Study of Crenolanib in Recurrent/Refractory Glioblastoma With PDGFRA Gene Amplification

This is a proof of concept, single-arm study to investigate crenolanib monotherapy in
patients with recurrent/refractory glioblastoma with PDGFRA gene amplification. Eligible
patients include those with recurrent/refractory glioblastoma after prior therapy including
surgery, radiation, and temozolomide. The trial is designed to assess the anti-tumor activity
of crenolanib in recurrent/refractory glioblastoma with PDGFRA gene amplification based on
the estimation of progression-free survival (PFS) at 6 months. Symptom burden will be
evaluated using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT).

Crenolanib will be administered orally continuously at 100 mg TID on a 28-day cycle basis .
Patients are allowed to receive crenolanib for a maximum of 26 cycles if clinical benefit has
been observed.

Inclusion Criteria:

1. Patients (male or female) ≥ 18 years of age.

2. Histopathologically confirmed glioblastoma or gliosarcoma (WHO Grade IV) confirmed by
local pathology tissue screening.

3. Radiologic evidence of first recurrence after initial treatment (including surgery,
radiation, and temozolomide) or tumor refractory to initial treatment without
subsequent treatment in glioblastoma or gliosarcoma (WHO Grade IV). Transformation
from a lower grade glioma previously treated with radiation and/or temozolomide to
glioblastoma will be considered first recurrence for the purpose of this trial

4. Tumor tissue available from original diagnosis and/or recurrence; a minimum of 1 FFPE
archival tumor tissue block (preferred) or a minimum of 20 FFPE unstained slides from
initial and/or most recent pre-registration biopsy or resection. It is recommended
that at least 1 cm^2 of tissue composed primarily (defined as greater than 85%) of
tumor is present.

5. Confirmed PDGFRA amplification in the tumor tissue at the time of diagnosis or time of
recurrence. Central confirmation of PDGFRA amplification will be performed by FISH in
CLIA certified lab (ProPath). Signal quantitation will be used to generate a
PDGFRA/centromere 4 ratio. PDGFRA to Centromere 4 ratios will be interpreted as
follows: 1.8 to 2.2, borderline for amplification; 2.2 to 5.0, low-level
amplification; and greater than 5.0 or clustered signals that are too numerous to
count would be considered highly amplified. Tumor samples with PDGFRA to Centromere 4
ratios of 2.2 or higher will be considered amplified and therefore eligible for this
trial. For patients with local CLIA testing demonstrating PDGFRA amplification by Next
Generation Sequencing (Foundation Medicine, CMS400), central testing will not be
required.

6. Patients must have adequate organ function at baseline as defined below:

• Adequate liver function (within 7 days of crenolanib commencement), as determined
by:

- Serum ALT, AST ≤ 2 × ULN

- Normal serum total bilirubin (lower and upper limits of local Laboratory)

- Adequate renal function assessed by: serum creatinine ≤ 1.5 × ULN

7. KPS ≥ 60

8. Recovered (returned to ≤ grade 1 as per CTCAE v4.03) from prior treatment-related
toxicity.

9. A minimum of 3 weeks must have elapsed from last intake of prior standard chemotherapy
treatment.

10. A minimum of 6 weeks must have elapsed from the last dose of nitrosoureas.

11. A minimum of 5 half-lives of last dose of investigational agent must have elapsed
prior to C1D1.

12. More than 12 weeks from completion of chemoradiation, unless RANO criteria for early
progression within 12 weeks of chemoradiation are met (See 18.1)

13. Non-pregnant and non-nursing women of childbearing potential must have a negative
serum or urine pregnancy test within 3 days of crenolanib commencement ("Women of
childbearing potential" is defined as a sexually active mature woman who has not
undergone a hysterectomy or who has had menses at any time in the preceding 24
consecutive months).

14. Women of childbearing potential and men must agree to use adequate contraception
(simultaneous use of 2 methods of birth control) prior to study entry, for the
duration of study participation and for 90 days following completion of therapy.

15. Patient able and willing to provide informed consent.

16. Ability to understand and willingness for follow-up visits.

Exclusion Criteria:

1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic
steatohepatitis, and sclerosing cholangitis, etc.)

2. Known positive for HIV

3. Patients previously treated with bevacizumab.

4. NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry,
and/or serious arrhythmia requiring anti-arrhythmic therapy

5. Patients receiving concurrent anti-cancer treatment (chemotherapy, investigational
agents, immunotherapy, endocrine therapy, or Optune®…)

6. Patients with any other severe and/or uncontrolled concurrent disease affecting the
cardiovascular system, liver, kidneys, hematopoietic system or else considered as
clinically important by the investigator and that could be incompatible with patient's
participation in this trial or would likely interfere with study procedures/results or
compromise compliance with the protocol.

7. Pregnant or breast-feeding women.

8. Patients unable to swallow pills.

9. Patients who are allergic to MRI contrast medium or unable to undergo MRI for any
other reason.

10. Patients unable to provide informed consent.

11. Patients on EIADs are not eligible, unless the antiepileptic drug can be safely
tapered and discontinued before C1D1.