Clinical Trials /

Brigatinib in Relapsed or Refractory ALK-Positive Anaplastic Large Cell Lymphoma

NCT03719898

Description:

FDA approved drugs to treat patients with relapsed or refractory anaplastic large cell lymphoma (ALCL) has a median progression free survival of 20 months. Majority of patients relapse in 2 years. This study will evaluate overall response rate of next generation ALK inhibitor brigatinib in ALK positive ALCL patients by overcoming mechanisms of resistance to ALK inhibitors on cancer patients.

Related Conditions:
  • Anaplastic Large Cell Lymphoma
  • Anaplastic Large Cell Lymphoma, ALK-Positive
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Brigatinib in Relapsed or Refractory ALK-Positive Anaplastic Large Cell Lymphoma
  • Official Title: A Phase II Study of Brigatinib in Relapsed or Refractory ALK-Positive Anaplastic Large Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: HM-117
  • SECONDARY ID: 18-1032
  • NCT ID: NCT03719898

Conditions

  • Anaplastic Large Cell Lymphoma, ALK-Positive

Interventions

DrugSynonymsArms
BrigatinibBrigatinib

Purpose

FDA approved drugs to treat patients with relapsed or refractory anaplastic large cell lymphoma (ALCL) has a median progression free survival of 20 months. Majority of patients relapse in 2 years. This study will evaluate overall response rate of next generation ALK inhibitor brigatinib in ALK positive ALCL patients by overcoming mechanisms of resistance to ALK inhibitors on cancer patients.

Detailed Description

      Although patients with ALK+ anaplastic large cell lymphoma (ALCL), a type of peripheral
      T-cell lymphoma (PTCL), are considered to have a favorable prognosis, relapse is not uncommon
      if multiple International Prognostic Index (IPI) risk factors, age ≥ 40, and beta-2
      microglobulin ≥ 3 mg/L are present at diagnosis. For patients older than 40 years at
      diagnosis and beta-2 microglobulin ≥ 3 mg/L, progression-free survival (PFS) and overall
      survival (OS) is less than 50% at 2.5 years when treated with standard anthracycline-based
      induction therapy. Patients with ALK+ ALCL with 3 or more IPI risk factors have a 5-year PFS
      rate of only 20% to 30%. In total, approximately 40 to 65% of patients with ALCL develop
      recurrent disease after front-line chemotherapy and at relapse, the disease is historically
      resistant to conventional chemotherapy.

      Current FDA approved for treatment of relapsed or refractory PTCLs have a median PFS of 20
      months and majority of patients relapse within 2 years. Despite ALK tyrosine kinase being an
      attractive target for management of relapsed or refractory ALK+ ALCL, ALK gene rearrangement
      makes cancer resistant to first and 2nd generation ALK inhibitors. Brigatinib is a next
      generation inhibitor with broad activity aganst a broad spetrum of resistant ALK mutants.
      Brigatinib has been shown to overcome mechanisms associated with resistane to 1st and 2nd
      generation ALK inhibitors. It is approved as 2nd line of treament in non small cell lung
      cancer patients. and is being tested in patients with relapsed or refractory ALK-positive
      ALCL.
    

Trial Arms

NameTypeDescriptionInterventions
BrigatinibExperimental90 mg daily orally for 7 days, then 180 mg daily orally during first cycle; 180 daily orally thereafter during every subsequent cycle. Each cycle has 28 days
  • Brigatinib

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have a histologically confirmed diagnosis of relapsed or refractory ALCL
             with documented ALK+ status

          2. Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension in accordance with RECIL 2017 criteria
             as described in detail in section 11.0

          3. Ongoing toxicities from prior therapy must be resolved to ≤ grade 1 (with the
             exceptions of grade 2 peripheral neuropathy and/or alopecia). Patients with existing
             toxicities that are non-significant even though greater than grade 1 can be enrolled
             after discussion with the sponsor-investigator.

          4. Age > 18 years.

          5. ECOG performance status 0-2

          6. Prior use of ALK inhibitors aside from brigatinib is permitted but 8 patients enrolled
             need to be ALK inhibitor treatment naive

          7. Patients with no archival tissue available must be agreeable to fresh biopsy at
             baseline.

          8. Patients with a known history of HIV are permitted provided the CD4 count ≥ 100
             cells/µL and serum HIV viral load < 50 copies/mL. Patients must be on stable
             combination antiretroviral therapy at the time of treatment initiation.

          9. Patients must have normal organ and marrow function as defined below

               -  Absolute neutrophil count > 1,000/mcL

               -  Platelets > 75,000/mcL (or 50,000/mcL if known bone marrow involvement by
                  lymphoma)

               -  Total bilirubin within normal institutional limits (up to 2x ULN if history of
                  Gilbert's syndrome or known liver involvement)

               -  AST/ALT (SGOT/SGPT) < 2 times institutional normal limits

               -  Creatinine within 1.5 x upper limit of normal institutional limits OR

               -  Creatinine clearance > 30 ml/min/1.73 m2 for patients with creatinine levels
                  above 1.5x upper institutional normal

               -  Serum lipase/amylase ≤1.5 × ULN

               -  Hemoglobin ≥10 g/dL (can be transfused to achieve Hgb ≥10 g/dL)

         10. Ability to understand and willingness to sign a written informed consent and HIPAA
             consent document. LARs are allowed to sign on patient's behalf with proper
             documentation.

         11. Female patients who are postmenopausal for at least 1 year before the screening visit,
             or are surgically sterile. Female patients of childbearing potential should agree to
             practice 2 effective methods of contraception, at the same time, from the time of
             signing the informed consent through 4 months after the last dose of study drug, or
             agree to completely abstain from heterosexual intercourse.

         12. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who agree
             to practice effective barrier contraception during the entire study treatment period
             and through 4 months after the last dose of study drug.

        Exclusion Criteria:

          1. History of another active primary malignancy within 2 years of initiating study
             treatment with the exception of non-melanomatous skin cancer, or any cancer that in
             the judgment of the investigator has been treated with curative intent and will not
             interfere with the study treatment plan and response assessment.

          2. Patients who have received chemotherapy or radiation therapy within 2 weeks of
             initiating study treatment.

          3. Patients may not be receiving any other investigational agents.

          4. Patients who have symptomatic CNS metastases (parenchymal or leptomeningeal) at
             screening or asymptomatic disease requiring an increasing dose of corticosteroids to
             control symptoms within 7 days prior to randomization.

             Note: If a patient has worsening neurological symptoms or signs due to CNS metastasis,
             the patient needs to complete local therapy and be neurologically stable (with no
             requirement for an increasing dose of corticosteroids or use of anticonvulsants) for 7
             days prior to enrollment.

          5. History of allergic reactions attributed to other ALK inhibitors

          6. History of interstitial pneumonitis or drug-related pneumonitis

          7. Impaired gastrointestinal function that may affect oral absorption of brigatinib

          8. Patients with known active Hepatitis B or Hepatitis C (defined as having a detectable
             hepatitis B or C viral load)

          9. 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. Physician's discretion may be exercised to determine eligibility
             for patients with psychiatric illness/social situations.

         10. Pregnant or breast-feeding. Refer to section 4.4 for further detail.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:objective response rate
Time Frame:2 years
Safety Issue:
Description:proportion of patients with tumor size reduction of a predefined amount and for a minimum time period measured using RECIL 2017 criteria

Secondary Outcome Measures

Measure:To assess the incidence of adverse events as assessed by NCI CTCAE v5.0 for 2 years
Time Frame:2 years
Safety Issue:
Description:Adverse events will be documented by NCI CTCAE v 5.0 criteria
Measure:To measure the overall survival (OS) at 1 and 2 years from treatment initiation
Time Frame:5 years
Safety Issue:
Description:Overall survival will be measured as the length of time patients survive from the day of treatment.
Measure:To measure progression-free survival (PFS) at 1 and 2 years from treatment initiation
Time Frame:5 years
Safety Issue:
Description:Progression free survival will be measured as the length of time from treatment to progression of disease as measured by radiologic evaluation
Measure:To measure the duration of response (DOR) for the period of 2 years
Time Frame:2 years
Safety Issue:
Description:DOR will be length of time from initial response to tumor progression documented by radiologic evaluation

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

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