A Phase 2 interventional study of Laboratory Biomarker Analysis and Lorvotuzumab Mertansine in Pleuropulmonary Blastoma, Recurrent Malignant Peripheral Nerve Sheath Tumor and Recurrent Neuroblastoma, sponsored by Children's Oncology Group. Completed at 69 sites in United States. Open to participants aged 12 Months to 30 Years. Per ClinicalTrials.gov, last updated 2022-01-13.
Sponsored by Children's Oncology Group · Phase 2, Interventional, and Treatment
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.
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.
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This study's enrollment of 62 is above the median of 44 across 59 interventional studies indexed under Neurofibrosarcoma.
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Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse
Primary strata
Secondary strata: miscellaneous CD56-expressing tumors:
Patients must have radiographically measurable disease (with the exception of those with neuroblastoma)
Note: the following do not qualify as measurable disease:
Patients must have received standard treatment appropriate for their tumor type
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:
Exclusion Criteria:
Concomitant medications
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.
Other: Laboratory Biomarker Analysis · Biological: Lorvotuzumab Mertansine · Other: Pharmacological Study
Correlative studies
Given IV
Also known as: Anti-Human NCAM-1 Monoclonal Antibody N901, BB-10901, huN901-DM1, IMGN901
Correlative studies
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.
Time frame: Up to 18 weeks (6 courses)
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.
Time frame: Up to 12 months (17 courses)
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.
Time frame: 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
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.
Time frame: Day 1 and 8 of course 1 prior to lorvotuzumab mertansine
Each of 6 disease strata enrolled up to 16 patients who were evaluable for the primary response criteria.
| Milestone | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma |
|---|---|---|---|---|---|---|
| Started | 17 | 17 | 12 | 1 | 5 | 10 |
| Completed | 0 | 0 | 1 | 0 | 0 | 1 |
| Not completed | 17 | 17 | 11 | 1 | 5 | 9 |
| Withdrew: Death | 2 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Lack of efficacy | 13 | 14 | 9 | 1 | 5 | 8 |
| Withdrew: Physician decision | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 | 2 | 0 | 0 | 1 |
| Withdrew: Ineligible | 0 | 1 | 0 | 0 | 0 | 0 |
| Withdrew: Never received treatment | 1 | 0 | 0 | 0 | 0 | 0 |
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.
| Percent of participants | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma |
|---|---|---|---|---|---|---|
| Objective Response by Response Evaluation Criteria in Solid Tumors Version 1.1 | 0.00 (0.00 to 20.59) | 6.25 (0.16 to 30.23) | 0.00 (0.00 to 26.46) | 0.00 (0.00 to 97.50) | 0.00 (0.00 to 52.18) | 0.00 (0.00 to 30.85) |
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.
| Treatment cycles | Treatment (Lorvotuzumab Mertansine) |
|---|---|
| Anemia: Grade 2 | 0 |
| Anemia: Grade 3 | 2 |
| Anemia: Grade 4 | 0 |
| Anemia: Grade 5 | 0 |
| Colonic fistula: Grade 2 | 0 |
| Colonic fistula: Grade 3 | 0 |
| Colonic fistula: Grade 4 | 1 |
| Colonic fistula: Grade 5 | 0 |
| Colonic perforation: Grade 2 | 0 |
| Colonic perforation: Grade 3 | 0 |
| Colonic perforation: Grade 4 | 0 |
| Colonic perforation: Grade 5 | 1 |
| Dental caries: Grade 2 | 0 |
| Dental caries: Grade 3 | 1 |
| Dental caries: Grade 4 | 0 |
| Dental caries: Grade 5 | 0 |
| Nausea: Grade 2 | 0 |
| Nausea: Grade 3 | 1 |
| Nausea: Grade 4 | 0 |
| Nausea: Grade 5 | 0 |
| Vomiting: Grade 2 | 1 |
| Vomiting: Grade 3 | 1 |
| Vomiting: Grade 4 | 0 |
| Vomiting: Grade 5 | 0 |
| Tooth infection: Grade 2 | 0 |
| Tooth infection: Grade 3 | 1 |
| Tooth infection: Grade 4 | 0 |
| Tooth infection: Grade 5 | 0 |
| Alanine aminotransferase increased: Grade 2 | 0 |
| Alanine aminotransferase increased: Grade 3 | 3 |
| Alanine aminotransferase increased: Grade 4 | 0 |
| Alanine aminotransferase increased: Grade 5 | 0 |
| Aspartate aminotransferase increased: Grade 2 | 0 |
| Aspartate aminotransferase increased: Grade 3 | 1 |
| Aspartate aminotransferase increased: Grade 4 | 0 |
| Aspartate aminotransferase increased: Grade 5 | 0 |
| Lymphocyte count decreased: Grade 2 | 0 |
| Lymphocyte count decreased: Grade 3 | 2 |
| Lymphocyte count decreased: Grade 4 | 0 |
| Lymphocyte count decreased: Grade 5 | 0 |
| Hyperglycemia: Grade 2 | 0 |
| Hyperglycemia: Grade 3 | 1 |
| Hyperglycemia: Grade 4 | 0 |
| Hyperglycemia: Grade 5 | 0 |
| Hyperuricemia: Grade 2 | 0 |
| Hyperuricemia: Grade 3 | 1 |
| Hyperuricemia: Grade 4 | 0 |
| Hyperuricemia: Grade 5 | 0 |
| Hypokalemia: Grade 2 | 0 |
| Hypokalemia: Grade 3 | 1 |
| Hypokalemia: Grade 4 | 0 |
| Hypokalemia: Grade 5 | 0 |
| Hypophosphatemia: Grade 2 | 0 |
| Hypophosphatemia: Grade 3 | 1 |
| Hypophosphatemia: Grade 4 | 0 |
| Hypophosphatemia: Grade 5 | 0 |
| Headache: Grade 2 | 1 |
| Headache: Grade 3 | 0 |
| Headache: Grade 4 | 0 |
| Headache: Grade 5 | 0 |
| Peripheral motor neuropathy: Grade 2 | 0 |
| Peripheral motor neuropathy: Grade 3 | 1 |
| Peripheral motor neuropathy: Grade 4 | 0 |
| Peripheral motor neuropathy: Grade 5 | 0 |
| Peripheral sensory neuropathy: Grade 2 | 0 |
| Peripheral sensory neuropathy: Grade 3 | 1 |
| Peripheral sensory neuropathy: Grade 4 | 0 |
| Peripheral sensory neuropathy: Grade 5 | 0 |
| All Reportable AEs: Grade 2 | 2 |
| All Reportable AEs: Grade 3 | 18 |
| All Reportable AEs: Grade 4 | 1 |
| All Reportable AEs: Grade 5 | 1 |
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
Collected over While patients were on Protocol Therapy: Up to 17, 28-day cycles. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Stratum 1: Wims Tumor | 10/17 (58.8%) | 7/16 (43.8%) | 5/16 (31.3%) |
| Stratum 2: Rhabdomyosarcoma | 11/16 (68.8%) | 8/16 (50%) | 4/16 (25%) |
| Stratum 3: Neuroblastoma | 4/12 (33.3%) | 1/12 (8.3%) | 4/12 (33.3%) |
| Stratum 4: Pleuropulmonary Blastoma | 1/1 (100%) | 0/1 (0%) | 1/1 (100%) |
| Stratum 5: Malignant Peripheral Nerve Sheath Tumor | 1/5 (20%) | 0/5 (0%) | 1/5 (20%) |
| Stratum 6: Synovial Sarcoma | 2/10 (20%) | 3/10 (30%) | 4/10 (40%) |
| Event | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma |
|---|---|---|---|---|---|---|
| VomitingGastrointestinal disorders | 0/16 | 1/16 | 0/12 | 0/1 | 0/5 | 2/10 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 3/16 | 0/16 | 0/12 | 0/1 | 0/5 | 1/10 |
| Abdominal painGastrointestinal disorders | 2/16 | 2/16 | 0/12 | 0/1 | 0/5 | 0/10 |
| DehydrationMetabolism and nutrition disorders | 0/16 | 2/16 | 0/12 | 0/1 | 0/5 | 0/10 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specifyNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/16 | 2/16 | 0/12 | 0/1 | 0/5 | 0/10 |
| Alanine aminotransferase increasedInvestigations | 1/16 | 0/16 | 0/12 | 0/1 | 0/5 | 1/10 |
| HeadacheNervous system disorders | 0/16 | 0/16 | 0/12 | 0/1 | 0/5 | 1/10 |
| NauseaGastrointestinal disorders | 0/16 | 0/16 | 0/12 | 0/1 | 0/5 | 1/10 |
| Dental cariesGastrointestinal disorders | 0/16 | 0/16 | 1/12 | 0/1 | 0/5 | 0/10 |
| Tooth infectionInfections and infestations | 0/16 | 0/16 | 1/12 | 0/1 | 0/5 | 0/10 |
| Event | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma |
|---|---|---|---|---|---|---|
| Abdominal painGastrointestinal disorders | 0/16 | 0/16 | 0/12 | 1/1 | 0/5 | 0/10 |
| AtelectasisRespiratory, thoracic and mediastinal disorders | 0/16 | 0/16 | 0/12 | 1/1 | 0/5 | 0/10 |
| DehydrationMetabolism and nutrition disorders | 1/16 | 0/16 | 0/12 | 1/1 | 0/5 | 0/10 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 0/16 | 1/16 | 0/12 | 1/1 | 0/5 | 0/10 |
| HyponatremiaMetabolism and nutrition disorders | 0/16 | 0/16 | 0/12 | 1/1 | 0/5 | 0/10 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 0/16 | 0/16 | 0/12 | 1/1 | 0/5 | 0/10 |
| Lymphocyte count decreasedInvestigations | 0/16 | 3/16 | 0/12 | 0/1 | 0/5 | 2/10 |
| Weight lossInvestigations | 0/16 | 0/16 | 0/12 | 0/1 | 1/5 | 0/10 |
| AnemiaBlood and lymphatic system disorders | 2/16 | 0/16 | 1/12 | 0/1 | 0/5 | 0/10 |
| FeverGeneral disorders | 0/16 | 0/16 | 0/12 | 0/1 | 0/5 | 1/10 |
| Age, Categorical(Participants) | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma | Total |
|---|---|---|---|---|---|---|---|
| <=18 years | 13 | 7 | 12 | 1 | 5 | 6 | 44 |
| Between 18 and 65 years | 4 | 10 | 0 | 0 | 0 | 4 | 18 |
| >=65 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Age, Continuous(Years) | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma | Total |
|---|---|---|---|---|---|---|---|
| Mean | 12.61 ± 6.48 | 18.43 ± 5.28 | 7.78 ± 1.94 | 3.69 ± NA | 12.96 ± 4.29 | 17.37 ± 4.59 | 13.2 ± 6.37 |
| Sex: Female, Male(Participants) | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma | Total |
|---|---|---|---|---|---|---|---|
| Female | 5 | 8 | 3 | 1 | 4 | 6 | 27 |
| Male | 12 | 9 | 9 | 0 | 1 | 4 | 35 |
| Ethnicity (NIH/OMB)(Participants) | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma | Total |
|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 2 | 3 | 1 | 0 | 1 | 1 | 8 |
| Not Hispanic or Latino | 13 | 14 | 10 | 1 | 4 | 9 | 51 |
| Unknown or Not Reported | 2 | 0 | 1 | 0 | 0 | 0 | 3 |
| Race (NIH/OMB)(Participants) | Stratum 1: Wims Tumor | Stratum 2: Rhabdomyosarcoma | Stratum 3: Neuroblastoma | Stratum 4: Pleuropulmonary Blastoma | Stratum 5: Malignant Peripheral Nerve Sheath Tumor | Stratum 6: Synovial Sarcoma | Total |
|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 1 | 0 | 0 | 0 | 1 | 0 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 2 | 3 | 1 | 0 | 1 | 2 | 9 |
| White | 10 | 14 | 10 | 1 | 3 | 5 | 43 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 4 | 0 | 1 | 0 | 0 | 3 | 8 |
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Studies of the drug tested here: Lorvotuzumab mertansine