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

Phase 2

Completed

• Conditions: Recurrent Rhabdomyosarcoma; Recurrent Malignant Peripheral Nerve Sheath Tumor; Recurrent Neuroblastoma; Recurrent Synovial Sarcoma; Pleuropulmonary Blastoma; Wilms Tumor
• Interventions: Other: Laboratory Biomarker Analysis; Biological: Lorvotuzumab Mertansine; Other: Pharmacological Study

• Registration Number: NCT02452554
• Lead Sponsor: Children's Oncology Group

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2015-05-20
• Study First Submitted QC: 2015-05-20
• Study First Posted: 2015-05-22
• Study Start: 2015-10-12
• Primary Completion: 2017-06-30
• Results First Submitted: 2019-07-17
• Results First Submitted QC: 2019-08-28
• Results First Posted: 2019-08-29
• Study Completion: 2021-09-30
• Status Verified: 2022-01
• Last Update Submitted: 2022-01-04
• Last Update Posted: 2022-01-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (lorvotuzumab mertansine)	Pharmacological Study	Patients receive lorvotuzumab mertansine 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.
Treatment (lorvotuzumab mertansine)	Laboratory Biomarker Analysis	Patients receive lorvotuzumab mertansine 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.
Treatment (lorvotuzumab mertansine)	Lorvotuzumab Mertansine	Patients receive lorvotuzumab mertansine 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.

Primary Outcome Measures

Name	Time	Method
Objective Response by Response Evaluation Criteria in Solid Tumors Version 1.1	Up to 18 weeks (6 courses)	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.
Incidence of Toxicities of Lorvotuzumab Mertansine, Using the NCI Common Terminology Criteria for Adverse Events Version 4.0	Up to 12 months (17 courses)	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.

Trial Locations

Locations (69)

Golisano Children's Hospital of Southwest Florida; 🇺🇸 Fort Myers, Florida, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

Rainbow Babies and Childrens Hospital; 🇺🇸 Cleveland, Ohio, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States

Alfred I duPont Hospital for Children; 🇺🇸 Wilmington, Delaware, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Dartmouth Hitchcock Medical Center; 🇺🇸 Lebanon, New Hampshire, United States

Prisma Health Richland Hospital; 🇺🇸 Columbia, South Carolina, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

University of Vermont and State Agricultural College; 🇺🇸 Burlington, Vermont, United States

Nicklaus Children's Hospital; 🇺🇸 Miami, Florida, United States

Rady Children's Hospital - San Diego; 🇺🇸 San Diego, California, United States

Loma Linda University Medical Center; 🇺🇸 Loma Linda, California, United States

Providence Sacred Heart Medical Center and Children's Hospital; 🇺🇸 Spokane, Washington, United States

UCSF Medical Center-Mission Bay; 🇺🇸 San Francisco, California, United States

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

Kapiolani Medical Center for Women and Children; 🇺🇸 Honolulu, Hawaii, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

University of Minnesota/Masonic Cancer Center; 🇺🇸 Minneapolis, Minnesota, United States

Children's Hospitals and Clinics of Minnesota - Minneapolis; 🇺🇸 Minneapolis, Minnesota, United States

Children's Hospital of Orange County; 🇺🇸 Orange, California, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Ascension Saint John Hospital; 🇺🇸 Detroit, Michigan, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Children's Hospital of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

C S Mott Children's Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Children's Hospital of Alabama; 🇺🇸 Birmingham, Alabama, United States

Kaiser Permanente Downey Medical Center; 🇺🇸 Downey, California, United States

Children's Hospital and Research Center at Oakland; 🇺🇸 Oakland, California, United States

Johns Hopkins All Children's Hospital; 🇺🇸 Saint Petersburg, Florida, United States

Saint Luke's Mountain States Tumor Institute; 🇺🇸 Boise, Idaho, United States

Children's Healthcare of Atlanta - Egleston; 🇺🇸 Atlanta, Georgia, United States

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

University of Kentucky/Markey Cancer Center; 🇺🇸 Lexington, Kentucky, United States

Riley Hospital for Children; 🇺🇸 Indianapolis, Indiana, United States

Saint Jude Midwest Affiliate; 🇺🇸 Peoria, Illinois, United States

Saint Vincent Hospital and Health Care Center; 🇺🇸 Indianapolis, Indiana, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Eastern Maine Medical Center; 🇺🇸 Bangor, Maine, United States

Maine Children's Cancer Program; 🇺🇸 Scarborough, Maine, United States

Helen DeVos Children's Hospital at Spectrum Health; 🇺🇸 Grand Rapids, Michigan, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

Mercy Hospital Saint Louis; 🇺🇸 Saint Louis, Missouri, United States

Mount Sinai Hospital; 🇺🇸 New York, New York, United States

State University of New York Upstate Medical University; 🇺🇸 Syracuse, New York, United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center; 🇺🇸 New York, New York, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Vanderbilt University/Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States

Children's Hospital of The King's Daughters; 🇺🇸 Norfolk, Virginia, United States

West Virginia University Healthcare; 🇺🇸 Morgantown, West Virginia, United States

University of Wisconsin Hospital and Clinics; 🇺🇸 Madison, Wisconsin, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

Ochsner Medical Center Jefferson; 🇺🇸 New Orleans, Louisiana, United States

Dell Children's Medical Center of Central Texas; 🇺🇸 Austin, Texas, United States