Carfilzomib and Umbralisib in Treating Patients with Relapsed or Refractory Lymphoma
This phase Ib trial studies the best dose and side effects of carfilzomib and umbralisib and how well they work in treating patients with lymphoma that has come back or does not respond to treatment. Carfilzomib and umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
- PHASE I: Patients with relapsed or refractory Hodgkin lymphoma or non-Hodgkin lymphoma; patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are also eligible; in addition, patients with NHL other than diffuse large B cell lymphomas (DLBCL) must have received at least 2 prior therapies; patients with DLBCL and Hodgkin lymphoma (HL) will be eligible if there is no available standard therapy
- PHASE Ib: Patients must have histologically confirmed R/R PTCL or C-MYC positive DLBCL (as defined by World Health Organization [WHO] criteria and immunohistochemistry [IHC] staining of C-MYC); the patients with PTCL or DLBCL will be eligible if there is no available standard therapy.
- Must have received front-line chemotherapy; no upper limit for the number of prior therapies; patients may have relapsed after prior autologous stem cell transplant or allogeneic stem cell transplant
- Evaluable disease in the phase I, and measurable disease for the phase Ib study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Absolute neutrophil count >= 1,000/dL
- Platelets >= 75,000
- Total bilirubin =< 1.5 X institutional limits; subjects with Gilbert's syndrome may have a bilirubin > 1.5 x upper limit of normal (ULN); activated partial thromboplastin time (aPTT), prothrombin time (PT) not to exceed 1.2 x ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.0 X institutional upper limit of normal
- Serum creatinine within normal institutional limits
- Measured creatinine clearance >= 50 mL/min/for patients with creatinine levels above institutional normal.
- Left ventricular ejection fraction (LVEF) > 50% as defined by echocardiography (ECHO) or multigated acquisition scan (MUGA).
- Negative urine or serum pregnancy test for females of childbearing potential; all females of childbearing potential must use an effective barrier method of contraception (either an intrauterine device [IUD] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter; male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter
- Ability to understand and the willingness to sign a written informed consent document
- Prior Therapy * Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier * Systemic steroids that have not been stabilized (>= 5 days) to the equivalent of =< 10 mg/day prednisone prior to the start of the study drugs * No other concurrent investigational agents are allowed
- Central nervous system metastases, including lymphomatous meningitis will be allowed in the phase II study, but will not be allowed in the phase I
- History of allergic reactions to TGR-1202 or carfilzomib
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women
- Nursing women
- Active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ of the cervix, low risk prostate cancer); if there is a history of prior malignancy, the patient must be disease-free for >= 2 years
- Patients with a low grade lymphoma or CLL and a concurrent high grade lymphoma transformed from the low grade lymphoma or CLL will be eligible
- Patients known to be human immunodeficiency virus (HIV)-positive
- Patients with active hepatitis A, hepatitis B, or hepatitis C infection
- Concomitant use of CYP3A4 inhibitors
- Significant cardiac abnormalities such as: * Myocardial infarction within 6 months of course 1 day 1 (C1D1) * An electrocardiogram (ECG) recorded at screening showing evidence of cardiac ischemia (ST depression of >= 2 mm, measured from isoelectric line to the ST segment); if in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not coronary artery disease (CAD) is present; * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 50% defined by multigated acquisition scan (MUGA) and echocardiogram (ECHO)
- A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsade de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter-defibrillator (AICD)
Locations & Contacts
Contact: Changchun Deng
Trial Objectives and Outline
I. Determine the maximum tolerated dose (MTD), maximally administered dose (MAD), and dose limiting toxicity (DLT) of the combination of umbralisib (TGR-1202) and carfilzomib. (Phase I)
II. Evaluate the safety and toxicity of the combination of TGR-1202 and carfilzomib. (Phase I)
III. Evaluate the safety and toxicity of the combination of TGR-1202 and carfilzomib at the MTD dose level in patients with relapsed and refractory (R/R) peripheral T cell lymphoma (PTCL) and C-MYC positive diffuse large B cell lymphoma (DLBCL). (Phase Ib)
I. Describe the maximum number of cycles administered. (Phase I)
II. Describe the number of dose delays and dose reductions at the MTD. (Phase I)
III. Describe the anti-tumor activity of the combination. (Phase I)
IV. Evaluate the objective response rate (ORR), progression free survival (PFS), and duration of response (DOR) of the study population. (Phase I)
V. Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post-treatment) including gene expression profiling (GEP) and immunohistochemistry (IHC). (Phase I)
VI. Establish the pharmacokinetic profile for TGR-1202 and carfilzomib when given as a combination in cycle 1. (Phase I)
VII. Estimate the ORR (complete + partial response) of the combination of TGR-1202 and carfilzomib in patients with R/R PTCL and C-MYC positive DLBCL. (Phase Ib)
VIII. Estimate the DOR and PFS of the combination in patients with R/R PTCL and C-MYC positive DLBCL. (Phase Ib)
OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase Ib study.
Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 8, and 15 and umbralisib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks, and every 3-4 months for 1 year.
Trial Phase & Type
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Secondary IDs NCI-2017-01352
Clinicaltrials.gov ID NCT02867618