Pevonedistat and Ibrutinib in Treating Participants With Relapsed or Refractory CLL or Non-Hodgkin Lymphoma

  • STATUS
    Recruiting
  • End date
    Apr 2, 2024
  • participants needed
    30
  • sponsor
    City of Hope Medical Center
Updated on 17 July 2021
ct scan
cancer
lymphoid leukemia
anemia
chronic lymphocytic leukemia
lymphoma
hodgkin's disease
flow cytometry
absolute neutrophil count
waldenstrom's macroglobulinemia
measurable disease
direct bilirubin
fatigue
leukemia
lymphocytic leukemia
gilbert's syndrome
thrombocytopenia
venetoclax
neutrophil count
blood transfusion
prolymphocytic leukemia
follicular lymphoma
conjugated bilirubin
diffuse large b-cell lymphoma
b-cell lymphoma
mantle cell lymphoma
idelalisib
withdrawn
marginal zone lymphoma
large b-cell lymphoma
ibrutinib
btk inhibitor
night sweats
lymphocytosis
refractory chronic lymphocytic leukemia
richter's transformation
richter's syndrome
b-cell prolymphocytic leukemia

Summary

This phase I trial studies the side effects and best dose of pevonedistat when given together with ibrutinib in participants with chronic lymphocytic leukemia or non-Hodgkin lymphoma that has come back or has stopped responding to other treatments. Pevonedistat and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of pevonedistat administered in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

SECONDARY OBJECTIVES:

I. Overall response rate (ORR) will be determined based on the proportion of study participants who achieve complete response (CR), complete response with incomplete marrow recovery (CRi), partial response (PR) or nodular partial response (nPR) assessed after completion of therapy.

II. Event-free survival (EFS), defined as the interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti-leukemic therapy, or death, whichever is first reported.

OUTLINE: This is a dose-escalation study of pevonedistat.

Participants receive pevonedistat intravenously (IV) over 1 hour on days 1, 3, and 5, and ibrutinib orally (PO) daily on days 2-21 of course 1 and days 1-21 of subsequent courses. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Participants then receive only ibrutinib PO daily on days 1-21. Treatment repeats every 21 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants will be followed up for every 3 months

Details
Condition Refractory Follicular Lymphoma, Recurrent Follicular Lymphoma, Refractory Marginal Zone Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Refractory Chronic Lymphocytic Leukemia, Chronic Lymphocytic Leukemia Refractory, Recurrent Non-Hodgkin Lymphoma, Refractory Lymphoplasmacytic Lymphoma, chronic lymphocytic leukemia, relapsed, Recurrent Lymphoplasmacytic Lymphoma, Refractory Small Lymphocytic Lymphoma, Recurrent Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Recurrent Marginal Zone Lymphoma, Richter's Transformation, Refractory Non Hodgkin Lymphoma, Richter Syndrome, Refractory Diffuse Large B Cell Lymphoma, B-cell prolymphocytic leukemia, Recurrent Mantle Cell Lymphoma, Richter's Syndrome, Refractory Mantle Cell Lymphoma
Treatment laboratory biomarker analysis, Ibrutinib, pharmacological study, Pevonedistat, Pharmacokinetic Study
Clinical Study IdentifierNCT03479268
SponsorCity of Hope Medical Center
Last Modified on17 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Dose escalation cohort
Histologically or flow cytometry confirmed diagnosis of B-CLL/small lymphocytic lymphoma (SLL) according to National Cancer Institute sponsored Working Group (NCI-WG) 1996 guidelines
The following types of NHL as documented by medical records and with histology based on criteria established by the World Health Organization (WHO)
Mantle cell lymphoma (MCL)
Follicular lymphoma (FL) - grades 1-3a
Lymphoplasmacytic lymphoma (LPL)
Marginal zone lymphoma (MZL)
CLL in Richter's transformation
B-cell prolymphocytic leukemia (B-PLL)
Diffuse large B-cell lymphoma (DLBCL)
Expansion cohort - histologically or flow cytometry confirmed diagnosis of B-CLL/SLL according to NCI-WG 1996 guidelines; 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
Patients with MCL underwent >= 1 chemoimmunotherapy-based regimen; patients with FL and MZL underwent >= 1 prior chemotherapy-based and/or immunotherapy-based regimen; patients with DLBCL and CLL in Richter's transformation underwent >= 1 chemoimmunotherapy-based regimen and are not transplant-eligible; patients with CLL, B-PLL and LPL underwent >= 1 chemotherapy-based, or immunotherapy-based or targeted therapy regimen (e.g., PI3K inhibitors [idelalisib], venetoclax, ibrutinib or an investigational agent, including an investigational BTK inhibitor); all regimens must have been administered for >= 2 cycles, and patients must have had either documented disease progression or no response (stable disease) to the most recent treatment regimen
Patients with CLL/SLL demonstrate active disease meeting at least 1 of the International Workshop on Chronic Lymphocytic Leukemia (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 100.5 F 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
Patients with NHL and with B-cell prolymphocytic leukemia must have an indication for treatment in the opinion of the investigator
For diseases other than LPL and CLL, presence of radiographically measurable lymphadenopathy or extra-nodal lymphoid malignancy (defined as the presence of >= 1 lesion that measures >= 2.0 cm in the longest dimension [LD] and >= 1.0 cm in the longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or magnetic resonance imaging [MRI]); for LPL, measurable disease will be defined as serum monoclonal IgM > 0.5 g/dL or meeting at least 1 of the recommendations from the Second International Workshop on LPL for requiring treatment
Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and expected survival > 3 months from study enrollment
Total bilirubin =< institutional upper limit of normal (ULN) (unless due to known Gilbert's syndrome or compensated hemolysis directly attributable to CLL); patients with Gilbert's syndrome may enroll if direct bilirubin =< 1.5 x ULN of the direct bilirubin; elevated indirect bilirubin due to post-transfusion hemolysis is allowed
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than 2.5 X institutional ULN
Estimated creatinine clearance (CrCL) using the Cockcroft-Gault equation >= 50 mL/min
Platelets >= 50,000/mm^3 independent of transfusion support, with no active bleeding, and absolute neutrophil count >= 1000/mm^3, unless due to disease involvement in the bone marrow
Albumin > 2.7 g/dL
Hemoglobin > 8 g/dL; patients may be transfused to achieve this value
Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care
Female patients who
Are postmenopausal for at least 1 year before the screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential
Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together)
Male patients, even if surgically sterilized (i.e., status post-vasectomy), who
Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, OR
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together)

Exclusion Criteria

Prior therapeutic intervention with any of the following
Therapeutic anticancer antibodies (rituximab, obinutuzumab) within 4 weeks
Radio- or toxin-immunoconjugates within 10 weeks
Inhibitors of PI3K (idelalisib), ibrutinib, BH3-mimetic venetoclax, lenalidomide, and other targeted therapy (including investigational BTK inhibitors and other investigational therapy) within 6 half-lives
All other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy
Intolerance of ibrutinib
Inadequate recovery from adverse events related to prior therapy to grade =< 1 (excluding grade 2 alopecia and neuropathy)
Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent
Stem cell transplant recipients must have no evidence of active graft-versus-host disease and should not be receiving treatment for it
Known involvement of central nervous system
Use of full dose, therapeutic anti-coagulation or patients with uncontrolled coagulopathy or bleeding disorder
Treatment with strong CYP3A inhibitors or inducers within 14 days before the first dose of study drug; strong CYP3A inhibitors/inducers are not permitted during the study, including nutraceutical preparations, e.g., grapefruit juice and St John's wort; patients must have no prior history of amiodarone in the 6 months prior to the first dose of pevonedistat
Patient requiring chronic treatment with BCRP inhibitors (cyclosporine, eltrombopag)
History prior malignancy except
Malignancy treated with curative intent and no known active disease present for >= 2 years prior to initiation of therapy on current study
Adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease
Adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease
Asymptomatic prostate cancer managed with watch and wait strategy
Myelodysplastic syndrome which is clinically well controlled and no evidence of the cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow at screening
Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test in absence of hemolysis or history of immune-mediated cytopenias are not exclusions)
History of human immunodeficiency virus (HIV) infection
Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C Infection; Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load
Known cardiopulmonary disease defined as one of the following
Unstable angina
Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mm Hg )
Congestive heart failure (New York Heart Association [NYHA] class III or IV)
Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as a (acute chest syndrome [ACS]), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll)
Cardiomyopathy
Clinically significant arrhythmia: 1) History of polymorphic ventricular fibrillation or torsade de pointes, 2) Permanent atrial fibrillation [a fib], defined as continuous a fib for >= 6 months, 3) Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening, 4) grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and 5) Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen
Implantable cardioverter defibrillator
Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)
Pulmonary hypertension
Prolong rate corrected QT (QTc) interval >= 500 msec. calculated according to institutional guidelines
Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography
Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial lung disease, and pulmonary fibrosis
Known hepatic cirrhosis or severe pre-existing hepatic impairment
Major surgery (requiring general anesthesia) within 14 days before the first dose of study drug or a scheduled surgery during study period
Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on day 1 before first dose of study drug
Inability to swallow and retain an oral medication; 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 ibrutinib
Active uncontrolled infection or severe infection disease (e.g., severe pneumonia, meningitis, septicemia, or methicillin resistant Staphylococcus aureus infection)
Any condition for which participation in the study is judged by the investigator to be detrimental to the patient with inter-current illness or psychiatric/social situations that would jeopardize compliance with study requirements
Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)
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