Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
This is an open-label, Phase I/Ib trial with a dose escalation phase, followed by a dose
 extension phase. The objective of the dose escalation phase is to evaluate the
 pharmacokinetics (PK) and MTD of P1446A-05 in relapsed/refractory CLL and the objective of
 the dose extension phase is to evaluate the safety, efficacy and pharmacodynamics of
 P1446A-05 in 14 patients at the MTD level.
Inclusion Criteria:

 1. Patients must have histologically or flow cytometry confirmed diagnosis of B-cell
 chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to the
 IWCLL 2008 criteria. The malignant B cells must co-express CD5 with CD19 or CD20.
 Patients who lack CD23 expression on their leukemia cells should be examined for (and
 found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle
 cell lymphoma.

 2. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring
 treatment:

 -  A minimum of any one of the following constitutional symptoms:

 Unintentional weight loss >10% within the previous 6 months prior to screening Extreme
 fatigue (unable to work or perform usual activities) Fevers of greater than 100.5ᵒF
 for ≥2 weeks without evidence of infection Night sweats without evidence of infection.

 -  Evidence of progressive marrow failure as manifested by the development of, or
 worsening of anemia or thrombocytopenia

 -  Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic
 splenomegaly

 -  Massive nodes or clusters (i.e., >10 cm in longest diameter) or progressive
 lymphadenopathy

 -  Progressive lymphocytosis with an increase of >50% over a 2-month period, or an
 anticipated doubling time of less than 6 months

 -  Autoimmune anemia or thrombocytopenia that is poorly responsive to
 corticosteroids

 3. Patients with relapsed/refractory CLL defined as having received ≥2 treatment regimens
 that included:

 -  A treatment regimen containing cytotoxic agents (eg, fludarabine, pentostatin,
 cladribine, cyclophosphamide, chlorambucil, bendamustine) AND

 -  A treatment regimen containing a therapeutic anti-CD20 antibody (e.g., rituximab,
 ofatumumab, obinutuzumab) AND

 -  A treatment regimen containing ibrutinib unless patient is not a candidate

 -  All treatment regimens must have been administered for ≥2 cycles unless patient
 is immediately allergic or intolerant to the regimen

 -  A disease expert at the study site must have a detailed discussion with the
 patient of other treatment options which either have been approved by the FDA or
 are part of or relevant to the standard care of patients with B-CLL/SLL in the
 multiply relapsed setting

 4. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2

 5. Patients ≥18 year old

 6. Patients must have organ function as defined below:

 -  Direct bilirubin ≤2 X institutional ULN (unless due to known Gilbert's syndrome
 or compensated hemolysis directly attributable to CLL)

 -  AST or ALT less than or equal to 2.5 X institutional ULN

 -  Creatinine ≤1.5 mg/dL OR estimated creatinine clearance ≥60 mL/min calculated
 using Cockcroft-Gault equation

 -  Total white blood cell count ≤200,000/mm3

 -  Platelets ≥10,000/mm3 with no active bleeding

 7. Ability to understand and the willingness to sign a written informed consent document

 8. Ability to swallow and retain oral medication

 9. Patients receiving chronic or acute warfarin treatment are not excluded, but should be
 monitored very closely or considered for switch to other therapies. P1446A-05 is both
 highly protein bound and a competitive inhibitor of CYP2C9 at higher concentrations
 and thus may potentiate the action of warfarin in patients

 10. Women of childbearing potential must have a negative serum β-human chorionic
 gonadotropin or urine pregnancy test at screening

 11. All patients of reproductive potential (heterosexually active men and women) must
 agree to a use of a barrier method of contraception and a second method of
 contraception and men must agree not to donate sperm during the study and for at least
 4 weeks after receiving the last dose of study treatment

 Exclusion Criteria:

 1. Recent therapeutic intervention including a) prior nitrosoureas or mitomycin C; prior
 radio- or toxin-immunoconjugates within 6 weeks; b) therapeutic anticancer antibodies
 (including rituximab, ofatumumab and obinituzumab) within 4 weeks; and c) all other
 chemotherapy or radiation therapy within 2 weeks prior to initiation of study drug

 2. The patient has not recovered from adverse events related to prior therapy to Grade ≤1
 (excluding Grade 2 alopecia and neuropathy)

 3. Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent

 4. Patients who have been in the past enrolled on a study of a Cdk inhibitor

 5. History of prior malignancy except: a) Malignancy treated with curative intent and no
 known active disease present for ≥2 years prior to initiation of current study; b)
 adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
 disease; c) adequately treated in situ carcinomas (e.g., cervical, esophageal, breast,
 etc.) without evidence of disease; d) asymptomatic prostate cancer managed with "watch
 and wait" strategy; e) myelodysplastic syndrome which is clinically well controlled
 and no evidence of the cytogenetic abnormalities characteristic of myelodysplasia on
 the bone marrow at screening

 6. Patients with uncontrolled immune hemolysis or thrombocytopenia (positive direct
 antiglobulin test in absence of hemolysis is not an exclusion)

 7. Patients with known Richter's transformation which is progressive and is deemed to
 require immediate chemotherapy (history of Richter's transformation is not an
 exclusion); patients with prolymphocytic leukemia (prolymphocytes in blood >55%)

 8. Patients with clinically significant medical condition of malabsorption, inflammatory
 bowel disease, chronic conditions which manifest with diarrhea, refractory nausea,
 vomiting or any other condition that will interfere significantly with the absorption
 of study drugs

 9. Patients with mean QTc interval >450 msec at screening and patients taking drugs known
 to prolong the QTc interval (see Section 9, Appendix D) who cannot be switched to an
 alternative drug

 10. Nursing woman

 11. Known history of Human Immunodeficiency Virus (HIV) or active Hepatitis B or C.
 Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If
 patients receiving routine IVIG have core antibody or surface antigen positivity
 without evidence of active viremia (negative hepatitis B DNA) they may still
 participate in the study, but should have hepatitis serologies and Hepatitis B DNA
 monitored periodically by the treating physician.

 12. Any condition for which participation in the study is judged by the Investigator to be
 detrimental to the patient with inter-current illness including, but not limited to an
 uncontrolled active infection; unstable angina pectoris; uncontrolled cardiac
 arrhythmia; transient ischemic attack or pulmonary embolism during the previous 1
 month or psychiatric/social situations that would jeopardize compliance with study
 requirements.