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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01780662
• Collaborator: (none)
• Enrollment: 46
• Locations: 116
• Arm: 1
• Actual Duration (Months): 104
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Adult Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Refractory Childhood Hodgkin Lymphoma	Drug: Brentuximab Vedotin; Drug: Gemcitabine Hydrochloride	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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).

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

3. 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:

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

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

3. 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.

4. 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.

5. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jan 31, 2013
• Actual Primary Completion Date: Sep 30, 2017
• Actual Study Completion Date: Sep 30, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (brentuximab vedotin, gemcitabine hydrochloride) Patients receive brentuximab vedotin 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.

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: Gemcitabine Hydrochloride; Given IV; Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride FF 10832 FF-10832 FF10832 Gemcitabine HCI Gemzar LY-188011 LY188011

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) for Brentuximab Vedotin [During cycle 1 of protocol therapy (21 days)]

   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.

2. Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [13 months from first dose]

   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.

3. The Number of Patients With Relapsed or Refractory HL Who Achieved Complete Response (CR) [After 4 cycles (21 days per cycle) of protocol therapy]

   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.

Secondary Outcome Measures

1. The Number of Patients Who Had Disease Response Assessed by Deauville Scales Among Those in Phase I With Dose Level 2. [Up to 13 months from first dose]

   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.

2. Percentage of Patients Who Achieved Overall Response (OR) as Measured by Complete Response (CR) and Partial Response (PR) [After 4 cycles (21 days per cycle) of protocol therapy]

   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.

3. The Number of Patients Who Had Successful Peripheral Blood Stem Cell (PBSC) Collection [From 1 to 5 cycles]

   Successful PBSC collection was defined as a collection of more than 2x10^6 CD34 positive cells.

4. Plasma Level of Thymus and Activation-Regulated Chemokine (TARC) [From baseline to time prior to cycle 2]

   Limit to 41 evaluable patients who received dose 1.8 mg/kg

5. Correlation Between Micro Ribonucleic Acid (miRNA) and Disease Response to Protocol Treatment [From the end of first dose to the end of last dose (Up to 13 Months)]

   Limit to 41 evaluable patients who received dose 1.8 mg/kg

6. Number of Patients With FcyRIIIa-158 V/F (Valine/Phenylalanine) Polymorphism [From the end of first dose to the end of last dose (Up to 13 Months)]

   Among patients who received 1.8mg/kg dose, the frequency of the FcγRIIIa-158 V/F polymorphism are described.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Months to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
4	Loma Linda University Medical Center	Loma Linda	California	United States	92354
5	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
6	Valley Children's Hospital	Madera	California	United States	93636
7	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
8	Children's Hospital of Orange County	Orange	California	United States	92868
9	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
10	Sutter Medical Center Sacramento	Sacramento	California	United States	95816
11	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
12	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
13	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
14	Children's Hospital Colorado	Aurora	Colorado	United States	80045
15	Yale University	New Haven	Connecticut	United States	06520
16	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
17	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
18	Children's National Medical Center	Washington	District of Columbia	United States	20010
19	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
20	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
21	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
22	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
23	Nicklaus Children's Hospital	Miami	Florida	United States	33155
24	AdventHealth Orlando	Orlando	Florida	United States	32803
25	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
26	Nemours Children's Hospital	Orlando	Florida	United States	32827
27	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
28	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
29	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
30	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
31	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
32	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
33	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
34	University of Illinois	Chicago	Illinois	United States	60612
35	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
36	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
37	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
38	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
39	Blank Children's Hospital	Des Moines	Iowa	United States	50309
40	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
41	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
42	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
43	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
44	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
45	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
46	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
47	Baystate Medical Center	Springfield	Massachusetts	United States	01199
48	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
49	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
50	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
51	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
52	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
53	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
54	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
55	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
56	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
57	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
58	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
59	Morristown Medical Center	Morristown	New Jersey	United States	07960
60	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
61	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
62	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
63	Albany Medical Center	Albany	New York	United States	12208
64	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
65	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
66	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
67	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
68	University of Rochester	Rochester	New York	United States	14642
69	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
70	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
71	New York Medical College	Valhalla	New York	United States	10595
72	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
73	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
74	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
75	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
76	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
77	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
78	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
79	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
80	Dayton Children's Hospital	Dayton	Ohio	United States	45404
81	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
82	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
83	Oregon Health and Science University	Portland	Oregon	United States	97239
84	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
85	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
86	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
87	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
88	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
89	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
90	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
91	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
92	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
93	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
94	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
95	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
96	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
97	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
98	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
99	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
100	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
101	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
102	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
103	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
104	Seattle Children's Hospital	Seattle	Washington	United States	98105
105	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
106	Madigan Army Medical Center	Tacoma	Washington	United States	98431
107	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
108	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
109	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
110	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
111	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
112	Children's Hospital	London	Ontario	Canada	N6A 5W9
113	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
114	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
115	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
116	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Peter D Cole, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 18, 2015

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01780662
• Other Study ID Numbers: NCI-2013-00107; NCI-2013-00107; AHOD1221; COG-AHOD1221; AHOD1221; AHOD1221; U10CA180886; UM1CA097452
• First Posted: Jan 31, 2013
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Recurrence; Gemcitabine; Brentuximab Vedotin; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoconjugates

Study Results

Participant Flow

Pre-assignment Detail	This is a Phase I /II study. Phase I determined the Maximum Tolerated Dose (MTD) between the first 2 treatment arms; 16 patients enrolled and 9 patients completed therapy. The study was closed and reopened to accrual for Phase II which enrolled an additional 30 patients. Overall, 46 patients were enrolled but only 29 patients completed therapy.

Arm/Group Title	Phase I, 1.4mg/kg	Phase I, 1.8mg/kg	Phase II, 1.8mg/kg
Arm/Group Description	Patients who were enrolled in Phase I and took dose 1.4mg/kg	Patients who were enrolled in Phase I and took dose 1.8mg/kg	Patients who were enrolled in Phase lI and took dose 1.8mg/kg
Period Title: Overall Study
STARTED	3	13	30
COMPLETED	2	7	20
NOT COMPLETED	1	6	10

Baseline Characteristics

Arm/Group Title	Phase I Dose 1.4 mg/kg	Phase I Dose 1.8 mg/kg	Phase 2 Dose 1.8 mg/kg	Total
Arm/Group Description	Patients who were enrolled in Phase I and took dose 1.4mg/kg	Patients who were enrolled in Phase I and took dose 1.8mg/kg	Patients who were enrolled in Phase lI and took dose 1.8mg/kg	Total of all reporting groups
Overall Participants	3	13	30	46
Age (Count of Participants)
<=18 years	3 100%	10 76.9%	24 80%	37 80.4%
Between 18 and 65 years	0 0%	3 23.1%	6 20%	9 19.6%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	1 33.3%	8 61.5%	16 53.3%	25 54.3%
Male	2 66.7%	5 38.5%	14 46.7%	21 45.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 15.4%	9 30%	11 23.9%
Not Hispanic or Latino	3 100%	11 84.6%	20 66.7%	34 73.9%
Unknown or Not Reported	0 0%	0 0%	1 3.3%	1 2.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	2 15.4%	6 20%	8 17.4%
White	3 100%	10 76.9%	19 63.3%	32 69.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 7.7%	5 16.7%	6 13%
Region of Enrollment (Count of Participants)
United States	3 100%	13 100%	28 93.3%	44 95.7%
Canada	0 0%	0 0%	2 6.7%	2 4.3%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) for Brentuximab Vedotin
Description	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.
Time Frame	During cycle 1 of protocol therapy (21 days)

Outcome Measure Data

Analysis Population Description

The first 9 out of 16 patients enrolled with relapsed/refractory HL in a phase 1 dose finding study of brentuximab vedotin in combination with gemcitabine, were used in determining MTD

Arm/Group Title	Treatment (Brentuximab Vedotin, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
Measure Participants	9
Number [mg/kg]	1.8

2. Primary Outcome

Title	Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Description	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.
Time Frame	13 months from first dose

Outcome Measure Data

Analysis Population Description

All eligible patients (N=45). One patient was ineligible due to exceeding the prescribed interval between disease evaluation and study entry.

Arm/Group Title	Dose 1.4mg/kg (Phase I)	Dose 1.8mg/kg (Phase I + Phase II)
Arm/Group Description	Patients who were enrolled in Phase I and took dose 1.4mg/kg	Patients who were enrolled in Phase I and Phase II and took dose 1.8mg/kg
Measure Participants	3	42
Abdominal pain	0 0%	1 7.7%
Adrenal insufficiency	0 0%	1 7.7%
Alanine aminotransferase increased	1 33.3%	13 100%
Anemia	1 33.3%	4 30.8%
Anorexia	0 0%	1 7.7%
Aspartate aminotransferase increased	1 33.3%	10 76.9%
Dehydration	0 0%	1 7.7%
Dental caries	0 0%	1 7.7%
Diarrhea	0 0%	3 23.1%
Febrile neutropenia	0 0%	2 15.4%
GGT increased	0 0%	1 7.7%
Hemolytic uremic syndrome	0 0%	1 7.7%
Hypophosphatemia	0 0%	2 15.4%
Hypotension	0 0%	4 30.8%
Infections and infestations - Other- Specify	0 0%	1 7.7%
Investigations - Other- Specify	0 0%	1 7.7%
Lung infection	0 0%	2 15.4%
Lymphocyte count decreased	3 100%	8 61.5%
Myositis	0 0%	1 7.7%
Nausea	0 0%	2 15.4%
Neutrophil count decreased	3 100%	28 215.4%
Non-cardiac chest pain	0 0%	1 7.7%
Pain in extremity	0 0%	1 7.7%
Pericardial effusion	0 0%	1 7.7%
Platelet count decreased	0 0%	13 100%
Pneumonitis	1 33.3%	0 0%
Pruritus	1 33.3%	0 0%
Rash maculo-papular	0 0%	3 23.1%
Skin infection	0 0%	1 7.7%
Urinary tract infection	0 0%	1 7.7%
White blood cell decreased	3 100%	15 115.4%

3. Primary Outcome

Title	The Number of Patients With Relapsed or Refractory HL Who Achieved Complete Response (CR)
Description	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.
Time Frame	After 4 cycles (21 days per cycle) of protocol therapy

Outcome Measure Data

Analysis Population Description

All eligible patients (N=42) at Dose Level 2 (brentuximab vedotin 1.8 mg/kg with gemcitabine). 4 patients were excluded. 3 patients did not receive dose level 2 and 1 patient was ineligible due to exceeding the prescribed interval between disease evaluation and study entry.

Arm/Group Title	Treatment (Brentuximab Vedotin, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
Measure Participants	42
Count of Participants [Participants]	28 933.3%

4. Secondary Outcome

Title	The Number of Patients Who Had Disease Response Assessed by Deauville Scales Among Those in Phase I With Dose Level 2.
Description	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.
Time Frame	Up to 13 months from first dose

Outcome Measure Data

Analysis Population Description

All eligible patients in phase 1, dose level 2 (N=13). 3 patients in phase 1 were not given dose level 2.

Arm/Group Title	Treatment (Brentuximab Vedotin, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
Measure Participants	13
Count of Participants [Participants]	8 266.7%

5. Secondary Outcome

Title	Percentage of Patients Who Achieved Overall Response (OR) as Measured by Complete Response (CR) and Partial Response (PR)
Description	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.
Time Frame	After 4 cycles (21 days per cycle) of protocol therapy

Outcome Measure Data

Analysis Population Description

All eligible patients (N=42) at Dose Level 2 (brentuximab vedotin 1.8 mg/kg with gemcitabine).4 patients were excluded. 3 patients did not receive dose level 2 and 1 patient was ineligible due to exceeding the prescribed interval between disease evaluation and study entry.

Arm/Group Title	Treatment (Brentuximab Vedotin, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
Measure Participants	42
Number (95% Confidence Interval) [percentage of participants]	74 2466.7%

6. Secondary Outcome

Title	The Number of Patients Who Had Successful Peripheral Blood Stem Cell (PBSC) Collection
Description	Successful PBSC collection was defined as a collection of more than 2x10^6 CD34 positive cells.
Time Frame	From 1 to 5 cycles

Outcome Measure Data

Analysis Population Description

For 21 of the eligible 45 subjects, PBSC collection was not attempted during protocol therapy, either because stem cells had been collected prior to study enrollment, or no autologous stem cell transplant was planned. 1 patient was ineligible due to exceeding the prescribed interval between disease evaluation and study entry.

Arm/Group Title	Treatment (Brentuximab Vedotin, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
Measure Participants	24
Count of Participants [Participants]	24 800%

7. Secondary Outcome

Title	Plasma Level of Thymus and Activation-Regulated Chemokine (TARC)
Description	Limit to 41 evaluable patients who received dose 1.8 mg/kg
Time Frame	From baseline to time prior to cycle 2

Outcome Measure Data

Analysis Population Description

4 eligible patients did not consent for genetic studies. 3 of the 41 did not have baseline TARC and 6 did not have TARC prior to cycle 2.

Arm/Group Title	Dose 1.8mg/kg
Arm/Group Description	Evaluable patients who received dose 1.8mg/kg.
Measure Participants	41
Baseline	5700
Prior to Cycle 2	668

8. Secondary Outcome

Title	Correlation Between Micro Ribonucleic Acid (miRNA) and Disease Response to Protocol Treatment
Description	Limit to 41 evaluable patients who received dose 1.8 mg/kg
Time Frame	From the end of first dose to the end of last dose (Up to 13 Months)

Outcome Measure Data

Analysis Population Description

These samples were banked but not analyzed, due to a change in research priorities.

Arm/Group Title	Treatment (Brentuximab Vedotin, Gemcitabine Hydrochloride)
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
Measure Participants	0

9. Secondary Outcome

Title	Number of Patients With FcyRIIIa-158 V/F (Valine/Phenylalanine) Polymorphism
Description	Among patients who received 1.8mg/kg dose, the frequency of the FcγRIIIa-158 V/F polymorphism are described.
Time Frame	From the end of first dose to the end of last dose (Up to 13 Months)

Outcome Measure Data

Analysis Population Description

4 eligible patients did not consent for genetic studies.

Arm/Group Title	Dose 1.8mg/kg
Arm/Group Description	Evaluable patients with received dose of 1.8mg/kg
Measure Participants	41
Homozygous FF- Phenylalanine	22 733.3%
Heterozygous FV- Valine/Phenylalanine	14 466.7%
Homozygous VV- Valine	5 166.7%

Adverse Events

Time Frame	From first dose up to 13 months.
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events.
Arm/Group Title	Dose1.4mg/kg		Dose 1.8mg/kg
Arm/Group Description	Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV		Patients receive brentuximab vedotin 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. Brentuximab Vedotin: Given IV Gemcitabine Hydrochloride: Given IV
All Cause Mortality
	Dose1.4mg/kg		Dose 1.8mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		2/42 (4.8%)
Serious Adverse Events
	Dose1.4mg/kg		Dose 1.8mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		37/42 (88.1%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	4/42 (9.5%)	4
Febrile neutropenia	0/3 (0%)	0	2/42 (4.8%)	2
Hemolytic uremic syndrome	0/3 (0%)	0	1/42 (2.4%)	1
Cardiac disorders
Pericardial effusion	0/3 (0%)	0	1/42 (2.4%)	1
Endocrine disorders
Adrenal insufficiency	0/3 (0%)	0	1/42 (2.4%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	1/42 (2.4%)	1
Dental caries	0/3 (0%)	0	1/42 (2.4%)	1
Diarrhea	0/3 (0%)	0	3/42 (7.1%)	3
Nausea	0/3 (0%)	0	2/42 (4.8%)	2
General disorders
Non-cardiac chest pain	0/3 (0%)	0	1/42 (2.4%)	1
Infections and infestations
Infections and infestations - Other- Specify	0/3 (0%)	0	1/42 (2.4%)	1
Lung infection	0/3 (0%)	0	2/42 (4.8%)	2
Skin infection	0/3 (0%)	0	1/42 (2.4%)	1
Urinary tract infection	0/3 (0%)	0	1/42 (2.4%)	1
Investigations
Alanine aminotransferase increased	1/3 (33.3%)	1	13/42 (31%)	13
Aspartate aminotransferase increased	1/3 (33.3%)	1	10/42 (23.8%)	10
GGT increased	0/3 (0%)	0	1/42 (2.4%)	1
Investigations - Other- Specify	0/3 (0%)	0	1/42 (2.4%)	1
Lymphocyte count decreased	3/3 (100%)	3	8/42 (19%)	8
Neutrophil count decreased	3/3 (100%)	3	28/42 (66.7%)	28
Platelet count decreased	0/3 (0%)	0	13/42 (31%)	13
White blood cell decreased	3/3 (100%)	3	15/42 (35.7%)	15
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	1/42 (2.4%)	1
Dehydration	0/3 (0%)	0	1/42 (2.4%)	1
Hypophosphatemia	0/3 (0%)	0	2/42 (4.8%)	2
Musculoskeletal and connective tissue disorders
Myositis	0/3 (0%)	0	1/42 (2.4%)	1
Pain in extremity	0/3 (0%)	0	1/42 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/3 (33.3%)	1	0/42 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	1/3 (33.3%)	1	0/42 (0%)	0
Rash maculo-papular	0/3 (0%)	0	3/42 (7.1%)	3
Vascular disorders
Hypotension	0/3 (0%)	0	4/42 (9.5%)	4
Other (Not Including Serious) Adverse Events
	Dose1.4mg/kg		Dose 1.8mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		28/42 (66.7%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	6/42 (14.3%)	6
Cardiac disorders
Chest pain - cardiac	0/3 (0%)	0	1/42 (2.4%)	1
Pericardial effusion	1/3 (33.3%)	1	1/42 (2.4%)	1
Sinus tachycardia	1/3 (33.3%)	1	2/42 (4.8%)	2
Ear and labyrinth disorders
Ear and labyrinth disorders - Other- Specify	1/3 (33.3%)	1	0/42 (0%)	0
Ear pain	0/3 (0%)	0	1/42 (2.4%)	1
Eye disorders
Photophobia	1/3 (33.3%)	1	1/42 (2.4%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	3/42 (7.1%)	3
Constipation	0/3 (0%)	0	2/42 (4.8%)	2
Diarrhea	0/3 (0%)	0	4/42 (9.5%)	4
Dyspepsia	0/3 (0%)	0	1/42 (2.4%)	1
Enterocolitis	0/3 (0%)	0	1/42 (2.4%)	1
Mucositis oral	1/3 (33.3%)	1	1/42 (2.4%)	1
Nausea	3/3 (100%)	3	9/42 (21.4%)	9
Oral pain	0/3 (0%)	0	1/42 (2.4%)	1
Stomach pain	0/3 (0%)	0	1/42 (2.4%)	1
Vomiting	2/3 (66.7%)	2	8/42 (19%)	8
General disorders
Chills	0/3 (0%)	0	2/42 (4.8%)	2
Edema limbs	1/3 (33.3%)	1	1/42 (2.4%)	1
Fatigue	2/3 (66.7%)	2	8/42 (19%)	8
Fever	1/3 (33.3%)	1	8/42 (19%)	8
General disorders and administration site conditions - Other- Specify	0/3 (0%)	0	1/42 (2.4%)	1
Malaise	0/3 (0%)	0	2/42 (4.8%)	2
Non-cardiac chest pain	0/3 (0%)	0	1/42 (2.4%)	1
Hepatobiliary disorders
Cholecystitis	0/3 (0%)	0	1/42 (2.4%)	1
Infections and infestations
Enterocolitis infectious	0/3 (0%)	0	2/42 (4.8%)	2
Lung infection	0/3 (0%)	0	1/42 (2.4%)	1
Phlebitis infective	0/3 (0%)	0	1/42 (2.4%)	1
Upper respiratory infection	1/3 (33.3%)	1	1/42 (2.4%)	1
Vaginal infection	0/3 (0%)	0	1/42 (2.4%)	1
Investigations
Alanine aminotransferase increased	2/3 (66.7%)	2	9/42 (21.4%)	9
Alkaline phosphatase increased	0/3 (0%)	0	7/42 (16.7%)	7
Aspartate aminotransferase increased	2/3 (66.7%)	2	10/42 (23.8%)	10
Blood bilirubin increased	0/3 (0%)	0	1/42 (2.4%)	1
Carbon monoxide diffusing capacity decreased	0/3 (0%)	0	2/42 (4.8%)	2
CPK increased	1/3 (33.3%)	1	0/42 (0%)	0
Creatinine increased	0/3 (0%)	0	2/42 (4.8%)	2
Forced expiratory volume decreased	1/3 (33.3%)	1	0/42 (0%)	0
INR increased	0/3 (0%)	0	1/42 (2.4%)	1
Investigations - Other- Specify	0/3 (0%)	0	2/42 (4.8%)	2
Lymphocyte count decreased	0/3 (0%)	0	4/42 (9.5%)	4
Lymphocyte count increased	1/3 (33.3%)	1	0/42 (0%)	0
Platelet count decreased	3/3 (100%)	3	5/42 (11.9%)	5
Weight gain	2/3 (66.7%)	2	0/42 (0%)	0
Weight loss	0/3 (0%)	0	1/42 (2.4%)	1
White blood cell decreased	0/3 (0%)	0	4/42 (9.5%)	4
Metabolism and nutrition disorders
Anorexia	2/3 (66.7%)	2	1/42 (2.4%)	1
Dehydration	0/3 (0%)	0	1/42 (2.4%)	1
Hypercalcemia	0/3 (0%)	0	1/42 (2.4%)	1
Hyperglycemia	0/3 (0%)	0	5/42 (11.9%)	5
Hyperkalemia	0/3 (0%)	0	1/42 (2.4%)	1
Hypernatremia	0/3 (0%)	0	1/42 (2.4%)	1
Hypoalbuminemia	1/3 (33.3%)	1	3/42 (7.1%)	3
Hypocalcemia	1/3 (33.3%)	1	4/42 (9.5%)	4
Hypoglycemia	1/3 (33.3%)	1	1/42 (2.4%)	1
Hypokalemia	0/3 (0%)	0	4/42 (9.5%)	4
Hypomagnesemia	0/3 (0%)	0	5/42 (11.9%)	5
Hyponatremia	0/3 (0%)	0	3/42 (7.1%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	1/42 (2.4%)	1
Back pain	0/3 (0%)	0	2/42 (4.8%)	2
Bone pain	0/3 (0%)	0	1/42 (2.4%)	1
Chest wall pain	1/3 (33.3%)	1	0/42 (0%)	0
Flank pain	0/3 (0%)	0	1/42 (2.4%)	1
Myositis	1/3 (33.3%)	1	0/42 (0%)	0
Neck pain	0/3 (0%)	0	2/42 (4.8%)	2
Pain in extremity	0/3 (0%)	0	2/42 (4.8%)	2
Nervous system disorders
Dizziness	0/3 (0%)	0	2/42 (4.8%)	2
Dysesthesia	0/3 (0%)	0	1/42 (2.4%)	1
Dysgeusia	0/3 (0%)	0	1/42 (2.4%)	1
Headache	2/3 (66.7%)	2	7/42 (16.7%)	7
Movements involuntary	0/3 (0%)	0	1/42 (2.4%)	1
Paresthesia	0/3 (0%)	0	3/42 (7.1%)	3
Peripheral motor neuropathy	0/3 (0%)	0	3/42 (7.1%)	3
Peripheral sensory neuropathy	0/3 (0%)	0	3/42 (7.1%)	3
Psychiatric disorders
Anxiety	0/3 (0%)	0	1/42 (2.4%)	1
Confusion	0/3 (0%)	0	1/42 (2.4%)	1
Depression	0/3 (0%)	0	1/42 (2.4%)	1
Psychiatric disorders - Other- Specify	0/3 (0%)	0	1/42 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/3 (66.7%)	2	3/42 (7.1%)	3
Dyspnea	1/3 (33.3%)	1	0/42 (0%)	0
Epistaxis	0/3 (0%)	0	2/42 (4.8%)	2
Hypoxia	0/3 (0%)	0	1/42 (2.4%)	1
Nasal congestion	1/3 (33.3%)	1	3/42 (7.1%)	3
Pleural effusion	1/3 (33.3%)	1	2/42 (4.8%)	2
Postnasal drip	0/3 (0%)	0	2/42 (4.8%)	2
Respiratory- thoracic and mediastinal disorders - Other- Specify	1/3 (33.3%)	1	2/42 (4.8%)	2
Sore throat	0/3 (0%)	0	3/42 (7.1%)	3
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)	1	1/42 (2.4%)	1
Dry skin	1/3 (33.3%)	1	2/42 (4.8%)	2
Hyperhidrosis	0/3 (0%)	0	1/42 (2.4%)	1
Pain of skin	0/3 (0%)	0	2/42 (4.8%)	2
Pruritus	1/3 (33.3%)	1	6/42 (14.3%)	6
Rash maculo-papular	1/3 (33.3%)	1	12/42 (28.6%)	12
Skin and subcutaneous tissue disorders - Other- Specify	0/3 (0%)	0	2/42 (4.8%)	2
Urticaria	0/3 (0%)	0	3/42 (7.1%)	3
Surgical and medical procedures
Surgical and medical procedures - Other- Specify	0/3 (0%)	0	1/42 (2.4%)	1
Vascular disorders
Hot flashes	1/3 (33.3%)	1	0/42 (0%)	0
Hypertension	0/3 (0%)	0	1/42 (2.4%)	1
Hypotension	0/3 (0%)	0	2/42 (4.8%)	2
Superior vena cava syndrome	0/3 (0%)	0	1/42 (2.4%)	1

Limitations/Caveats

Samples have been banked, but data will never be analyzed for Outcome measure #8, Correlation between micro ribonucleic acid (miRNA) and disease response to protocol treatment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.