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Ibrutinib and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT02744612
Recruitment Status : Recruiting
First Posted : April 20, 2016
Last Update Posted : April 9, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Pharmacyclics LLC.
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
This phase II trial studies how well ibrutinib and brentuximab vedotin work in treating patients with Hodgkin lymphoma that has returned (relapsed) or does not respond to treatment (refractory). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as brentuximab vedotin, may interfere with the ability of cancer cells to grow and spread. Giving ibrutinib together with brentuximab vedotin may be a better treatment for Hodgkin lymphoma.

Condition or disease Intervention/treatment Phase
Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma Drug: Brentuximab Vedotin Drug: Ibrutinib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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. Courses 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multi-Center Phase II Trial of Ibrutinib Plus Brentuximab Vedotin in Relapsed/Refractory Hodgkin Lymphoma
Study Start Date : June 20, 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Treatment (Ibrutinib plus Brentuximab Vedotin) Drug: Brentuximab Vedotin
Given IV
Other Names:
  • ADC SGN-35
  • Adcetris
  • Anti-CD30 Antibody-Drug Conjugate SGN-35
  • Anti-CD30 Monoclonal Antibody-MMAE SGN-35
  • Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
  • cAC10-vcMMAE
  • SGN-35

Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • PCI-32765




Primary Outcome Measures :
  1. CR rate; based on the Cheson criteria [ Time Frame: Up to 2 years ]
    The complete response rate will be calculated as the percent of evaluable patients that have confirmed CR; exact 95% confidence intervals will be calculated for this estimate.


Secondary Outcome Measures :
  1. Duration of overall response [ Time Frame: Up to 2 years ]
    The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR), per Cheson criteria, (whichever is first recorded) until the first date that relapsed or progressive disease is objectively documented.

  2. Number of patients with treatment-related adverse events (overall), scored using the CTCAE version 4.03 [ Time Frame: Up to 2 years ]

    3a. Number of patients with treatment-related adverse events (by organ system), as assessed by CTCAE version 4.03.

    3b. Number of patients with treatment-related adverse events (by grade, within each organ system), as assessed by CTCAE version 4.03.

    3c. Time to onset for each treatment-related adverse event, calculated as time from start of treatment to time of onset.

    3d. Duration of each treatment-related adverse event, calculated as time from initial detection (start date) of adverse event to documented resolution (stop date).

    3e. Association of adverse event to treatment, defined as an adverse event with an attribution of at least possibly related to the study regimen.


  3. ORR: Overall Response Rate [ Time Frame: Up to 2 years ]
    The overall response rate will be calculated as the percent of evaluable patients that have confirmed CR or PR; exact 95% confidence intervals will be calculated for this estimate.

  4. OS: Overall Survival [ Time Frame: Duration of time from start of treatment to time of death (due to any cause), assessed up to 2 years ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  5. PFS: Progression-free Survival [ Time Frame: Duration of time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
    Will be estimated using the product-limit method of Kaplan and Meier.



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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically documented or cytologically confirmed Hodgkin lymphoma with cluster of differentiation (CD)30 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
  • 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 radiation therapy is allowed
  • 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; 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 history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); 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 (eg, 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02744612


Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Robert W. Chen, MD    626-256-4673      
Principal Investigator: Robert W. Chen, MD         
University of California San Diego Not yet recruiting
La Jolla, California, United States, 92093
Contact: Carolyn M. Mulroney, MD    858-822-6600      
Principal Investigator: Carolyn M. Mulroney, MD         
United States, New York
Weill Medical College of Cornell University Not yet recruiting
New York, New York, United States, 10065
Contact: Peter Martin, MD    646-962-2064      
Principal Investigator: Peter Martin, MD         
United States, Ohio
Ohio State University Comprehensive Cancer Center Not yet recruiting
Columbus, Ohio, United States, 43210
Contact: Kami Maddocks, MD    614-688-7942      
Principal Investigator: Kami Maddocks, MD         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Pharmacyclics LLC.
Investigators
Principal Investigator: Robert Chen, MD City of Hope Medical Center

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02744612     History of Changes
Other Study ID Numbers: 15334
NCI-2016-00176 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15334 ( Other Identifier: City of Hope Medical Center )
First Posted: April 20, 2016    Key Record Dates
Last Update Posted: April 9, 2018
Last Verified: April 2018

Additional relevant MeSH terms:
Hodgkin Disease
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs