Clinical trial NCT01217749: Efficacy and Safety Study of PCI-32765 Combine With Ofatumumab in CLL
Official title: An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: B-cell Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Prolymphocyctic Leukemia
Richter's Transformation
Lead sponsor: Pharmacyclics LLC.
Sponsor class: INDUSTRY
Collaborators: name: Ohio State University
First posted: 2010-10-08
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the efficacy and safety of a fixed-dose, daily regimen of orally administered PCI-32765 combined with ofatumumab in subjects with relapsed/refractory CLL/SLL and related diseases


Eligibility criteria: Inclusion Criteria:

1. Subjects with histologically confirmed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or Richter's transformation arising out of CLL/SLL as defined by WHO classification of hematopoietic neoplasms and satisfying ≥ 1 of the following conditions:

   * Progressive splenomegaly and/or lymphadenopathy identified by physical examination or radiographic studies
   * Anemia (\<11 g/dL) or thrombocytopenia (\<100,000/μL) due to bone marrow involvement
   * Presence of unintentional weight loss \> 10% over the preceding 6 months
   * NCI CTCAE Grade 2 or 3 fatigue
   * Fevers \> 100.5 degree or night sweats for \> 2 weeks without evidence of infection
   * Progressive lymphocytosis with an increase of \> 50% over a 2 month period or an anticipated doubling time of \< 6 months
   * Need for cytoreduction prior to stem cell transplant
2. Subjects must have failed ≥ 2 prior therapies for CLL including a nucleoside analog or ≥ 2 prior therapies not including nucleoside analog if there is a contraindication to such therapy
3. 10% expression of CD20 on CLL/SLL cells
4. ECOG performance status ≤ 2
5. Life expectancy ≥ 12 weeks
6. Subjects must have organ and marrow function as defined below:

   * Absolute neutrophil count (ANC) ≥ 1000/µL in the absence of bone marrow involvement
   * Platelets ≥ 30,000/μL in the absence of bone marrow involvement
   * Total bilirubin ≤ 1.5 x institutional upper limit of normal unless due to Gilbert's disease
   * AST (SGOT) ≤ 2.5 x institutional upper limit of normal unless due to infiltration of the liver
   * Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min
7. No history of prior exposure to ofatumumab
8. Age ≥ 18 years
9. Body weight ≥ 40 kg

Exclusion Criteria:

1. A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk
2. Significant cardiovascular disease
3. Any condition which could interfere with the absorption or metabolism of PCI-32765 including unable to swallow capsules, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
4. Known history of Human Immunodeficiency Virus (HIV) or active infection with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) or any uncontrolled active systemic infection
5. Any anticancer immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 4 weeks before first dose of study drug. Corticosteroids for disease-related symptoms are allowed provided 1 week washout occurs
6. Active central nervous system (CNS) involvement by lymphoma
7. Major surgery within 4 weeks before first dose of study drug
8. Lactating or pregnant
9. Known moderate to severe chronic obstructive pulmonary disease (COPD)
10. History of prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for at least 2 years or which will not limit survival to \< 2 years
11. History of Grade ≥ 2 toxicity continuing from prior anticancer therapy including radiation

Primary outcomes:
measure: Percentage of Participants Achieving Response
timeFrame: The median follow-up time on study for all treated participants is 12.5 (range 0.5-19.6) months
measure: Safety During Dose-Limiting Toxicity (DLT) Observation Period
timeFrame: 56 days for Group 1 and 28 days for Group 2
Secondary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (AEs)
timeFrame: From first dose of study treatment to within 30 days of last dose or until study closure
measure: Progression Free Survival (PFS) at 12 Months
timeFrame: From first dose of study treatment until disease progression, death, or until 12 months
Other outcomes:
Locations:
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
Study officials:
affiliation: Ohio State University
name: Samantha Jaglowski, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JA. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015 Apr;1(1):80-7. doi: 10.1001/jamaoncol.2014.218.
citation: Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. doi: 10.1182/blood-2014-12-617522. Epub 2015 Jun 26.
citation: Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, Hessler JD, Liu TM, Chang BY, Larkin KM, Stefanovski MR, Chappell DL, Frissora FW, Smith LL, Smucker KA, Flynn JM, Jones JA, Andritsos LA, Maddocks K, Lehman AM, Furman R, Sharman J, Mishra A, Caligiuri MA, Satoskar AR, Buggy JJ, Muthusamy N, Johnson AJ, Byrd JC. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013 Oct 10;122(15):2539-49. doi: 10.1182/blood-2013-06-507947. Epub 2013 Jul 25.