Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01041638
• Collaborator: (none)
• Enrollment: 105
• Locations: 32
• Arm: 1
• Actual Duration (Months): 138.3
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase III trial is studying the side effects of giving monoclonal antibody Ch14.18 together with sargramostim, aldesleukin, and isotretinoin after autologous stem cell transplant in treating patients with neuroblastoma. Monoclonal antibodies, such as Ch14.18, may find tumor cells and help kill them. Colony-stimulating factors, such as sargramostim, may increase the number of immune cells found in bone marrow or peripheral blood. Aldesleukin may stimulate the white blood cells to kill tumor cells. Isotretinoin may help neuroblastoma cells become more like normal cells, and to grow and spread more slowly. Giving monoclonal antibody Ch14.18 with sargramostim, aldesleukin, and isotretinoin after autologous stem cell transplant may be an effective treatment for neuroblastoma.

Condition or Disease	Intervention/Treatment	Phase
High Risk Neuroblastoma	Biological: Aldesleukin; Other: Diagnostic Laboratory Biomarker Analysis; Biological: Dinutuximab; Drug: Isotretinoin; Biological: Sargramostim	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. To comprehensively define the safety profile of ch14.18 when administered with cytokines and isotretinoin in high-risk neuroblastoma patients after autologous stem cell transplant (ASCT).

SECONDARY OBJECTIVES:

1. To further describe and refine the event-free survival (EFS) and overall survival (OS) estimates and baseline characteristics for subjects receiving chl4.18 + cytokines + isotretinoin.

2. To further describe the safety and toxicity of chl4.18 + cytokines + isotretinoin with focus on: a) number of courses delivered per patient; b) number of dose reductions or stoppage (ch14.18 and/or interleukin [IL]-2 [aldesleukin]); and c) number of toxic deaths.

3. To further describe the immune reconstitution of patients following ASCT, based on laboratory data obtained just prior to, during, and after treatment with this regimen.

4. To obtain correlative laboratory data to evaluate and describe mechanisms related to response, toxicity of immune activation, and allergic phenomena.

OUTLINE:

Patients receive sargramostim subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13 of courses 1, 3, and 5; monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4; and isotretinoin orally (PO) twice daily (BID) on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5. Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4. Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Comprehensive Safety Trial of Chimeric Antibody 14.18 (Ch14.18) With GM-CSF, IL-2 and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy
• Actual Study Start Date: Dec 21, 2009
• Actual Primary Completion Date: Dec 31, 2013
• Actual Study Completion Date: Jun 30, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (Ch14.18, GM-CSF, IL-2, isotretinoin) Patients receive sargramostim SC or IV over 2 hours on days 0-13 of courses 1, 3, and 5; monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4; and isotretinoin PO BID on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5. Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4. Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Biological: Aldesleukin; Given IV; Other Names: 125-L-Serine-2-133-interleukin 2 Proleukin r-serHuIL-2 Recombinant Human IL-2 Recombinant Human Interleukin-2 ; Other: Diagnostic Laboratory Biomarker Analysis; Correlative studies; Biological: Dinutuximab; Given IV; Other Names: Ch 14.18UTC Ch14.18 MOAB Ch14.18 monoclonal antibody Ch14.18 Unituxin ; Drug: Isotretinoin; Given PO; Other Names: 13-cis retinoic acid 13-cis-Retinoate 13-cis-Retinoic Acid 13-cis-Vitamin A Acid 13-cRA Absorica Accure Accutane Amnesteem cis-Retinoic Acid Cistane Claravis Isotretinoinum Isotrex Isotrexin Myorisan Neovitamin A Neovitamin A Acid Oratane Retinoicacid-13-cis Ro 4-3780 Ro-4-3780 Roaccutan Roaccutane Roacutan Sotret ZENATANE ; Biological: Sargramostim; Given IV or SC; Other Names: 23-L-Leucinecolony-Stimulating Factor 2 DRG-0012 Leukine Prokine rhu GM-CFS Sagramostim Sargramostatin

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Who Experienced a Significant (CTC Grade 3-5) Nonhematologic Toxicity of Interest (Pain, Hypotension, Allergic Reactions, Capillary Leak Syndrome, or Fever). [Up to 6 courses of therapy]

   Designed to collect comprehensive safety/toxicity data, as well as additional efficacy data for the immunotherapy. To address the primary objective, descriptive analyses summarizing the number and type of AEs will be performed. The percentage of patients reporting each unacceptable (Grade 3 or higher) CTC toxicity code, tabulated by course, are reported.

Secondary Outcome Measures

1. Event-free Survival (EFS) [From enrollment until the first occurrence of relapse, progressive disease, secondary malignancy, or death, or until last contact if no event occurred, up to 3 years]

   Event-free Survival (EFS) for all eligible patients enrolled on the study

2. Overall Survival (OS) [From enrollment until death, or until last contact with the patient, up to 3 years]

   Overall Survival (OS) for all eligible patients enrolled on the study

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All patients must be diagnosed with neuroblastoma, and categorized as high-risk at the time of diagnosis

• At pre-ASCT evaluation, patients must meet the International Neuroblastoma Response Criteria (INRC) for complete response (CR), very good partial response (VGPR), or partial response (PR) for primary site, soft tissue metastases and bone metastases; patients who meet those criteria must also meet the protocol specified criteria for bone marrow response as outlined below: =< 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy; patients who have no tumor seen on the prior bone marrow, and then have =< 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible; (Note that, per INRC, this would have been defined as an "overall" response of progressive disease [PD])

• Prior to enrollment on ANBL0931, a determination of residual disease must be performed (tumor imaging studies including metaiodobenzylguanidine [MIBG] scan, computed tomography [CT] or magnetic resonance imaging [MRI], bone marrow aspiration and biopsy); this disease assessment is required for eligibility, and should be done preferably within 2 weeks but must be done within a maximum of 4 weeks before enrollment

• Patients with residual disease are eligible; biopsy is not required

• Patients must not have progressive disease except for protocol specified bone marrow response

• All patients must have completed therapy including intensive induction chemotherapy followed by ASCT and radiotherapy to be eligible; radiotherapy may be waived for patients who either had a small adrenal mass which was completely resected upfront, or who never had an identifiable primary tumor

• No more than 9 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; Exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/ or relapsed) to high risk neuroblastoma, the 9 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT

• Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; required patients must have a Lansky or Karnofsky performance scale score of >= 50%

• Patients must have a life expectancy of >= 2 months (8 weeks)

• Total absolute phagocyte count (APC = neutrophils + monocytes) is at least 1000/uL

• 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:

• 1 month to < 6 months: 0.4 mg/dL

• 6 months to < 1 year: 0.5 mg/dL

• 1 to < 2 years: 0.6 mg/dL

• 2 to < 6 years: 0.8 mg/dL

• 6 to < 10 years: 1 mg/dL

• 10 to < 13 years: 1.2 mg/dL

• 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)

• = 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN) for age

• SOS (sinusoidal obstruction syndrome, formerly known as veno-occlusive disease [VOD]), if present, should be stable or improving

• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 55% by radionuclide angiography

• No evidence of dyspnea at rest

• If pulmonary function tests (PFTs) are performed, forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 60% by pulmonary function test

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

• Central nervous system (CNS) toxicity < grade 2

Exclusion Criteria:

• Females of childbearing potential must have a negative pregnancy test

• Patients of childbearing potential must agree to use an effective birth control method

• Female patients who are lactating must agree to stop breast-feeding

• Patients must not have received prior anti-GD2 antibody therapy

• Patients must not have received prior vaccine therapy administered as treatment of neuroblastoma not routine infectious disease vaccinations

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Medical Center	Loma Linda	California	United States	92354
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	Children's Hospital of Orange County	Orange	California	United States	92868
4	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
5	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
6	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
7	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
8	Children's Hospital Colorado	Aurora	Colorado	United States	80045
9	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
10	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
11	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
12	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
13	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
14	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
15	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
16	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
17	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
18	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
19	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
20	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
21	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
22	New York Medical College	Valhalla	New York	United States	10595
23	Duke University Medical Center	Durham	North Carolina	United States	27710
24	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
25	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
26	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
27	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
28	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
29	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
30	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
31	Seattle Children's Hospital	Seattle	Washington	United States	98105
32	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mehmet F Ozkaynak, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01041638
• Other Study ID Numbers: NCI-2011-01997; NCI-2011-01997; COG-ANBL0931; ANBL0931; CDR0000662673; ANBL0931; ANBL0931; U10CA098543
• First Posted: Jan 1, 2010
• Last Update Posted: Aug 17, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Neuroblastoma; Vitamin A; Aldesleukin; Interleukin-2; Tretinoin; Dinutuximab; Isotretinoin; Sargramostim

Study Results

Participant Flow

Arm/Group Title	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
Arm/Group Description	Patients receive sargramostim subcutaneously or IV over 2 hours on days 0-13 of courses 1, 3, and 5 (dose: 250 micrograms/m²/dose); monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4 (dose: 25 mg/m2/dose); and oral isotretinoin twice daily on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5 (Weight based dosage: > 12 kg: 80 mg/m2/dose BID; total daily dose 160 mg/m2/day, divided BID. ≤ 12 kg: 2.67 mg/kg/dose BID; total daily dose is 5.33 mg/kg/day, divided BID. Round dose up to the nearest 10 mg). Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4 (actual dosage is body surface area based and varies by course). Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	105
COMPLETED	78
NOT COMPLETED	27

Baseline Characteristics

Arm/Group Title	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
Arm/Group Description	Patients receive sargramostim subcutaneously or IV over 2 hours on days 0-13 of courses 1, 3, and 5 (dose: 250 micrograms/m²/dose); monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4 (dose: 25 mg/m2/dose); and oral isotretinoin twice daily on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5 (Weight based dosage: > 12 kg: 80 mg/m2/dose BID; total daily dose 160 mg/m2/day, divided BID. ≤ 12 kg: 2.67 mg/kg/dose BID; total daily dose is 5.33 mg/kg/day, divided BID. Round dose up to the nearest 10 mg). Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4 (actual dosage is body surface area based and varies by course). Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Overall Participants	105
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	4.1
Age (Count of Participants)
<=18 years	103 98.1%
Between 18 and 65 years	2 1.9%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	46 43.8%
Male	59 56.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1%
Asian	2 1.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	10 9.5%
White	82 78.1%
More than one race	0 0%
Unknown or Not Reported	10 9.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 8.6%
Not Hispanic or Latino	87 82.9%
Unknown or Not Reported	9 8.6%
Region of Enrollment (participants) [Number]
United States	105 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Who Experienced a Significant (CTC Grade 3-5) Nonhematologic Toxicity of Interest (Pain, Hypotension, Allergic Reactions, Capillary Leak Syndrome, or Fever).
Description	Designed to collect comprehensive safety/toxicity data, as well as additional efficacy data for the immunotherapy. To address the primary objective, descriptive analyses summarizing the number and type of AEs will be performed. The percentage of patients reporting each unacceptable (Grade 3 or higher) CTC toxicity code, tabulated by course, are reported.
Time Frame	Up to 6 courses of therapy

Outcome Measure Data

Analysis Population Description

There was one patient that did not receive treatment, represented on the baseline form as "withdrawal by patient", not included in outcome measure tabulation.

Arm/Group Title	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
Arm/Group Description	Patients receive sargramostim subcutaneously or IV over 2 hours on days 0-13 of courses 1, 3, and 5 (dose: 250 micrograms/m²/dose); monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4 (dose: 25 mg/m2/dose); and oral isotretinoin twice daily on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5 (Weight based dosage: > 12 kg: 80 mg/m2/dose BID; total daily dose 160 mg/m2/day, divided BID. ≤ 12 kg: 2.67 mg/kg/dose BID; total daily dose is 5.33 mg/kg/day, divided BID. Round dose up to the nearest 10 mg). Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4 (actual dosage is body surface area based and varies by course). Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	104
Abdominal pain (10300), course 1	17.3077 16.5%
Abdominal pain (10300), course 2	5.0000 4.8%
Abdominal pain (10300), course 3	6.1224 5.8%
Abdominal pain (10300), course 4	4.4444 4.2%
Abdominal pain (10300), course 5	5.6818 5.4%
Abdominal pain (10300), course 6	0.00000 0%
Allergic reaction (12000), Course 1	1.92308 1.8%
Allergic reaction (12000), Course 2	5.00000 4.8%
Allergic reaction (12000), Course 3	3.06122 2.9%
Allergic reaction (12000), Course 4	2.22222 2.1%
Allergic reaction (12000), Course 5	1.13636 1.1%
Allergic reaction (12000), Course 6	0.00000 0%
Anal pain (12800), Course 1	0.00000 0%
Anal pain (12800), Course 2	1.00000 1%
Anal pain (12800), Course 3	0.00000 0%
Anal pain (12800), Course 4	0.00000 0%
Anal pain (12800), Course 5	0.00000 0%
Anal pain (12800), Course 6	0.00000 0%
Anaphylaxis (13100), Course 1	0.96154 0.9%
Anaphylaxis (13100), Course 2	4.00000 3.8%
Anaphylaxis (13100), Course 3	1.02041 1%
Anaphylaxis (13100), Course 4	3.33333 3.2%
Anaphylaxis (13100), Course 5	1.13636 1.1%
Anaphylaxis (13100), Course 6	0.00000 0%
Back pain (16200), Course 1	4.80769 4.6%
Back pain (16200), Course 2	5.00000 4.8%
Back pain (16200), Course 3	3.06122 2.9%
Back pain (16200), Course 4	3.33333 3.2%
Back pain (16200), Course 5	4.54545 4.3%
Back pain (16200), Course 6	0.00000 0%
Capillary leak syndrome (19800) - Course 1	0.96154 0.9%
Capillary leak syndrome (19800) - Course 2	4.00000 3.8%
Capillary leak syndrome (19800) - Course 3	0.00000 0%
Capillary leak syndrome (19800) - Course 4	2.22222 2.1%
Capillary leak syndrome (19800) - Course 5	0.00000 0%
Capillary leak syndrome (19800) - Course 6	0.00000 0%
Chest wall pain (21400) - Course 1	0.00000 0%
Chest wall pain (21400) - Course 2	0.00000 0%
Chest wall pain (21400) - Course 3	1.02041 1%
Chest wall pain (21400) - Course 4	0.00000 0%
Chest wall pain (21400) - Course 5	1.13636 1.1%
Chest wall pain (21400) - Course 6	0.00000 0%
Fever (33900) - Course 1	21.1538 20.1%
Fever (33900) - Course 2	58.0000 55.2%
Fever (33900) - Course 3	6.1224 5.8%
Fever (33900) - Course 4	31.1111 29.6%
Fever (33900) - Course 5	4.5455 4.3%
Fever (33900) - Course 6	1.2346 1.2%
Flank pain (34200) - Course 1	0.96154 0.9%
Flank pain (34200) - Course 2	0.00000 0%
Flank pain (34200) - Course 3	0.00000 0%
Flank pain (34200) - Course 4	0.00000 0%
Flank pain (34200) - Course 5	0.00000 0%
Flank pain (34200) - Course 6	0.00000 0%
Hypotension (43600) - Course 1	9.6154 9.2%
Hypotension (43600) - Course 2	17.0000 16.2%
Hypotension (43600) - Course 3	4.0816 3.9%
Hypotension (43600) - Course 4	14.4444 13.8%
Hypotension (43600) - Course 5	7.9545 7.6%
Hypotension (43600) - Course 6	0.00000 0%
Neck pain (57800) - Course 1	0.96154 0.9%
Neck pain (57800) - Course 2	3.00000 2.9%
Neck pain (57800) - Course 3	0.00000 0%
Neck pain (57800) - Course 4	0.00000 0%
Neck pain (57800) - Course 5	1.13636 1.1%
Neck pain (57800) - Course 6	0.00000 0%
Non-cardiac chest pain (58600) - Course 1	0.96154 0.9%
Non-cardiac chest pain (58600) - Course 2	0.00000 0%
Non-cardiac chest pain (58600) - Course 3	0.00000 0%
Non-cardiac chest pain (58600) - Course 4	0.00000 0%
Non-cardiac chest pain (58600) - Course 5	0.00000 0%
Non-cardiac chest pain (58600) - Course 6	0.00000 0%
Pain (60600) - Course 1	23.0769 22%
Pain (60600) - Course 2	16.0000 15.2%
Pain (60600) - Course 3	13.2653 12.6%
Pain (60600) - Course 4	20.0000 19%
Pain (60600) - Course 5	11.3636 10.8%
Pain (60600) - Course 6	1.2346 1.2%
Pain in extremity (60700) - Course 1	4.80769 4.6%
Pain in extremity (60700) - Course 2	4.00000 3.8%
Pain in extremity (60700) - Course 3	3.06122 2.9%
Pain in extremity (60700) - Course 4	6.66667 6.3%
Pain in extremity (60700) - Course 5	2.27273 2.2%
Pain in extremity (60700) - Course 6	1.23457 1.2%
Peripheral sensory neuropathy (64100) - Course 1	0.96154 0.9%
Peripheral sensory neuropathy (64100) - Course 2	0.00000 0%
Peripheral sensory neuropathy (64100) - Course 3	1.02041 1%
Peripheral sensory neuropathy (64100) - Course 4	0.00000 0%
Peripheral sensory neuropathy (64100) - Course 5	0.00000 0%
Peripheral sensory neuropathy (64100) - Course 6	0.00000 0%

2. Secondary Outcome

Title	Event-free Survival (EFS)
Description	Event-free Survival (EFS) for all eligible patients enrolled on the study
Time Frame	From enrollment until the first occurrence of relapse, progressive disease, secondary malignancy, or death, or until last contact if no event occurred, up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible patients.

Arm/Group Title	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
Arm/Group Description	Patients receive sargramostim subcutaneously or IV over 2 hours on days 0-13 of courses 1, 3, and 5 (dose: 250 micrograms/m²/dose); monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4 (dose: 25 mg/m2/dose); and oral isotretinoin twice daily on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5 (Weight based dosage: > 12 kg: 80 mg/m2/dose BID; total daily dose 160 mg/m2/day, divided BID. ≤ 12 kg: 2.67 mg/kg/dose BID; total daily dose is 5.33 mg/kg/day, divided BID. Round dose up to the nearest 10 mg). Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4 (actual dosage is body surface area based and varies by course). Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	105
Number (95% Confidence Interval) [percentage]	67.6

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) for all eligible patients enrolled on the study
Time Frame	From enrollment until death, or until last contact with the patient, up to 3 years

Outcome Measure Data

Analysis Population Description

All eligible patients

Arm/Group Title	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
Arm/Group Description	Patients receive sargramostim subcutaneously or IV over 2 hours on days 0-13 of courses 1, 3, and 5 (dose: 250 micrograms/m²/dose); monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4 (dose: 25 mg/m2/dose); and oral isotretinoin twice daily on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5 (Weight based dosage: > 12 kg: 80 mg/m2/dose BID; total daily dose 160 mg/m2/day, divided BID. ≤ 12 kg: 2.67 mg/kg/dose BID; total daily dose is 5.33 mg/kg/day, divided BID. Round dose up to the nearest 10 mg). Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4 (actual dosage is body surface area based and varies by course). Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	105
Number (95% Confidence Interval) [percentage]	79.1

Adverse Events

Adverse Event Reporting Description	SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs / CAeRs). The AE field contains grade 3 and higher CTCAEs reported on study excluding those that were reported as SAEs.
Arm/Group Title	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
Arm/Group Description	Patients receive sargramostim subcutaneously or IV over 2 hours on days 0-13 of courses 1, 3, and 5 (dose: 250 micrograms/m²/dose); monoclonal antibody Ch14.18 IV over 10 hours on days 3-6 of courses 1, 3, and 5 and on days 7-10 of courses 2 and 4 (dose: 25 mg/m2/dose); and oral isotretinoin twice daily on days 11-24 of course 1, on days 14-27 of courses 2, 4, and 6, and on days 10-23 of courses 3 and 5 (Weight based dosage: > 12 kg: 80 mg/m2/dose BID; total daily dose 160 mg/m2/day, divided BID. ≤ 12 kg: 2.67 mg/kg/dose BID; total daily dose is 5.33 mg/kg/day, divided BID. Round dose up to the nearest 10 mg). Patients also receive aldesleukin IV continuously on days 0-3 and on days 7-10 of courses 2 and 4 (actual dosage is body surface area based and varies by course). Treatment repeats every 24-32 days for 6 courses in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
	Affected / at Risk (%)	# Events
Total	103/104 (99%)
Blood and lymphatic system disorders
13200-Anemia	65/104 (62.5%)	148
18100-Bone marrow hypocellular	1/104 (1%)	1
33300-Febrile neutropenia	6/104 (5.8%)	9
Cardiac disorders
20000-Cardiac arrest	1/104 (1%)	1
74500-Sinus tachycardia	1/104 (1%)	1
Ear and labyrinth disorders
28000-Ear pain	1/104 (1%)	1
38900-Hearing impaired	9/104 (8.7%)	9
Gastrointestinal disorders
10300-Abdominal pain	21/104 (20.2%)	56
12800-Anal pain	1/104 (1%)	1
22100-Colitis	1/104 (1%)	1
22400-Colonic obstruction	1/104 (1%)	1
25700-Diarrhea	15/104 (14.4%)	20
27600-Dysphagia	1/104 (1%)	1
44200-Ileal obstruction	1/104 (1%)	1
53900-Malabsorption	1/104 (1%)	1
55600-Mucositis oral	1/104 (1%)	1
57600-Nausea	2/104 (1.9%)	2
81900-Typhlitis	2/104 (1.9%)	2
87900-Vomiting	4/104 (3.8%)	7
General disorders
28200-Edema face	1/104 (1%)	1
33900-Fever	69/104 (66.3%)	204
37200-General disorders and administration site conditions - Other	1/104 (1%)	1
48700-Irritability	3/104 (2.9%)	3
58600-Non-cardiac chest pain	1/104 (1%)	2
60600-Pain	46/104 (44.2%)	134
Immune system disorders
12000-Allergic reaction	9/104 (8.7%)	13
13100-Anaphylaxis	9/104 (8.7%)	11
24400-Cytokine release syndrome	1/104 (1%)	1
Infections and infestations
20500-Catheter related infection	33/104 (31.7%)	63
25600-Device related infection	4/104 (3.8%)	4
29500-Enterocolitis infectious	3/104 (2.9%)	3
44800-Infections and infestations - Other	16/104 (15.4%)	23
53100-Lung infection	5/104 (4.8%)	7
60100-Otitis media	2/104 (1.9%)	3
73700-Sepsis	1/104 (1%)	1
75200-Skin infection	3/104 (2.9%)	3
76000-Small intestine infection	1/104 (1%)	1
82300-Upper respiratory infection	2/104 (1.9%)	2
83100-Urinary tract infection	4/104 (3.8%)	4
Injury, poisoning and procedural complications
86400-Vascular access complication	1/104 (1%)	1
Investigations
10900-Activated partial thromboplastin time prolonged	2/104 (1.9%)	2
11600-Alanine aminotransferase increased	24/104 (23.1%)	49
11800-Alkaline phosphatase increased	2/104 (1.9%)	2
15000-Aspartate aminotransferase increased	11/104 (10.6%)	17
17400-Blood bilirubin increased	2/104 (1.9%)	6
24100-Creatinine increased	2/104 (1.9%)	2
37500-GGT increased	11/104 (10.6%)	27
53700-Lymphocyte count decreased	78/104 (75%)	339
53800-Lymphocyte count increased	4/104 (3.8%)	4
58300-Neutrophil count decreased	55/104 (52.9%)	193
65800-Platelet count decreased	58/104 (55.8%)	355
83600-Urine output decreased	5/104 (4.8%)	5
88200-Weight gain	2/104 (1.9%)	2
88300-Weight loss	4/104 (3.8%)	7
88500-White blood cell decreased	25/104 (24%)	82
Metabolism and nutrition disorders
10700-Acidosis	5/104 (4.8%)	6
13500-Anorexia	23/104 (22.1%)	25
24700-Dehydration	5/104 (4.8%)	5
41300-Hypercalcemia	5/104 (4.8%)	7
41400-Hyperglycemia	11/104 (10.6%)	13
41600-Hyperkalemia	7/104 (6.7%)	10
41700-Hypermagnesemia	1/104 (1%)	1
41800-Hypernatremia	1/104 (1%)	1
42400-Hypertriglyceridemia	2/104 (1.9%)	3
42600-Hypoalbuminemia	9/104 (8.7%)	11
42700-Hypocalcemia	5/104 (4.8%)	5
42900-Hypoglycemia	2/104 (1.9%)	2
43100-Hypokalemia	51/104 (49%)	117
43300-Hyponatremia	42/104 (40.4%)	63
43500-Hypophosphatemia	17/104 (16.3%)	17
Musculoskeletal and connective tissue disorders
16200-Back pain	10/104 (9.6%)	23
21400-Chest wall pain	1/104 (1%)	3
34200-Flank pain	1/104 (1%)	1
57800-Neck pain	4/104 (3.8%)	6
60700-Pain in extremity	17/104 (16.3%)	34
Nervous system disorders
15300-Ataxia	1/104 (1%)	1
25300-Depressed level of consciousness	1/104 (1%)	1
38800-Headache	6/104 (5.8%)	7
42000-Hypersomnia	1/104 (1%)	1
58200-Neuralgia	8/104 (7.7%)	23
59000-Oculomotor nerve disorder	1/104 (1%)	1
63900-Peripheral motor neuropathy	1/104 (1%)	1
64100-Peripheral sensory neuropathy	2/104 (1.9%)	2
76700-Somnolence	2/104 (1.9%)	2
Psychiatric disorders
11400-Agitation	4/104 (3.8%)	9
13700-Anxiety	2/104 (1.9%)	2
25000-Delirium	1/104 (1%)	1
38500-Hallucinations	1/104 (1%)	1
Renal and urinary disorders
11100-Acute kidney injury	1/104 (1%)	1
68300-Proteinuria	1/104 (1%)	2
83000-Urinary retention	1/104 (1%)	1
Respiratory, thoracic and mediastinal disorders
14100-Apnea	2/104 (1.9%)	2
19300-Bronchospasm	4/104 (3.8%)	5
23800-Cough	2/104 (1.9%)	2
27800-Dyspnea	12/104 (11.5%)	25
43900-Hypoxia	29/104 (27.9%)	58
68700-Pulmonary edema	1/104 (1%)	1
71600-Respiratory thoracic and mediastinal disorders - Other	2/104 (1.9%)	5
78100-Stridor	4/104 (3.8%)	4
88400-Wheezing	2/104 (1.9%)	3
Skin and subcutaneous tissue disorders
26200-Dry skin	1/104 (1%)	1
63600-Periorbital edema	1/104 (1%)	1
68400-Pruritus	3/104 (2.9%)	6
69700-Rash maculo-papular	1/104 (1%)	1
84100-Urticaria	11/104 (10.6%)	22
Surgical and medical procedures
79000-Surgical and medical procedures - Other	1/104 (1%)	1
Vascular disorders
19800-Capillary leak syndrome	7/104 (6.7%)	7
42100-Hypertension	4/104 (3.8%)	5
43600-Hypotension	33/104 (31.7%)	67
Other (Not Including Serious) Adverse Events
	Chimeric Antibody 14.18 With GM-CSF, IL-2 and Isotretinoin
	Affected / at Risk (%)	# Events
Total	104/104 (100%)
Blood and lymphatic system disorders
13200-Anemia	99/104 (95.2%)	1181
17200-Blood and lymphatic system disorders - Other	2/104 (1.9%)	2
18100-Bone marrow hypocellular	1/104 (1%)	1
25800-Disseminated intravascular coagulation	1/104 (1%)	1
Cardiac disorders
20100-Cardiac disorders - Other	6/104 (5.8%)	16
21300-Chest pain - cardiac	3/104 (2.9%)	3
61000-Palpitations	2/104 (1.9%)	2
63100-Pericardial effusion	2/104 (1.9%)	3
74200-Sinus bradycardia	7/104 (6.7%)	18
74500-Sinus tachycardia	85/104 (81.7%)	740
78900-Supraventricular tachycardia	3/104 (2.9%)	5
81400-Tricuspid valve disease	1/104 (1%)	1
Ear and labyrinth disorders
27900-Ear and labyrinth disorders - Other	2/104 (1.9%)	2
28000-Ear pain	3/104 (2.9%)	3
31600-External ear pain	1/104 (1%)	1
38900-Hearing impaired	10/104 (9.6%)	10
Endocrine disorders
11200-Adrenal insufficiency	1/104 (1%)	1
29200-Endocrine disorders - Other	1/104 (1%)	1
41900-Hyperparathyroidism	1/104 (1%)	1
42200-Hyperthyroidism	5/104 (4.8%)	5
43400-Hypoparathyroidism	1/104 (1%)	1
43800-Hypothyroidism	5/104 (4.8%)	7
Eye disorders
17800-Blurred vision	5/104 (4.8%)	7
23200-Conjunctivitis	1/104 (1%)	1
26000-Dry eye	3/104 (2.9%)	3
31900-Eye disorders - Other	13/104 (12.5%)	14
32100-Eye pain	5/104 (4.8%)	5
32200-Eyelid function disorder	1/104 (1%)	1
59300-Optic nerve disorder	2/104 (1.9%)	2
61900-Papilledema	1/104 (1%)	1
65600-Photophobia	3/104 (2.9%)	3
73200-Scleral disorder	1/104 (1%)	1
Gastrointestinal disorders
10100-Abdominal distension	14/104 (13.5%)	27
10300-Abdominal pain	70/104 (67.3%)	284
12800-Anal pain	2/104 (1.9%)	2
17100-Bloating	1/104 (1%)	1
21200-Cheilitis	10/104 (9.6%)	14
22100-Colitis	1/104 (1%)	1
23400-Constipation	36/104 (34.6%)	72
25700-Diarrhea	60/104 (57.7%)	203
26100-Dry mouth	3/104 (2.9%)	3
27500-Dyspepsia	2/104 (1.9%)	2
27600-Dysphagia	4/104 (3.8%)	4
29400-Enterocolitis	4/104 (3.8%)	4
34400-Flatulence	5/104 (4.8%)	7
36400-Gastritis	6/104 (5.8%)	7
36500-Gastroesophageal reflux disease	3/104 (2.9%)	3
36700-Gastrointestinal disorders - Other	5/104 (4.8%)	8
36900-Gastrointestinal pain	1/104 (1%)	1
37600-Gingival pain	1/104 (1%)	1
39800-Hemorrhoidal hemorrhage	1/104 (1%)	1
55600-Mucositis oral	3/104 (2.9%)	3
57600-Nausea	55/104 (52.9%)	188
59700-Oral pain	4/104 (3.8%)	4
70800-Rectal ulcer	1/104 (1%)	1
77900-Stomach pain	7/104 (6.7%)	13
80200-Toothache	2/104 (1.9%)	2
87900-Vomiting	65/104 (62.5%)	309
General disorders
21500-Chills	21/104 (20.2%)	34
28200-Edema face	56/104 (53.8%)	110
28300-Edema limbs	36/104 (34.6%)	61
28400-Edema trunk	5/104 (4.8%)	6
32500-Facial pain	2/104 (1.9%)	2
33200-Fatigue	34/104 (32.7%)	73
33900-Fever	102/104 (98.1%)	1117
34600-Flu like symptoms	2/104 (1.9%)	7
35000-Gait disturbance	3/104 (2.9%)	5
37200-General disorders and administration site conditions - Other	4/104 (3.8%)	7
43700-Hypothermia	1/104 (1%)	2
45000-Infusion related reaction	4/104 (3.8%)	10
45200-Injection site reaction	16/104 (15.4%)	23
48700-Irritability	33/104 (31.7%)	74
52800-Localized edema	10/104 (9.6%)	14
54000-Malaise	4/104 (3.8%)	4
58600-Non-cardiac chest pain	6/104 (5.8%)	7
60600-Pain	82/104 (78.8%)	746
Immune system disorders
12000-Allergic reaction	33/104 (31.7%)	123
24400-Cytokine release syndrome	2/104 (1.9%)	2
Infections and infestations
18800-Bronchial infection	1/104 (1%)	1
20500-Catheter related infection	5/104 (4.8%)	6
23300-Conjunctivitis infective	1/104 (1%)	1
29500-Enterocolitis infectious	9/104 (8.7%)	13
30400-Esophageal infection	1/104 (1%)	1
44800-Infections and infestations - Other	21/104 (20.2%)	28
53100-Lung infection	3/104 (2.9%)	3
55500-Mucosal infection	1/104 (1%)	1
57200-Nail infection	1/104 (1%)	1
60100-Otitis media	4/104 (3.8%)	5
62000-Papulopustular rash	1/104 (1%)	1
62200-Paronychia	1/104 (1%)	3
65200-Pharyngitis	3/104 (2.9%)	5
72600-Rhinitis infective	3/104 (2.9%)	4
74600-Sinusitis	2/104 (1.9%)	2
75200-Skin infection	6/104 (5.8%)	8
76000-Small intestine infection	1/104 (1%)	1
82300-Upper respiratory infection	9/104 (8.7%)	11
83100-Urinary tract infection	6/104 (5.8%)	8
Injury, poisoning and procedural complications
19400-Bruising	8/104 (7.7%)	9
25500-Dermatitis radiation	2/104 (1.9%)	2
45700-Injury poisoning and procedural complications - Other	2/104 (1.9%)	3
66800-Postoperative hemorrhage	1/104 (1%)	1
86400-Vascular access complication	8/104 (7.7%)	13
Investigations
10900-Activated partial thromboplastin time prolonged	8/104 (7.7%)	10
11600-Alanine aminotransferase increased	90/104 (86.5%)	507
11800-Alkaline phosphatase increased	20/104 (19.2%)	64
15000-Aspartate aminotransferase increased	91/104 (87.5%)	399
17400-Blood bilirubin increased	15/104 (14.4%)	40
21700-Cholesterol high	3/104 (2.9%)	3
24100-Creatinine increased	31/104 (29.8%)	137
28700-Electrocardiogram QT corrected interval prolonged	1/104 (1%)	1
37500-GGT increased	20/104 (19.2%)	87
39400-Hemoglobin increased	9/104 (8.7%)	29
45800-INR increased	5/104 (4.8%)	5
48400-Investigations - Other	3/104 (2.9%)	6
53700-Lymphocyte count decreased	87/104 (83.7%)	904
53800-Lymphocyte count increased	4/104 (3.8%)	4
58300-Neutrophil count decreased	67/104 (64.4%)	376
65800-Platelet count decreased	97/104 (93.3%)	780
88200-Weight gain	56/104 (53.8%)	227
88300-Weight loss	21/104 (20.2%)	54
88500-White blood cell decreased	89/104 (85.6%)	737
Metabolism and nutrition disorders
10700-Acidosis	3/104 (2.9%)	10
13500-Anorexia	32/104 (30.8%)	84
24700-Dehydration	13/104 (12.5%)	16
41300-Hypercalcemia	26/104 (25%)	48
41400-Hyperglycemia	61/104 (58.7%)	195
41600-Hyperkalemia	35/104 (33.7%)	71
41700-Hypermagnesemia	17/104 (16.3%)	52
41800-Hypernatremia	12/104 (11.5%)	18
42400-Hypertriglyceridemia	84/104 (80.8%)	205
42500-Hyperuricemia	2/104 (1.9%)	2
42600-Hypoalbuminemia	101/104 (97.1%)	890
42700-Hypocalcemia	96/104 (92.3%)	579
42900-Hypoglycemia	43/104 (41.3%)	95
43100-Hypokalemia	85/104 (81.7%)	392
43200-Hypomagnesemia	41/104 (39.4%)	119
43300-Hyponatremia	95/104 (91.3%)	524
43500-Hypophosphatemia	69/104 (66.3%)	211
54900-Metabolism and nutrition disorders - Other	2/104 (1.9%)	5
Musculoskeletal and connective tissue disorders
14700-Arthralgia	2/104 (1.9%)	2
16200-Back pain	25/104 (24%)	70
18200-Bone pain	5/104 (4.8%)	5
19700-Buttock pain	4/104 (3.8%)	4
21400-Chest wall pain	6/104 (5.8%)	22
37300-Generalized muscle weakness	2/104 (1.9%)	3
49800-Joint range of motion decreased	1/104 (1%)	1
55900-Muscle weakness lower limb	1/104 (1%)	1
56300-Musculoskeletal and connective tissue disorder - Other	2/104 (1.9%)	6
56500-Myalgia	10/104 (9.6%)	11
57800-Neck pain	14/104 (13.5%)	32
60700-Pain in extremity	48/104 (46.2%)	155
Nervous system disorders
11500-Akathisia	2/104 (1.9%)	2
22000-Cognitive disturbance	1/104 (1%)	1
22800-Concentration impairment	1/104 (1%)	1
25300-Depressed level of consciousness	1/104 (1%)	1
25900-Dizziness	3/104 (2.9%)	5
38800-Headache	31/104 (29.8%)	76
42000-Hypersomnia	1/104 (1%)	1
51800-Lethargy	5/104 (4.8%)	5
54400-Memory impairment	1/104 (1%)	1
54500-Meningismus	1/104 (1%)	2
55400-Movements involuntary	4/104 (3.8%)	4
58100-Nervous system disorders - Other	2/104 (1.9%)	3
58200-Neuralgia	5/104 (4.8%)	13
58700-Nystagmus	1/104 (1%)	1
59000-Oculomotor nerve disorder	1/104 (1%)	1
62100-Paresthesia	2/104 (1.9%)	2
64100-Peripheral sensory neuropathy	11/104 (10.6%)	16
73600-Seizure	2/104 (1.9%)	2
76700-Somnolence	7/104 (6.7%)	7
81300-Tremor	3/104 (2.9%)	3
Pregnancy, puerperium and perinatal conditions
67200-Premature delivery	1/104 (1%)	1
Psychiatric disorders
11400-Agitation	24/104 (23.1%)	40
13700-Anxiety	14/104 (13.5%)	23
23000-Confusion	7/104 (6.7%)	10
25400-Depression	3/104 (2.9%)	6
38500-Hallucinations	10/104 (9.6%)	14
45900-Insomnia	7/104 (6.7%)	8
54100-Mania	1/104 (1%)	1
68500-Psychiatric disorders - Other	3/104 (2.9%)	3
71700-Restlessness	4/104 (3.8%)	6
Renal and urinary disorders
11100-Acute kidney injury	2/104 (1.9%)	3
21800-Chronic kidney disease	1/104 (1%)	1
39300-Hematuria	36/104 (34.6%)	93
68300-Proteinuria	43/104 (41.3%)	144
71000-Renal and urinary disorders - Other	2/104 (1.9%)	4
82800-Urinary frequency	1/104 (1%)	1
82900-Urinary incontinence	1/104 (1%)	1
83000-Urinary retention	30/104 (28.8%)	63
83300-Urinary tract pain	4/104 (3.8%)	9
83400-Urinary urgency	1/104 (1%)	1
83500-Urine discoloration	5/104 (4.8%)	13
Reproductive system and breast disorders
37400-Genital edema	1/104 (1%)	4
62600-Pelvic pain	1/104 (1%)	1
62900-Penile pain	2/104 (1.9%)	3
71400-Reproductive system and breast disorders - Other	1/104 (1%)	3
85600-Vaginal inflammation	1/104 (1%)	1
Respiratory, thoracic and mediastinal disorders
12100-Allergic rhinitis	15/104 (14.4%)	18
15400-Atelectasis	6/104 (5.8%)	9
19000-Bronchial stricture	2/104 (1.9%)	2
19300-Bronchospasm	10/104 (9.6%)	16
23800-Cough	74/104 (71.2%)	220
27800-Dyspnea	8/104 (7.7%)	11
29700-Epistaxis	4/104 (3.8%)	6
40700-Hiccups	1/104 (1%)	1
41000-Hoarseness	2/104 (1.9%)	2
43900-Hypoxia	32/104 (30.8%)	99
51500-Laryngopharyngeal dysesthesia	1/104 (1%)	1
51600-Laryngospasm	1/104 (1%)	1
57500-Nasal congestion	23/104 (22.1%)	39
65300-Pharyngolaryngeal pain	2/104 (1.9%)	2
65900-Pleural effusion	4/104 (3.8%)	5
66200-Pleuritic pain	1/104 (1%)	3
66300-Pneumonitis	3/104 (2.9%)	3
66700-Postnasal drip	1/104 (1%)	1
67600-Productive cough	4/104 (3.8%)	4
68700-Pulmonary edema	3/104 (2.9%)	3
71600-Respiratory thoracic and mediastinal disorders - Other	34/104 (32.7%)	242
72200-Retinoic acid syndrome	1/104 (1%)	1
76200-Sneezing	6/104 (5.8%)	6
76800-Sore throat	7/104 (6.7%)	12
88400-Wheezing	17/104 (16.3%)	37
Skin and subcutaneous tissue disorders
12200-Alopecia	28/104 (26.9%)	36
19500-Bullous dermatitis	1/104 (1%)	1
26200-Dry skin	69/104 (66.3%)	175
29900-Erythema multiforme	8/104 (7.7%)	11
42300-Hypertrichosis	1/104 (1%)	1
57300-Nail loss	1/104 (1%)	1
60900-Palmar-plantar erythrodysesthesia syndrome	1/104 (1%)	1
63600-Periorbital edema	16/104 (15.4%)	27
65700-Photosensitivity	2/104 (1.9%)	2
68400-Pruritus	62/104 (59.6%)	223
69600-Rash acneiform	5/104 (4.8%)	6
69700-Rash maculo-papular	58/104 (55.8%)	130
74700-Skin and subcutaneous tissue disorders - Other	20/104 (19.2%)	51
74800-Skin atrophy	1/104 (1%)	1
74900-Skin hyperpigmentation	2/104 (1.9%)	2
75000-Skin hypopigmentation	2/104 (1.9%)	4
75100-Skin induration	3/104 (2.9%)	3
75300-Skin ulceration	4/104 (3.8%)	4
84100-Urticaria	46/104 (44.2%)	139
Vascular disorders
19800-Capillary leak syndrome	53/104 (51%)	131
34700-Flushing	8/104 (7.7%)	10
41100-Hot flashes	2/104 (1.9%)	2
42100-Hypertension	56/104 (53.8%)	406
43600-Hypotension	81/104 (77.9%)	768
79600-Thromboembolic event	1/104 (1%)	1
86500-Vascular disorders - Other	3/104 (2.9%)	10

Limitations/Caveats

[Not Specified]

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.