Brentuximab Vedotin and Gemcitabine Hydrochloride in Treating Younger Patients With Relapsed or Refractory Hodgkin Lymphoma

Recurrent Adult Hodgkin Lymphoma Clinical Trial

Official title:

A Phase 1/2 Study of Brentuximab Vedotin (SGN35) in Combination With Gemcitabine for Pediatric and Young Adult Patients With Relapsed or Refractory Hodgkin Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01780662
• Other study ID #: NCI-2013-00107
• Secondary ID: NCI-2013-00107AH
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 31, 2013
• Est. completion date: September 30, 2021

Study information

• Verified date: October 2021
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I/II trial studies the side effects and the best dose of brentuximab vedotin when given together with gemcitabine hydrochloride and to see how well they work in treating younger patients with Hodgkin lymphoma that has returned or does not respond to treatment. Monoclonal antibodies, such as brentuximab vedotin, may find cancer cells and help kill them. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving brentuximab vedotin together with gemcitabine hydrochloride may kill more cancer cells.

Description:

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of brentuximab vedotin in combination with gemcitabine administered every three weeks to children with relapsed or primary refractory Hodgkin lymphoma (HL).

II. To define and describe the toxicities of brentuximab vedotin in combination with gemcitabine administered on this schedule.

III. To determine the complete response (CR) rate after treatment with four cycles of gemcitabine with brentuximab vedotin among patients with relapsed or refractory HL.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of brentuximab vedotin in combination with gemcitabine within the confines of a Phase 1 study.

II. To describe the overall response rate (ORR) after 4 cycles of therapy among patients with relapsed or refractory HL.

III. To describe the proportion of patients with HL able to mobilize an adequate yield of cluster of differentiation (CD) 34+ stem cells after gemcitabine with brentuximab vedotin.

IV. To describe the relationship between disease response among patients with HL and changes in thymus and activation-regulated chemokine (TARC) during treatment, and to determine if specific micro ribonucleic acid (miRNA) profiles correlate with response to treatment.

V. To describe the frequency of the Fc gamma receptor IIIa (FcγRIIIa)-158 valine (V)/phenylalanine (F) polymorphism among patients who experience pulmonary toxicity on this protocol.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study. (Phase I completed as of amendment 4)

Patients receive brentuximab vedotin intravenously (IV) over 30 minutes on day 1 and gemcitabine hydrochloride IV over 100 minutes on days 1 and 8. Treatment repeats every 21 days for up to 15 more courses in the absence of disease progression or unacceptable toxicity. Patients with CR after any course may go off protocol therapy for stem cell transplant.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 30, 2021
• Est. primary completion date: September 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Months to 30 Years

Eligibility

Inclusion Criteria:

• Patients must have had histologic verification of the malignancy at original diagnosis; patients must have histologic verification of recurrent Hodgkin disease at the time of relapse; no additional biopsy is required for patients with primary refractory disease (i.e. no prior CR)

• PARTS A AND B: Patients with Hodgkin lymphoma (HL) are eligible for both the phase 1 and 2 portions, if they are in one of the following categories:

• Primary refractory disease (i.e. no prior CR)

• Very early relapse (< 6 months from the end of initial therapy, including chemotherapy ± radiation)

• Advanced stage (III or IV) at diagnosis who relapse less than one year from the end of initial therapy

• Note that patients with low-stage disease (IA or IIA) at initial diagnosis, who were treated with radiation alone or fewer than four cycles of chemotherapy will NOT be eligible

• Patients must have measurable disease, documented by clinical and radiographic criteria

• Patients must have a life expectancy of >= 8 weeks (>= 56 days)

• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy

• At least 14 days after the last dose of myelosuppressive chemotherapy (28 days if prior nitrosourea); Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of therapy

• At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair

• At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair

• At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines

• At least 3 half-lives of the antibody after the last dose of a monoclonal antibody

• At least 14 days after local palliative radiation therapy (XRT) (small port); at least 150 days must have elapsed if prior total body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation

• Patients with prior autologous or allogeneic stem cell transplant (SCT) are excluded from this study

• At least 28 days must have elapsed since the most recent dose of bleomycin, to allow adequate time to detect evidence of bleomycin-related pulmonary toxicity

• PART A: FOR PATIENTS WITH KNOWN BONE MARROW INVOLVEMENT (Completed as of Amendment 4)

• Peripheral absolute neutrophil count (ANC) >= 1000/uL

• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• PART B: FOR PATIENTS WITHOUT KNOWN BONE MARROW INVOLVEMENT

• Peripheral absolute neutrophil count (ANC) >= 750/uL

• Platelet count >= 75,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• Patients with lymphoma metastatic to bone marrow who have granulocytopenia, anemia, and/or thrombocytopenia will be eligible for study but not evaluable for hematologic toxicity (in Part A, there will be a maximum of one per cohort); such patients must meet the blood counts as in Part A (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled in Part A must be evaluable for hematologic toxicity

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 OR

• A serum creatinine based on age/gender as follows:

• =< 0.6 mg/dL (for 1 to < 2 years of age)

• =< 0.8 mg/dL (for 2 to < 6 years of age)

• =< 1.0 mg/dL (for 6 to < 10 years of age)

• =< 1.2 mg/dL (for 10 to < 13 years of age)

• =< 1.4 mg/dL (for females >= 13 years of age)

• =< 1.5 mg/dL (for males 13 to < 16 years of age)

• =< 1.7 mg/dL (for males >= 16 years of age)

• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age; for the purpose of this study, the ULN for SGPT is 45 U/L

• Serum albumin >= 2 g/dL

• No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry > 92% while breathing room air

• Forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and forced vital capacity all > 50% predicted value; Note: pulmonary function testing is not required for children < 8 years old, or for any child who is developmentally unable to comply with pulmonary function testing

• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled

• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4) resulting from prior therapy must be < grade 2

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during protocol therapy and for at least 30 days after the last dose of brentuximab vedotin; abstinence is an acceptable method of birth control

• Concomitant medications

• Patients receiving stable or decreasing corticosteroids are not eligible for other concurrent conditions (e.g. asthma, autoimmune diseases, rash, documented adrenal insufficiency) are eligible for this study

• Patients who are currently receiving another investigational drug are not eligible

• Patients who are currently receiving other anti-cancer agents are not eligible

• Patients who have an uncontrolled infection are not eligible

• Patients with an immunodeficiency that existed prior to diagnosis, such as primary immunodeficiency syndromes, organ transplant recipients and children on current systemic immunosuppressive agents are not eligible

• Patients known to be positive for human immunodeficiency virus (HIV) are not eligible

• Prior therapy

• Patients with prior exposure to brentuximab vedotin are not eligible; NOTE: prior exposure to gemcitabine is NOT an exclusion criterion

• Patients who have undergone prior autologous or allogeneic SCT are not eligible

• Patients with HL who were stage IA or IIA at initial diagnosis and treated with either radiation alone or < 4 cycles of chemotherapy are not eligible

• Patients who have received a prior solid organ transplantation are not eligible

• Patients with known hypersensitivity to Escherichia coli (E.coli)-derived proteins, filgrastim, or any component of filgrastim are not eligible

• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Related Conditions & MeSH terms

• Hodgkin Disease
• Lymphoma
• Recurrent Adult Hodgkin Lymphoma
• Recurrent Childhood Hodgkin Lymphoma
• Refractory Childhood Hodgkin Lymphoma

Intervention

Drug:
• Brentuximab Vedotin
Given IV
• Gemcitabine Hydrochloride
Given IV

Locations

Country	Name	City	State
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Children's Hospital	London	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD) for Brentuximab Vedotin	MTD was determined as the maximum dose at which fewer than one-third of patients experience Dose Limiting Toxicities (DLT) as assessed by National Cancer Institute (NCI) CTCAE v 4.0 during Cycle 1 of therapy. Gemcitabine was administered on days 1 and 8 of a 21 day cycle at a fixed dose. Brentuximab vedotin was investigated at a starting dose of 1.4 mg/kg administered on day 1 and escalated if tolerated.	During cycle 1 of protocol therapy (21 days)
Primary	Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	The number of eligible patients assigned to receive brentuximab vedotin in combination with gemcitabine that experienced CTC Version 4, grade 3 or higher adverse events during Phase 1 and Phase 2.	13 months from first dose
Primary	The Number of Patients With Relapsed or Refractory HL Who Achieved Complete Response (CR)	The number of patients who experienced complete Response (CR) within the first four cycles. By modern response criteria, those with partial response (PR) or stable disease with all target lesions with Deauville scores <=3 after cycle 4 are also considered as CR. Patients were assessed after treatment with four cycles of gemcitabine with brentuximab vedotin. CR was only reported for Dose level 2 across both phases of study.	After 4 cycles (21 days per cycle) of protocol therapy
Secondary	The Number of Patients Who Had Disease Response Assessed by Deauville Scales Among Those in Phase I With Dose Level 2.	The Deauville five-point scale was used to assess the number of participants with complete response (CR) and partial response (PR). A lower score indicates a better outcome. Scores of 1-3 represent CR and 4-5 represent PR.	Up to 13 months from first dose
Secondary	Percentage of Patients Who Achieved Overall Response (OR) as Measured by Complete Response (CR) and Partial Response (PR)	The percentage of patients who experienced complete Response (CR) within the first four cycles.By modern response criteria, those with partial response (PR) or stable disease with all target lesions with Deauville scores <=3 after cycle 4 are also considered as CR. Patients were assessed after treatment with four cycles of gemcitabine with brentuximab vedotin. CR was only reported for Dose level 2 across both phases of study.	After 4 cycles (21 days per cycle) of protocol therapy
Secondary	The Number of Patients Who Had Successful Peripheral Blood Stem Cell (PBSC) Collection	Successful PBSC collection was defined as a collection of more than 2x10^6 CD34 positive cells.	From 1 to 5 cycles
Secondary	Plasma Level of Thymus and Activation-Regulated Chemokine (TARC)	Limit to 41 evaluable patients who received dose 1.8 mg/kg	From baseline to time prior to cycle 2
Secondary	Correlation Between Micro Ribonucleic Acid (miRNA) and Disease Response to Protocol Treatment	Limit to 41 evaluable patients who received dose 1.8 mg/kg	From the end of first dose to the end of last dose (Up to 13 Months)
Secondary	Number of Patients With FcyRIIIa-158 V/F (Valine/Phenylalanine) Polymorphism	Among patients who received 1.8mg/kg dose, the frequency of the Fc?RIIIa-158 V/F polymorphism are described.	From the end of first dose to the end of last dose (Up to 13 Months)