Lorvotuzumab Mertansine in Treating Younger Patients With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma

Recurrent Neuroblastoma Clinical Trial

Official title:

A Phase 2 Study of IMGN901 (Lorvotuzumab Mertansine; NSC#: 783609) in Children With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor (MPNST) and Synovial Sarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02452554
• Other study ID #: ADVL1522
• Secondary ID: NCI-2015-00746AD
• Status: Completed
• Phase: Phase 2
• Start date: October 12, 2015
• Est. completion date: September 30, 2021

Study information

• Verified date: January 2022
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well lorvotuzumab mertansine works in treating younger patients with Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), or synovial sarcoma that has returned or that does not respond to treatment. Antibody-drug conjugates, such as lorvotuzumab mertansine, are created by attaching an antibody (protein used by the body?s immune system to fight foreign or diseased cells) to an anti-cancer drug. The antibody is used to recognize tumor cells so the anti-cancer drug can kill them.

Description:

PRIMARY OBJECTIVES:

I. To assess the efficacy of IMGN901 (lorvotuzumab mertansine) in Wilms tumor, rhabdomyosarcoma, neuroblastoma and other cluster of differentiation (CD)56-expressing tumors such as pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST) and synovial sarcoma.

II. To determine the tolerability of the adult recommended phase 2 dose (RP2D) of IMGN901 administered as an intravenous infusion, administered on days 1 and 8 of a 21-day cycle, to children with refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, MPNST, or synovial sarcoma.

III. To define and describe the toxicities of IMGN901 administered on this schedule.

EXPLORATORY OBJECTIVES:

I. To correlate tumor response with tumor CD56+ expression. II. To characterize the pharmacokinetics of IMGN901 in children with refractory cancer, including an assessment of impact on circulating CD56+ peripheral blood cells.

OUTLINE:

Patients receive lorvotuzumab mertansine intravenously (IV) over 1-1.5 hours on days 1 and 8. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: September 30, 2021
• Est. primary completion date: June 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 30 Years

Eligibility

Inclusion Criteria:

• Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse

• Primary strata

• Wilms tumor

• Rhabdomyosarcoma

• Neuroblastoma

• Secondary strata: miscellaneous CD56-expressing tumors:

• Pleuropulmonary blastoma

• Malignant peripheral nerve sheath tumor (MPNST)

• Synovial sarcoma

• Patients must have radiographically measurable disease (with the exception of those with neuroblastoma)

• Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm)

• Note: the following do not qualify as measurable disease:

• Malignant fluid collections (e.g., ascites, pleural effusions)

• Bone marrow infiltration except that detected by metaiodobenzylguanidine (MIBG) scan for neuroblastoma

• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted in patients with neuroblastoma who do not have measurable disease but have MIBG-avid evaluable disease

• Elevated tumor markers in plasma or cerebrospinal fluid (CSF)

• Previously radiated lesions that have not demonstrated clear progression post radiation

• Leptomeningeal lesions that do not meet the measurements noted above

• Patients with neuroblastoma who do not have measurable disease but have MIBG-avid evaluable disease are eligible

• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky 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 chemotherapy, immunotherapy, or radiotherapy prior to entering this study

• Patients must have received standard treatment appropriate for their tumor type

• Myelosuppressive chemotherapy: patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)

• Hematopoietic growth factors: at least 14 days must have elapsed after receiving pegfilgrastim and least 7 days must have elapsed since the completion of therapy with a non-pegylated growth factor

• Biologic (anti-neoplastic agent): at least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur

• Monoclonal antibodies: at least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody

• Radiotherapy: >= 2 weeks must have elapsed since local palliative external beam radiation therapy (XRT) (small port); >= 6 weeks must have elapsed since treatment with therapeutic doses of MIBG; >= 3 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given

• Stem cell transplant or rescue without TBI: no evidence of active graft vs. host disease and >= 2 months must have elapsed since transplant

• For patients with solid tumors without bone marrow involvement: peripheral absolute neutrophil count (ANC) >= 1000/uL

• For patients with solid tumors without bone marrow involvement: platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)

• For patients with solid tumors and known bone marrow metastatic disease: peripheral absolute neutrophil count (ANC) >= 750/uL

• For patients with solid tumors and known bone marrow metastatic disease: platelet count >= 75,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)

• 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 1 to < 2 years: maximum serum creatinine: 0.6 mg/dL in males and females

• Age 2 to < 6 years: maximum serum creatinine: 0.8 mg/dL in males and females

• Age 6 to < 10 years: maximum serum creatinine: 1 mg/dL in males and females

• Age 10 to < 13 years: maximum serum creatinine: 1.2 mg/dL in males and females

• Age 13 to < 16 years: maximum serum creatinine: 1.5 mg/dL in males and 1.4 mg/dL in females

• Age >= 16 years: maximum serum creatinine: 1.7 mg/dL in males and 1.4 mg/dL in females

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

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)

• Serum albumin >= 2 g/dL

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

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

• 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

Exclusion Criteria:

• Patients who are pregnant or breast-feeding are not eligible for this study; negative 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 for the duration of study therapy and for 4 weeks after the last dose of study therapy; breastfeeding women are excluded

• Concomitant medications

• Corticosteroids: patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible

• Patients who have received previous treatment with IMGN901 are not eligible

• Investigational drugs: patients who are currently receiving another investigational drug are not eligible

• Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible

• Anti-graft-versus-host disease (GVHD) or agents to prevent organ rejection post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial

• Patients who have a CNS toxicity > grade 2 are not eligible

• Patients must not have known active central nervous system (CNS) metastases; patients with known central nervous system metastases are excluded unless treated surgically or with radiotherapy, and stable with no recurrent lesions for at least 6 months

• Patients who have baseline peripheral neuropathy >= grade 2 are not eligible

• Patients who have an uncontrolled infection 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

Related Conditions & MeSH terms

• Neoplasms
• Nerve Sheath Neoplasms
• Neuroblastoma
• Pleuropulmonary Blastoma
• Recurrent Malignant Peripheral Nerve Sheath Tumor
• Recurrent Neuroblastoma
• Recurrent Rhabdomyosarcoma
• Recurrent Synovial Sarcoma
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Synovial
• Wilms Tumor

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Biological:
• Lorvotuzumab Mertansine
Given IV

Other:
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Mount Sinai Hospital	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacokinetic (PK) Parameters of Lorvotuzumab Mertansine	A descriptive analysis of PK parameters of lorvotuzumab mertansine will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). Analyses will be descriptive and exploratory and hypotheses generating in nature.	Pre-treatment, end of infusion, and 2, 6, 24, 48, and 96 hours after end of infusion on day 1 of course 1, and pre-treatment, end of infusion, and 2 and 6 hours after end of infusion on day 8 of course 1
Other	CD56 Expression	The association between CD56+ expression and response will be evaluated using the exact conditional test of proportions (Fisher?s Exact test). Analyses will be descriptive and exploratory and hypotheses generating in nature.	Day 1 and 8 of course 1 prior to lorvotuzumab mertansine
Primary	Objective Response by Response Evaluation Criteria in Solid Tumors Version 1.1	The best response of disease will be examined separately in each stratum. A responder is defined as a patient who achieves a best response of partial response or complete response on the study. Response rates will be calculated as the percent of evaluable patients who are responders, and Clopper-Pearson confidence intervals will be constructed.	Up to 18 weeks (6 courses)
Primary	Incidence of Toxicities of Lorvotuzumab Mertansine, Using the NCI Common Terminology Criteria for Adverse Events Version 4.0	Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade for toxicities with Possible, Probable, or Definite attribution to the study drug. Tables will summarize incidence by cycle.	Up to 12 months (17 courses)