PRIMARY OBJECTIVE:
I. Evaluate the anti-tumor activity of the two agent combination ibrutinib and brentuximab
vedotin, as assessed by complete response (CR) rate.
SECONDARY OBJECTIVES:
I. Assess the safety and tolerability of the two agent combination through evaluation of
toxicities, including type, frequency, severity, attribution, time course and duration.
II. Obtain estimates of overall response rate (ORR), response duration and survival (overall
and progression-free).
III. Describe outcomes of patients who ultimately undergo autologous or allogeneic
hematopoietic cell transplantation following treatment with ibrutinib/brentuximab vedotin.
EXPLORATORY OBJECTIVE:
I. Collect deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) from lymphoma specimens and
serial plasma samples for future biomarker evaluation.
OUTLINE:
Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21 and brentuximab vedotin
intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for up to 2
years.
Inclusion Criteria:
- Patients must have histologically documented or cytologically confirmed Hodgkin
lymphoma with CD30 expression
- Patients must have absolute neutrophil count (ANC) >= 1000/uL; neupogen can be given
before and during treatment to achieve target ANC >= 1000/uL
- Patients must have platelets (plt) >= 50,000/uL; platelet transfusion and packed red
blood cell transfusion can also be given prior to the start of treatment and during
treatment to achieve a target plt >= 50,000/uL provided that patients have not
received growth factors for at least 14 days prior to entering trial
- Patients must have hemoglobin >= 8.5 g/dl; platelet transfusion and packed red blood
cell transfusion can also be given prior to the start of treatment and during
treatment to achieve a target hemoglobin of >= 8.5/ul provided that patients have not
received growth factors for at least 14 days prior to entering trial
- Patients must have measurable disease > 1.5 cm evidenced by computed tomography (CT)
scan of the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET)
scans
- Patients must be either refractory to or relapsed after 1 line of therapy
- Prior radiation therapy is allowed
- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care
- Female subject is either post-menopausal, surgically sterilized, or willing to use an
acceptable method of birth control (i.e. a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study
- Male subject agrees to use an acceptable method of contraception for the duration of
the study
- Over 40 kg; life expectancy of greater than 3 months
- Eastern Cooperative Oncology Group (ECOG) of 0-2
- Total bilirubin within 1.5 x the upper limit of normal institutional limits; patients
with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional
upper limit of normal (unless demonstrated Hodgkin lymphoma involvement of the liver);
estimated creatinine clearance >= 30 ml/min (Cockcroft-Gault) and/or 24 urine analysis
as needed
- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x upper limit of
normal (ULN) and partial thromboplastin time (PTT) (activated PTT [aPTT]) < 1.5 x ULN
- The effects of brentuximab vedotin and ibrutinib on the developing fetus is unknowm;
for this reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) prior to
study entry and for six months following duration of study participation; should a
woman become pregnant or suspect that she is pregnant while participating on the
trial, she should inform her treating physician immediately
- All subjects must have the ability to understand and the willingness to sign a written
informed consent; they are to give voluntary written informed consent before
performance of any study-related procedure not part of normal medical care, with the
understanding that consent may be withdrawn by the subject at any time without
prejudice to future medical care
- Patient must be either refractory to or relapsed after 1 line of therapy
- Prior hematopoietic transplantation is allowed (autologous and/or allogeneic)
- Prior brentuximab vedotin is allowed provided that patients were not refractory
(defined as developing progressive disease while on treatment or progressed within 3
months of finished last dose of brentuximab vedotin)
- Prior ibrutinib for Hodgkin lymphoma is not allowed
Exclusion Criteria:
- Less than or equal to 40 kg
- Any life-threatening illness, medical condition, or organ system dysfunction that, in
the investigator's opinion, could compromise the subject's safety or put the study
outcomes at undue risk
- Unwilling or unable to participate in all required study evaluations and procedures
- Unable to understand the purpose and risks of the study and to provide a signed and
dated informed consent form (ICF) and authorization to use protected health
information (in accordance with national and local subject privacy regulations)
- Patients should not have any uncontrolled illness including ongoing or active
infection
- Patients may not be receiving any other investigational agents, or concurrent
biological therapy, chemotherapy, or radiation therapy
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ibrutinib and brentuximab vedotin (BV)
- Patients must not have received prior chemotherapy or radiation for =< 3 weeks before
study enrollment, or those who have not recovered from the adverse events due to
agents administered more than 3 weeks earlier are excluded
- Myocardial infarction within 6 months prior to enrollment or New York Heart
Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; prior to study entry, any
electrocardiogram (ECG) abnormality at screening has to be documented by the
investigator as not medically relevant
- Significant screening electrocardiogram (ECG) abnormalities including, but not limited
to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd
degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac
pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are
considered not clinically significant as documented via a cardiology evaluation
- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
- Patients with active central nervous system (CNS) disease or history of brain
metastases are excluded from study
- Patients may be on steroids prior to initiation of treatment, provided that, by cycle
1 day 1, steroids use was tapered down to less than or equal to 20 mg of prednisone
- Pregnant women are excluded from this study because of the potential teratogenic or
abortifacient effects; because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother, breastfeeding should
be discontinued
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
- Recent infection requiring systemic treatment that was completed =< 14 days before the
first dose of study drug
- Known active infection with human immunodeficiency virus (HIV), hepatitis C virus
(HCV) or hepatitis B virus (HBV); testing to be done only if patients suspected of
having infections or exposures; subjects who are positive for hepatitis B core
antibody or hepatitis B surface antigen must have a negative polymerase chain reaction
(PCR) result before enrollment; those who are PCR positive will be excluded; subjects
who have an undetectable human immunodeficiency virus (HIV) viral load with CD4 >= 200
and are on highly active antiretroviral therapy (HAART) medication are allowed
- Currently active, clinically significant hepatic impairment Child-Pugh class B or C
according to the Child Pugh classification
- STUDY-SPECIFIC EXCLUSIONS:
- Patient has hypersensitivity to brentuximab vedotin
- Refractory to prior brentuximab vedotin (defined as developing progressive disease
while on treatment or progressed within 3 month of finished last dose of brentuximab
vedotin)
- No active graft-versus-host disease (GVHD) or on immunosuppressive medication for GVHD
- Recent infection requiring intravenous anti-infective treatment that was completed =<
14 days before the first dose of study drug
- Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade 0 or 1, or
to the levels dictated in the inclusion/exclusion criteria, with the exception of
alopecia
- Baseline grade II peripheral neuropathy
- Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment
- Major surgery within 4 weeks of first dose of study drug
- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
gastrointestinal function, or resection of the stomach or small bowel, symptomatic
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
obstruction
- Concomitant use of warfarin or other vitamin K antagonists
- Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
- Subjects, who in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study
