Buparlisib and Ofatumumab or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

NCT02614508 | Terminated Phase 1 DMC

• 3 other identifiers: IRB00071983NCI-2015-00652Winship2494-13/CBKM120ZUS36T
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of buparlisib when given together with ofatumumab or ibrutinib in treating patients with chronic lymphocytic leukemia that has returned after a period of improvement or does not respond to treatment. Buparlisib and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as ofatumumab, may block cancer growth in different ways by targeting certain cells. Giving buparlisib or ibrutinib and ofatumumab together may work better in treating patients with chronic lymphocytic leukemia.

Conditions

Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Small Lymphocytic Lymphoma

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) of buparlisib when combined with ibrutinib in relapsed/refractory CLL for ibrutinib naive patients defined as the dose level at which no more than 1 of 6 patients experiences a dose-limiting toxicity

  Adverse events and toxicities will be summarized using NCI CTCAE version 4 and based on severity and perceived attribution to study treatment.

  28 days

• MTD of buparlisib when combined with ofatumumab in relapsed/refractory CLL for ibrutinib pre-treated patients defined as the dose level at which no more than 1 of 6 patients experiences a dose-limiting toxicity

  Adverse events and toxicities will be summarized using NCI CTCAE version 4 and based on severity and perceived attribution to study treatment.

  28 days

Secondary Outcomes (6)

• Complete response rate

  Up to 5 years

• Incidence of non-dose limiting toxicities and adverse events

  Up to 5 years

• Nodal response rate

  Up to 5 years

• Overall response rate

  Up to 5 years

• Overall survival

  Up to 5 years

Study Arms (2)

Cohort A (buparlisib, ofatumumab)

EXPERIMENTAL

Patients receive buparlisib PO QD on days 1-28 and ofatumumab IV on days 1, 8, 15, and 22 during of courses 1-2; and day 1 of courses 4-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Buparlisib; Biological: Ofatumumab

Cohort B (buparlisib, ibrutinib)

EXPERIMENTAL

Patients receive buparlisib as in Cohort A and ibrutinib PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Buparlisib; Drug: Ibrutinib

Interventions

Buparlisib DRUG

Given PO

Also known as: BKM120, PI3K Inhibitor BKM120

Cohort A (buparlisib, ofatumumab); Cohort B (buparlisib, ibrutinib)

Ibrutinib DRUG

Given PO

Also known as: BTK Inhibitor PCI-32765, CRA-032765, PCI-32765

Cohort B (buparlisib, ibrutinib)

Ofatumumab BIOLOGICAL

Given IV

Also known as: Arzerra, GSK1841157, HuMax-CD20, HuMax-CD20, 2F2

Cohort A (buparlisib, ofatumumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) according to World Health Organization (WHO) criteria with at least one of the following indications for treatment:
• Progressive disease or marked splenomegaly or hepatomegaly
• Anemia (hemoglobin \[Hgb\] \< 11 mg/dL) or thrombocytopenia (platelets \< 100,000 /mm³)
• Unexplained weight loss exceeding 10% of body weight over the preceding 6 months
• Fevers \> 100.5° F or night sweats for greater than 2 weeks without evidence of infection
• Progressive lymphocytosis, with an increase exceeding 50% over a 2 month period or a doubling time of less than 6 months
• Significant fatigue (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 4.03 grade 2 or higher)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• At least one prior therapy for CLL/SLL; prior autologous or allogeneic stem cell transplant is allowed; patients may not be on chronic immunosuppressive therapy for graft-versus-host disease (GVHD); patients who are on only oral steroids must be on an oral dose of 10mg or less of prednisone (or equivalent) daily
• Prior therapy with a selective phosphoinositide 3-kinase (PI3K) inhibitor or other B-cell receptor targeting agents is allowed
• Patients who have been previously treated with ibrutinib (or any Bruton's tyrosine kinase \[BTK\] inhibitor) are eligible for the ibrutinib pre-treated cohort as long as prior ibrutinib or BTK inhibitor therapy was not discontinued due to toxicity/adverse event; there is no minimum dose of ibrutinib; any prior administration will disqualify patients for the ibrutinib-naïve cohort and will require enrollment on the ibrutinib pre-treated cohort
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) and/or creatinine clearance \> 50% lower limit of normal
• Total bilirubin ≤ upper limit of normal (or ≤ 1.5 x upper limit of normal if live metastases are present; or total bilirubin ≤ 3.0 x upper limit of normal with direct bilirubin within normal range in patients with well documented Gilbert's syndrome, which is defined as presence of several episodes of unconjugated hyperbilirubinemia with normal results from complete blood count \[CBC\] count \[including normal reticulocyte count and blood smear\], normal liver function test results, and absence of other contributing disease processes at the time of diagnosis)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ upper limit of normal (or \< 3.0 x ULN if liver metastases are present)
• Serum lipase ≤ upper limit of normal

You may not qualify if:

• Patient has a known hypersensitivity to any of the excipients of buparlisib
• Patient who has received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (except alopecia)
• Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects
• Patient is currently receiving increasing or chronic treatment (\> 5 days) with corticosteroids or another immunosuppressive agent, as chronic administration of corticosteroids (\> 5 days) can induce cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); see also section "concomitant medication"; the following uses of corticosteroids are permitted: single doses; e.g. with standard premedication for infusions; topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular); patients may take 10mg or less (or equivalent) of oral prednisone daily
• Patient is being treated at start of study treatment with any of the following drugs:
• Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A4 including herbal medications
• Drugs with a known risk to induce Torsades de Pointes
• Note: the patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment is initiated; switching to a different medication prior to starting study treatment is allowed
• Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise; therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
• Patients who have other concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate patient participation in the clinical study (eg. active or uncontrolled severe infection, chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease, etc.)
• Patient has a known history of human immunodeficiency virus (HIV) infection (testing not mandatory)
• Patients has any of the following cardiac abnormalities:
• Symptomatic congestive heart failure
• History of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy

Sponsors & Collaborators

• Emory University: lead
• Novartis: collaborator

Study Sites (1)

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

NVP-BKM120; ibrutinib; ofatumumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Jonathon Cohen, MD, MS

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 23, 2015
• First Posted: November 25, 2015
• Study Start: January 1, 2016
• Primary Completion: August 1, 2019
• Study Completion: August 1, 2019
• Last Updated: September 3, 2019

Record last verified: 2019-08

Locations

US (1)