Clinical Study of Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

A Phase I/Ib Study of P1446A-05 in Patients With 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.