Clinical Trials /

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

NCT04043845

Description:

This research is studying the safety of combining ibrutinib with the study drug LY3214996 for chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL).

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: ERK 1/2 Signaling in Ibrutinib Resistant B-cell Malignancies
  • Official Title: A Phase 1 Study Targeting ERK 1/2 Signaling in Ibrutinib Resistant B-cell Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 19-277
  • NCT ID: NCT04043845

Conditions

  • Chronic Lymphocytic Leukemia
  • Waldenstrom Macroglobulinemia
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma

Interventions

DrugSynonymsArms
IbrutinibImbruvicaLY3214996+Ibrutinib
LY3214996LY3214996+Ibrutinib

Purpose

This research is studying the safety of combining ibrutinib with the study drug LY3214996 for chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL).

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of an investigational
      combination of drugs and also tries to define the appropriate dose of the investigational
      drug to use for further studies. "Investigational" means that the drug is being studied.

      The U.S. Food and Drug Administration (FDA) has not approved LY3214996 as a treatment for any
      disease.

      The U.S. Food and Drug Administration (FDA) has approved ibrutinib as a treatment option for
      this disease.

      LY3214996 is an extracellular signal-regulated kinase (ERK) inhibitor that is being developed
      as a treatment for patients with advanced cancer. ERK inhibitors stop the signal that a
      cancer cell receives telling it to grow. In this research study, the investigators are
      testing to see if LY3214996 is safe when combined with ibrutinib in patients with specific
      gene mutations. Making treatment decisions based on genetic testing is investigational, and
      the FDA has not approved this genetic testing. Several doses of LY3214996 will be explored in
      this study.
    

Trial Arms

NameTypeDescriptionInterventions
LY3214996+IbrutinibExperimentalLY3214996 will be administered by mouth once daily continuously throughout each treatment cycle Ibrutinib will be administered by mouth once daily continuously throughout each treatment cycle.
  • Ibrutinib
  • LY3214996

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity
Time Frame:42 days
Safety Issue:
Description:Toxicities occurring following administration of protocol therapy, measured using CTCAE 5.0 criteria.

Secondary Outcome Measures

Measure:Best Response
Time Frame:From date of study drug initiation up to a maximum of 2 years
Safety Issue:
Description:Best response to study treatment measured using disease-specific criteria.
Measure:Time to Progression
Time Frame:From date of study drug initiation until the date of first documented progression or date of death from any cause, whichever comes first, up to a maximum of 2 years
Safety Issue:
Description:Assess the amount of time to disease progression

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Chronic Lymphocytic Leukemia
  • Waldenstrom Macroglobulinemia
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • CLL
  • WM
  • MCL
  • MZL
  • ERK
  • Ibrutinib
  • BTKCys481
  • PLCG2
  • PLCγ2
  • LY3214996

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