sign a written informed consent document.
* Ability to swallow and retain oral medication.

Exclusion Criteria:

* Participants who have had major surgery within 4 weeks prior to the first dose of study medication.
* Participants who have previously received treatment with an ERK inhibitor, including but not limited to previous treatment with LY3214996.
* Participants with known CNS disease involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to LY3214996 or ibrutinib.
* Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 3 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed within the past 3 years: basal or squamous cell carcinomas of the skin, breast or cervical carcinomas in situ, and low risk prostate cancer that does not require treatment as judged by the treating investigator.
* Participants who are known at the time of trial enrollment to require concomitant therapy with strong or moderate CYP3A inhibitors or inducers. The use of strong or moderate CYP3A inhibitors or inducers is prohibited for the duration of trial treatment.
* Participants who are known at the time of trial enrollment to require concomitant therapy with sensitive substrates of CYP3A4 or drugs cleared by CYP3A4 that have a narrow therapeutic range. The use of these drugs is prohibited for the duration of trial treatment.
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because LY3214996 and ibrutinib are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY3214996 or ibrutinib, breastfeeding should be discontinued if the mother is treated with LY3214996 or ibrutinib. A negative serum pregnancy test is required for women of childbearing potential prior to the first dose of study medication.
* Participants who are known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B or C.
* Participants with a history or findings of central or branch retinal artery or venous occlusion with significant vision less, or other retinal diseases causing visual impairment