Study of Lorlatinib (PF-06463922)

Lorlatinib is a novel inhibitor across ALK variants, including those resistant to crizotinib.
An adult phase 1 study established an RP2D of 100mg QD for lorlatinib. In this first
pediatric phase 1 trial of lorlatinib, the drug will be utilized as a single agent and in
combination with chemotherapy in patients with relapsed/refractory neuroblastoma. The dose
escalation phase of this study (Cohort A1) uses a traditional Phase I 3+3 design. Once a
recommended phase 2 pediatric dose is identified, an expansion cohort of 6 patients (Cohort
B1), within which ALKi naïve patients will be prioritized, will be initiated. Parallel
cohorts will be initiated in adults or patients with large BSA (Cohort A2) and in combination
with chemotherapy upon establishing RP2D (Cohort B2).

Lorlatinib will be administered orally via tablets or via oral dispersion if patient is
unable to swallow tablets whole

All patients will participate in mandatory pharmacokinetic testing.

Inclusion Criteria:

- Patients must have a diagnosis of neuroblastoma either by histologic verification of
neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
urinary catecholamines

- Patients are required to have an activating ALK aberration in their tumor detected by
certified assay (i.e. CLIA in the US.) prior to registration. The report from this
test is required to be submitted for eligibility. Patients with at least one of the
following genetic features in their tumor will be considered to have an activating ALK
aberration:

1. An ALK activating mutation;

2. ALK amplification (> 10 signals of the ALK gene);

3. Presence of any ALK fusion protein that arises from a chromosomal translocation.

- Patients must have high risk neuroblastoma according to COG risk classification at the
time of study registration. Patients who were initially considered low or intermediate
risk, but then reclassified as high risk are also eligible.

- Patients must have at least ONE of the following: 1) Recurrent/progressive disease at
any time prior to study enrollment, 2) Refractory disease, 3) Persistent disease

- Patients must have at least ONE of the following: 1) Bone disease, 2) Any amount of
neuroblastoma tumor cells in the bone marrow, 3) At least one soft tissue lesion that
meets criteria for a TARGET lesion, 4) At least one non-target soft tissue lesion that
is not measurable, but had a biopsy positive for neuroblastoma and/or
ganglioneuroblastoma at any time prior to enrollment or is MIBG avid

- Patients must have a Lansky (≤16 years) or Karnofsky (> 16 years) score of at least 50

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

- Patients must not have been previously treated with lorlatinib.

- Patients must not have received any of the specified therapies as stated in the
protocol in the time period prior to registration

- Patients must not be receiving any other anti-cancer agents or radiotherapy at the
time of study entry or while on study.

- Patients must not be receiving other investigational medications (covered under
another IND) within 30 days of study entry or while on study.

- Patients must not be receiving chronic systemic corticosteroids at doses greater than
physiologic dosing (inhaled corticosteroids acceptable).

- Patient must meet the organ function and system function requirements as stated in the
protocol

Exclusion Criteria:

- Pregnancy, breast feeding, or unwillingness to use effective contraception during the
study.

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.

- Patients with disease of any major organ system that would compromise their ability to
withstand therapy.

- Patients who have received prior allogeneic stem cell transplant

- Patients who are on hemodialysis.

- Patients with an active or uncontrolled infection.

- Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C.

- Patient declines participation in NANT 2004-05, the NANT Biology Study