TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea

The escalation will include 2 initial sequential stages. Stage 1 will include myelofibrosis
or hydroxyurea-resistant/refractory PV patients already taking therapeutic levels of
ruxolitinib, but who are not achieving maximal response at the highest tolerated dose of
ruxolitinib as discussed among investigators. Only TGR-1202 will be escalated in a modified
3+3 dose escalation algorithm to determine the MTD of TGR-1202 to be given with any given
dose of ruxolitinib.

Stage 2 will include myelofibrosis or hydroxyurea-resistant/refractory PV patients who have
never been on JAK-STAT inhibitory agents, and includes simultaneously initiation of both
ruxolitinib and TGR-1202. In Stage 2, JAK Inhibitor naïve patients will receive TGR-1202 at
the recommended dose established in Cohort 1, and ruxolitinib. As patients in Stage 1 will be
on ruxolitinib at different doses, dose levels in Stage 2 will expand to meet requirements
for safety analysis.

Inclusion Criteria:

- Must voluntarily sign an ICF; and must be able to meet all study requirements

- For escalation, subjects must have a pathologically confirmed diagnosis of PPV-MF,
PETMF, or PMF as per the EHA or WHO diagnostic criteria (see Appendix B) (note that
all diagnoses must include the presence of at least Grade 1 marrow fibrosis according
to the European Consensus on Grading of BM Fibrosis as well as int-1, int-2, or high
risk disease according to the IWG-MRT Dynamic IPSS; Patients with PV may enter the
trial if they meet the labeled indication for ruxolitinib (eg hydroxyurea resistant or
refractory);

- Escalation Stage 1 patients: who have not achieved normalization of splenomegaly,
symptomology, or blood counts with at least 8 weeks therapy with a steady dose of
ruxolitinib

- Escalation Stage 2: patients who have not yet received therapy with any JAK-STAT
inhibitory agents or patients on at least 8 weeks of a steady dose of ruxolitinib;
patients with exposure to other JAK-STAT inhibitory agents are not eligible. After
discussion with the study chair or designee, patients with suboptimal response on at
least 8 weeks of a steady dose of ruxolitinib may be allowed to de-escalate
ruxolitinib therapy in order to enter a safety cohort which is enrolling patients at a
lower dose; patients must receive the lower dose of ruxolitinib for at least 7
consecutive days without event before adding TGR-1202. If the patient completed
screening evaluation including bone marrow biopsy/aspirate prior to ruxolitinib
de-escalation, it need not be repeated after de-escalation provided that all
evaluation occurred within 28 days prior to the first dose of TGR-1202.

- For expansion, subjects may have a pathologically confirmed diagnosis of MF or PV
as noted above in #2. There are also two expansion cohorts for patients with
MDS/MPN (CMML, aCML, RARS-T or MDS/MPN-U) which warrants treatment. Patients with
these diagnoses may be eligible, provided they are able to obtain ruxolitinib
from commercial supply.

- A bone marrow biopsy must be performed within four weeks prior to Cycle 1 Day 1
treatment to establish the baseline fibrosis score, and consent is required prior
to that bone marrow biopsy to assure tissue is collected for protocol mandated
testing;

- Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance
Status of 0-2;

- Life expectancy of at least six months;

- Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic
treatments, excluding alopecia;

- Women of child bearing potential (WCBP), defined as a sexually mature woman not
surgically sterilized or not post-menopausal for at least 24 consecutive months
if ≤55 years or 12 months if >55 years, must have a negative serum pregnancy test
within 72 hours prior to the first dose of study drug and must agree to use
highly effective methods of birth control throughout the study. Highly effective
methods of contraception include total abstinence, sterilization of patient
and/or patient's partner, or use of combination of two methods, including barrier
methods (double barrier method is acceptable), IUD or IUS, and hormonal implants
or combined oral contraceptives

- Must have adequate organ function as demonstrated by the following:

- ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN), or ≤ 4 x ULN (if
upon judgment of the treating physician, it is believed to be due to
extramedullary hematopoiesis [EMH] related to MF); Total bilirubin ≤ 1.5 x ULN;
or ≤ 2x ULN (if upon judgment of the treating physician, it is believed to be due
to EMH related to MF); Serum creatinine ≤ 2.5 mg/dL x ULN; Hgb ≥ 8 g/dL; Plt ≥
30k; ANC ≥ 750/uL

Exclusion Criteria

- Patients who meet any of the following criteria will be excluded from trial entry:

- Other invasive malignancies within the last 2 years, except non-melanoma skin cancer
and localized cured prostate, cervical cancer, and DCIS

- History of cerebral vascular accident, unstable angina, myocardial infarction, or
ventricular arrhythmia within the last 6 months;

- Any serious, unstable medical or psychiatric condition that would prevent, (as judged
by the Investigator) the subject properly providing informed consent or any condition
which would jeopardize compliance with the protocol

- Known history of human immunodeficiency virus (HIV), or known active hepatitis A, B,
or C infection (hepatitis B carriers with normal LFTs and undetectable viral loads are
allowed);

- Organ transplant recipients other than bone marrow transplant;

- Women who are pregnant or lactating;

- Autologous hematologic stem cell transplant within 3 months of study entry. Allogeneic
stem cell transplant within 6 months. Grade II, or greater, active graft versus-host
disease.

- Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of TGR-1202. For investigational drugs for which 5 half-lives
is less than 21 days, a minimum of 10 days between termination of the investigational
drug and administration of TGR-1202 is required.

- Previous therapy with GS-1101 (CAL-101), IPI-145 or any drug that specifically
inhibits PI3K or mTOR within last 6 months;

- Any major surgery, chemotherapy, or immunotherapy within the last 21 days (limited
palliative radiation is allowed ≥ 2 weeks); concurrent hydroxyurea is allowed if less
than 2 grams daily and on stable dose for ≥14 days prior to study entry;

- Patient has received wide field radiotherapy (including therapeutic radioisotopes such
as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior
to starting trial medications or has not recovered from side effects of such therapy;

- Ongoing immunosuppressive therapy (prednisone or equivalent ≤10 mg daily allowed as
clinically warranted). Patients are allowed to use topical or inhaled corticosteroids;

- Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol

- Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol.