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

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.

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.