Treatment With Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma (NBL)

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT04385277
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 40
• Locations: 78
• Arm: 1
• Anticipated Duration (Months): 37
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies if dinutuximab, GM-CSF, isotretinoin in combination with irinotecan, and temozolomide (chemo-immunotherapy) can be given safely to patients with high-risk neuroblastoma after Consolidation therapy (which usually consists of two autologous stem cell transplants and radiation) who have not experienced worsening or recurrence of their disease. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby healthy cells. Sargramostim helps the body produce normal infection-fighting white blood cells. Isotretinoin helps the neuroblastoma cells become more mature. These 3 drugs (standard immunotherapy) are already given to patients with high-risk neuroblastoma after Consolidation because they have been proven to be beneficial in this setting. Chemotherapy drugs, such as irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. They may also affect how well immunotherapy works on neuroblastoma cells. Giving chemo-immunotherapy after intensive therapy may work better in treating patients with high-risk neuroblastoma compared to standard immunotherapy.

Condition or Disease	Intervention/Treatment	Phase
Ganglioneuroblastoma, Nodular; Neuroblastoma	Biological: Dinutuximab; Drug: Irinotecan; Drug: Isotretinoin; Biological: Sargramostim; Drug: Temozolomide	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To determine the feasibility of administering dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the frontline Post-Consolidation setting in patients with high-risk neuroblastoma who have undergone Induction and Consolidation therapy with tandem high-dose chemotherapy with stem cell rescue (ASCT).

SECONDARY OBJECTIVES:

1. To describe the toxicity profile of dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the Post-Consolidation setting.

2. To describe the event-free survival and overall survival of patients who receive dinutuximab in combination with irinotecan and temozolomide, GM-CSF, and isotretinoin in the Post-Consolidation setting.

EXPLORATORY OBJECTIVES:

1. To describe the toxicity profiles associated with chemo-immunotherapy in the Post-Consolidation setting according to the type of prior therapy.

2. To describe response to chemo-immunotherapy in the Post-Consolidation setting using the revised International Neuroblastoma Risk Classification (INRC) in patients with evaluable or measurable disease at study entry.

3. To characterize immune and cytokine profiles in patients receiving Post-Consolidation chemo-immunotherapy.

4. To bank serial blood samples to investigate the relationship between factors related to the tumor, host, and immune environment and clinical outcomes in patients treated with chemo-immunotherapy.

OUTLINE:

Patients receive temozolomide orally (PO) or via enteral tube daily and irinotecan intravenously (IV) over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim subcutaneously (SC) or IV over 2 hours daily on days 6-12, and isotretinoin PO twice daily (BID) on days 8-21. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma
• Actual Study Start Date: Nov 30, 2020
• Anticipated Primary Completion Date: Dec 31, 2023
• Anticipated Study Completion Date: Dec 31, 2023

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (temozolomide, irinotecan, dinutuximab) Patients receive temozolomide PO or via enteral tube daily and irinotecan IV over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim SC or IV over 2 hours daily on days 6-12, and isotretinoin PO BID on days 8-21. Treatment repeats every 28 days for 5 cycles (6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.

Biological: Dinutuximab; Given IV; Other Names: Ch 14.18UTC Ch14.18 MOAB Ch14.18 monoclonal antibody Ch14.18 Unituxin ; Drug: Irinotecan; Given IV; 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 SC or IV; Other Names: 23-L-Leucinecolony-Stimulating Factor 2 DRG-0012 Leukine Prokine rhu GM-CFS Sagramostim Sargramostatin ; Drug: Temozolomide; Given PO or via enteral tube; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ

Outcome Measures

Primary Outcome Measures

1. Proportion of patients who complete 5 cycles of dinutuximab + chemotherapy without progressive disease (PD) [Within 30 weeks from the date of first treatment]

   Will be assessed by estimation of the feasibility therapy completion rate together with a 95% Wilson confidence interval (CI).

Secondary Outcome Measures

1. Event-free survival (EFS) [From the time of start of protocol therapy to the occurrence of disease relapse or progression, secondary malignancy, or death, assessed up to 60 months]

   EFS Kaplan-Meier estimates will be generated.

2. Overall survival (OS) [From the time of start of protocol therapy to death, assessed up to 60 months]

   OS Kaplan-Meier estimates will be generated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) (verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites at the time of diagnosis) and have been designated as having high-risk disease based on Children's Oncology

Group (COG) risk classification. The following disease groups are eligible:

• Patients with International Neuroblastoma Risk Group (INRG) Stage M disease with any of the following features:

• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR

• Age > 547 days at the time of diagnosis regardless of biologic features; OR

• Age 365-547 days at the time of diagnosis with tumors with unfavorable histology and/or deoxyribonucleic acid (DNA) index = 1

• Patients with INRG Stage MS disease with MYCN amplification

• Patients with INRG Stage L2 disease with either of the following features:

• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR

• Age > 547 days at the time of diagnosis with MYCN non-amplified tumors with unfavorable histology

• Note: Patients observed or patients treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high-risk disease but subsequently found to meet criteria will also be eligible

• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years

• Prior therapy

• All patients must have completed high-risk Induction therapy with 4-6 cycles of chemotherapy

• After completion of Induction therapy, patients may have received no more than 4 cycles of bridging chemotherapy or chemo-immunotherapy prior to ASCT

• Patients cannot have previously progressed on immunotherapy with dinutuximab or other anti-GD2 monoclonal antibody

• All patients must have had undergone surgical resection of their primary tumor as part of frontline therapy. Exceptions to this requirement include patients who had a complete response to Induction chemotherapy, patients with no identifiable primary tumor, and patients for whom the institutional surgical team determined that potential risks outweighed potential benefits of resection

• All patients must have undergone tandem high-dose chemotherapy with ASCT as part of Consolidation

• Patients must enroll between day +56 and day +200 from the peripheral blood stem cell (PBSC) infusion following the last dose of high-dose chemotherapy during Consolidation

• All patients must have undergone external beam radiation therapy. Exceptions to this requirement include patients who had no identifiable primary tumor and no persistent metastatic disease at the end of Induction. For patients who received radiotherapy, at least 7 days must have elapsed between completion of radiotherapy and enrollment on this study

• Patients must not have received long-acting myeloid growth factors (e.g., Neulasta) within 14 days of entry on this study. Seven days must have elapsed since administration of a short-acting myeloid growth factor

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

• Platelet count >= 50,000/uL (transfusion independent for >= 7 days)

• 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:

• Age: Maximum Serum Creatinine (mg/dL)

• 6 months to < 1 year: 0.5 (male and female)

• 1 to < 2 years: 0.6 (male and female)

• 2 to < 6 years: 0.8 (male and female)

• 6 to < 10 years: 1 (male and female)

• 10 to < 13 years: 1.2 (male and female)

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

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

• Note: Patients with history of transplant associated-thrombotic microangiopathy (TA-TMA) must have a creatinine clearance or radioisotope GFR at baseline to assess renal function and must meet the above criteria

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

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x ULN for age (=< 225 U/L)

• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by echocardiogram or radionuclide angiogram

• Absence of dyspnea at rest

• If pulmonary function tests (PFTs) are performed, forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) must be > 60%

• No clinical evidence of active central nervous system (CNS) disease at the time of study enrollment

• Patients with seizure disorder may be enrolled if on non-enzyme-inducing anticonvulsants and well controlled

• CNS toxicity from prior therapy =< grade 2

Exclusion Criteria:

• Patients must not have had progressive disease (PD) per the revised International Neuroblastoma Risk Criteria (INRC) since the initial diagnosis of high-risk neuroblastoma

• Exception: Progressive disease within the first 2 cycles of Induction chemotherapy consisting of cyclophosphamide and topotecan is allowed. Patients with progression subsequent to initial cyclophosphamide and topotecan cycles are excluded

• Patients may not have received additional systemic cancer-directed therapy following completion of the last planned high-dose chemotherapy with ASCT prior to enrollment on this trial

• Patients may not have received iodine-131 (131I)-metaiodobenzylguanidine (MIBG) therapy at any time prior to enrollment on this trial

• Patients who received single (rather than tandem) high-dose chemotherapy with ASCT are excluded

• Patients cannot be receiving other ongoing anticancer therapy

• Patients who were enrolled onto ANBL1531 AND underwent arm assignment are not eligible. Patients who enrolled onto ANBL1531 who declined second consent may be eligible for ANBL19P1 if all other criteria are met

• Patients enrolled onto ANBL17P1 are not eligible

• Patients must have been off pharmacologic doses of systemic steroids for at least 7 days prior to enrollment

• Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study are ineligible. The only exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an equivalent dose of an alternative corticosteroid) as premedication for blood product administration in order to avoid allergic transfusion reactions

• Note: The use of conventional doses of inhaled steroids for the treatment of asthma is permitted, as is the use of physiologic doses of steroids for patients with known adrenal insufficiency

• Patients on any other immunosuppressive medications (e.g., cyclosporine, tacrolimus) are not eligible. However, prior or planned concomitant treatment with eculizumab is permitted (e.g., treatment of TA-TMA)

• Patients must not have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study enrollment

• Note: Patients receiving non-enzyme inducing anticonvulsants such as gabapentin or levetiracetam are eligible

• Patients must not have received drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment

• Patients must not have been diagnosed with myelodysplastic syndrome or with any malignancy other than neuroblastoma

• Patients with symptoms of congestive heart failure are not eligible

• Patients with moderate or large pericardial effusions are not eligible

• Patients must not have >= grade 2 diarrhea

• Patients must not have uncontrolled infection

• Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or reactions that required discontinuation of the anti-GD2 therapy are not eligible

• Patients with a significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of study agents or to significantly increase the severity of the toxicities experienced from study treatment are not eligible

• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential

• Lactating females who plan to breastfeed their infants

• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

• 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	Banner Children's at Desert	Mesa	Arizona	United States	85202
2	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
3	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
4	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
5	Kaiser Permanente-Oakland	Oakland	California	United States	94611
6	Children's Hospital of Orange County	Orange	California	United States	92868
7	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
8	Children's Hospital Colorado	Aurora	Colorado	United States	80045
9	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
10	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
11	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
12	Children's National Medical Center	Washington	District of Columbia	United States	20010
13	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
14	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
15	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
16	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
17	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
18	Nemours Children's Hospital	Orlando	Florida	United States	32827
19	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
20	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
21	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
22	University of Illinois	Chicago	Illinois	United States	60612
23	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
24	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
25	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
26	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
27	Norton Children's Hospital	Louisville	Kentucky	United States	40202
28	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
29	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
30	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
31	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
32	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
33	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
34	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
35	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
36	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
37	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
38	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
39	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
40	Morristown Medical Center	Morristown	New Jersey	United States	07960
41	Albany Medical Center	Albany	New York	United States	12208
42	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
43	NYU Winthrop Hospital	Mineola	New York	United States	11501
44	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
45	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
46	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
47	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
48	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
49	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
50	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
51	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
52	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
53	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
54	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
55	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
56	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
57	The Children's Hospital at TriStar Centennial	Nashville	Tennessee	United States	37203
58	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
59	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
60	Medical City Dallas Hospital	Dallas	Texas	United States	75230
61	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
62	El Paso Children's Hospital	El Paso	Texas	United States	79905
63	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
64	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
65	Covenant Children's Hospital	Lubbock	Texas	United States	79410
66	UMC Cancer Center / UMC Health System	Lubbock	Texas	United States	79415
67	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
68	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
69	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
70	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
71	Seattle Children's Hospital	Seattle	Washington	United States	98105
72	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
73	Queensland Children's Hospital	South Brisbane	Queensland	Australia	4101
74	Royal Children's Hospital	Parkville	Victoria	Australia	3052
75	Perth Children's Hospital	Perth	Western Australia	Australia	6009
76	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
77	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
78	Christchurch Hospital	Christchurch		New Zealand	8011

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ami V Desai, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT04385277
• Other Study ID Numbers: ANBL19P1; NCI-2020-02950; ANBL19P1; ANBL19P1; U10CA180886
• First Posted: May 12, 2020
• Last Update Posted: Aug 18, 2022
• Last Verified: Aug 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Neuroblastoma; Ganglioneuroblastoma; Vitamin A; Irinotecan; Temozolomide; Tretinoin; Dinutuximab; Isotretinoin; Sargramostim

Study Results

No Results Posted as of Aug 18, 2022