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

Primary Purpose

Anaplastic Large Cell Lymphoma, ALK-Positive

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Brigatinib
Sponsored by
Fox Chase Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anaplastic Large Cell Lymphoma, ALK-Positive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Fox Chase Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Brigatinib

Arm Description

90 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

Outcomes

Primary Outcome Measures

objective response rate
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

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

Full Information

First Posted
October 16, 2018
Last Updated
January 4, 2021
Sponsor
Fox Chase Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT03719898
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Slow accrual
Study Start Date
December 6, 2018 (Actual)
Primary Completion Date
March 18, 2020 (Actual)
Study Completion Date
June 16, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fox Chase Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anaplastic Large Cell Lymphoma, ALK-Positive

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Refractory or relapsed ALK positive ALCL patients who may or my not have previously received treatment with any ALK inhibitor for any indication
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Brigatinib
Arm Type
Experimental
Arm Description
90 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
Intervention Type
Drug
Intervention Name(s)
Brigatinib
Intervention Description
Brigatininb is administered in tablet form. It is to be taken until disease progression, unacceptable toxicity or completion of 24 cycles. patients may continue to take brigatininb beyond 24 cycles if they are benefiting from the drug
Primary Outcome Measure Information:
Title
objective response rate
Description
proportion of patients with tumor size reduction of a predefined amount and for a minimum time period measured using RECIL 2017 criteria
Time Frame
2 years
Secondary Outcome Measure Information:
Title
To assess the incidence of adverse events as assessed by NCI CTCAE v5.0 for 2 years
Description
Adverse events will be documented by NCI CTCAE v 5.0 criteria
Time Frame
2 years
Title
To measure the overall survival (OS) at 1 and 2 years from treatment initiation
Description
Overall survival will be measured as the length of time patients survive from the day of treatment.
Time Frame
5 years
Title
To measure progression-free survival (PFS) at 1 and 2 years from treatment initiation
Description
Progression free survival will be measured as the length of time from treatment to progression of disease as measured by radiologic evaluation
Time Frame
5 years
Title
To measure the duration of response (DOR) for the period of 2 years
Description
DOR will be length of time from initial response to tumor progression documented by radiologic evaluation
Time Frame
2 years
Other Pre-specified Outcome Measures:
Title
To evaluate the frequency of NPM/ALK quantitative polymerase chain reaction (qPCR) positivity in plasma
Description
Detection of the NPM/ALK fusion gene via quantitative PCR (qPCR) in plasma
Time Frame
2 years
Title
The evaluate the persistence of NPM/ALK DNA construct in plasma and correlation with rate of relapse
Description
NPM-ALK DNA construct in plasma will be measured prospectively by polymerase chain reaction
Time Frame
2 years
Title
To evaluate for ALK mutations in tumor and plasma at baseline and at time of relapse
Description
ALK mutations in tumor and plasma will be analyzed by next generation sequencing
Time Frame
2 years
Title
Changes in ALK-dependent NF-kB activation
Description
NFKB1 and NFKB2 nuclear translocation/accumulation will be tested by immune histochemistry (IHC)
Time Frame
2 years
Title
Changes in ALK phosphorylation
Description
ALK phosphorylation (indicator of brigatinib efficacy) will be tested by immune histochemistry (IHC)
Time Frame
2 years
Title
Changes in TRAF2 expression
Description
TRAF2 expression (E3 ligase required for ALK mediation of NF-kB activation) will be tested by immune histochemistry (IHC)
Time Frame
2 years
Title
To evaluate gene expression profiles before and after treatment with brigatinib
Description
Gene expression profiling of NF-kB will be performed in tumor before and after treatment with brigatinib
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have a histologically confirmed diagnosis of relapsed or refractory ALCL with documented ALK+ status 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 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. Age > 18 years. ECOG performance status 0-2 Prior use of ALK inhibitors aside from brigatinib is permitted but 8 patients enrolled need to be ALK inhibitor treatment naive Patients with no archival tissue available must be agreeable to fresh biopsy at baseline. 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. 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) 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. 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. 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: 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. Patients who have received chemotherapy or radiation therapy within 2 weeks of initiating study treatment. Patients may not be receiving any other investigational agents. 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. History of allergic reactions attributed to other ALK inhibitors History of interstitial pneumonitis or drug-related pneumonitis Impaired gastrointestinal function that may affect oral absorption of brigatinib Patients with known active Hepatitis B or Hepatitis C (defined as having a detectable hepatitis B or C viral load) 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. Pregnant or breast-feeding. Refer to section 4.4 for further detail.
Facility Information:
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19011
Country
United States

12. IPD Sharing Statement

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

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