PHASE 1 STUDY OF LORLATINIB (PF-06463922), AN ORAL SMALL MOLECULE INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH ALK-DRIVEN RELAPSED OR REFRACTORY NEUROBLASTOMA

Lorlatinib is a novel inhibitor across ALK variants, including those resistant to
crizotinib. 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).

Inclusion Criteria:

1) 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 2)
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.

3) Patients must have a history of 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.

4) All patients must have at least one of the following

a) Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any
time prior to enrollment regardless of response to frontline therapy b) No prior history
of recurrent/progressive disease since the diagnosis of high risk neuroblastoma b1)
Refractory disease- a best overall response of no response/stable disease since diagnosis
of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history
of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.

b2) Persistent disease- a best overall response of no partial response since diagnosis of
high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of
recurrent/progressive disease since the diagnosis of high risk neuroblastoma.

5) Patients must have at least ONE of the following (lesions may have received prior
radiation therapy as long as they meet the other criteria listed below):

1. For recurrent/progressive or refractory disease, at least one MIBG avid bone site.

2. For persistent disease, if a patient has 3 or more MIBG avid lesions, then no biopsy
is required. If a patients has only 1 or 2 MIBG avid bone lesion sites then biopsy
confirmation of neuroblastoma or ganglioneuroblastoma in at least one MIBG avid site
present at the time of enrollment is required to be obtained at any time point prior
to enrollment.

3. For MIBG non-avid tumors, patients must have at least one FDG avid site and a biopsy
confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to
enrollment from at least one FDG-avid site.

6) Any amount of neuroblastoma tumor cells in the bone marrow done at the time of
study enrollment based on routine morphology with or without
immunocytochemistry in at least one sample from bilateral aspirates and
biopsies.

7) At least one soft tissue lesion that meets criteria for a TARGET lesion as
defined by:

1. SIZE: Lesion can be accurately measured in at least one dimension with a longest
diameter ≥ 10 mm, or for lymph nodes ≥ 15 mm on short axis. Lesions meeting size
criteria will be considered measurable.

2. In addition to size, a lesion needs to meet one of the following criteria except for
patients with parenchymal CNS lesions which only need to meet size criteria:

b1) MIBG avid. For patients with recurrent/progressive or refractory disease, no
biopsy is required. For patients with persistent disease only: If a patient has only
1 or 2 MIBG avid lesions sites, then biopsy confirmation of neuroblastoma and/or
ganglioneuroblastoma in at least one MIBG avid site present at time of enrollment is
required to be obtained. If a patient has 3 or more MIBG avid lesions, then no
biopsy is required.

b2) MIBG non avid tumors: Patients must have at least one FDG avid site and biopsy
confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET
avid site present at the time of enrollment.

8) At least one non-target soft tissue lesion that is not measurable, but had a
biopsy positive for neuroblastoma and/or ganglioneuroblastoma or is MIBG avid
at any time prior to enrollment.

9) Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16
years) or Karnofsky (>16 years) score of at least 50.

10) Prior Therapy

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

2. Patients must not have received the therapies indicated below after disease
evaluation or within the specified time period prior to registration on this
study as follows:

1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior to
registration.

2. Biologic anti-neoplastics- agents not known to be associated with reduced
platelet or ANC counts (including retinoids): must not have received within 7
days prior to registration.

3. Monoclonal antibodies: must have received last dose at least 7 days or 3
half-lives whichever is longer, but no longer than 30 days (with recovery of
any associated toxicities), prior to protocol therapy.

4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.): must
not have received within 3 weeks and resolution of all toxicities.

5. Radiation: must not have received small port radiation within 7 days prior to
registration.

6. Hematopoietic Stem Cell Transplant: 7. IVIG 11) All patients must have adequate
organ function defined as:

- Hematological Function:

1. Absolute Phagocyte count (APC= neutrophils and monocytes): ≥ 1000/µL

2. Absolute Neutrophil count: ≥750/µL

3. Absolute Lymphocyte count ≥ 500/µL

4. Platelet count: ≥ 50,000/µL (A1, A2, and B1); ≥ 75,000/µL (B2), transfusion
independent (no platelet transfusions within 1 week)

5. Hemoglobin ≥ 10 g/dL (may transfuse)

6. Patients with known bone marrow metastatic disease will be eligible for study
as long as they meet hematologic function criteria above.

- Renal Function: Age-adjusted serum creatinine ≤ to 1.5 x normal for age/gender
OR creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2

- Liver Function: Total bilirubin ≤ 1.5 x normal for age, AND SGPT (ALT) 135 and
SGOT (AST) ≤ 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS)
if present, must be stable or improving clinically

- Cardiac Function: Normal ejection fraction documented by either echocardiogram
or radionuclide MUGA evaluation OR Normal fractional shortening documented by
echocardiogram

- Pulmonary Function: No dyspnea at rest, no oxygen requirement.

- Neuropsychological Function: Patients must exhibit ≤ grade 1 as defined by
CTCAE V4 of nervous system disorders and psychiatric disorders 12) Reproductive
Status: All post-menarchal females must have a negative beta-HCG. Males and
females of reproductive age and childbearing potential must use effective
contraception for the duration of their participation.

13) Patients with other ongoing serious medical issues must be approved by the
study chair prior to registration.

14) Prior ALK inhibitor treatment- patients must not have been previously
treated with lorlatinib. Prior therapy with other ALK inhibitors is
allowed.

15) Concomitant Therapy Restrictions:

1. Patients may not receive any other anti-cancer agents or radiotherapy
while on protocol therapy.

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

3. CYP34A inhibitors

4. CYP34A inducers

5. CYP34A substrates

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 with known history of acute or chronic severe psychiatric disorders

- Patient with current history of suicidal ideation and history of suicide
attempt in their lifetime

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