Summary

This phase II trial studies the effects of trastuzumab deruxtecan in treating patients with HER2 positive osteosarcoma that is newly diagnosed or has come back (recurrent). Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them.

Objectives

PRIMARY OBJECTIVE:
I. To estimate the proportion of patients with recurrent measurable osteosarcoma treated with trastuzumab deruxtecan (DS-8201a) who are event free (%EF) at 24 weeks.

SECONDARY OBJECTIVES:
I. To assess the safety of DS-8201a in patients with recurrent osteosarcoma.
II. To describe the pharmacokinetics of DS-8201a in patients with recurrent osteosarcoma.
III. To estimate the objective response rate (ORR), event free survival (EFS), overall survival (OS) and duration of response (DOR) of patients with recurrent, measurable osteosarcoma.

EXPLORATORY OBJECTIVES:
I. To describe the relationship between potential biomarkers and response to DS-8201a.
II. To evaluate quantitative circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and circulating tumor cells (CTCs) as a surrogate markers of response in recurrent osteosarcoma.

OUTLINE:
Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days for 35 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 months.

Eligibility

1. Patients must be > 12 years and =< 39 years of age at the time of study enrollment
2. Patients must have had histologic verification of osteosarcoma at original diagnosis or relapse * Patients with diagnoses of osteosarcoma and confirmed HER2 expression of > 10% of osteosarcoma cells are eligible for the intervention ** Note: There is a mandatory tissue submission for HER2 staining during the Step 0 Eligibility Screening process. Metastatic tissue, when possible from the most recent relapse, is strongly preferred for HER2 staining over archival tissue from primary resection or diagnostic biopsy. The evaluation period for HER2 staining to determine eligibility for therapy will be less than 4 weeks from screening enrollment
3. Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients with clinically inactive brain metastases may be included in the study. Patients with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. Lastly, patient must have unresectable lesions or lesions with no intention to surgically remove in the 6 months following enrollment
4. Patient’s current disease state must be one for which they have received at least standard initial therapy, defined as systemic therapy combined with either radiation or surgery for local control of the primary tumor at diagnosis. Prior therapy after relapse is not required
5. Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. Patients who are non-ambulatory as a result of prior surgical treatment for osteosarcoma should be considered ambulatory for the purposes of assessing performance status
6. Patients must have recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately * Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned Research Coordinator prior to enrollment ** >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) * Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent * Antibodies: >= 4 weeks (28 days) must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1 * Corticosteroids * Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur * Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors) * Stem cell Infusions (with or without total body irradiation [TBI]): ** Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD) ** Autologous stem cell infusion including boost infusion: >= 30 days * Vellular therapy: >= 30 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.) * Radiation therapy (XRT)/external beam irradiation including protons: >= 4 weeks (28 days) including palliative radiation therapy to the chest. >= 14 days after palliative local XRT to areas other than the chest or for whole brain radiotherapy * Radiopharmaceutical therapy (e.g., radiolabeled antibody, samarium): >= 42 days after systemically administered radiopharmaceutical therapy * Patients must not have received prior HER2 therapies including antibody drug conjugates (e.g. TDM-1 or DS-8201a), HER2 directed cellular therapies, HER2 receptor therapy (e.g. trastuzumab, pertuzumab) or small molecule antagonists of HER2 (e.g lapatinib or neratinib)
7. Patients must be at least 7 days from the date of last surgery
8. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3, (granulocyte colony-stimulating factor [G-CSF] administration is not allowed within 1 week prior to Step 1 screening assessment) (for patients with solid tumors without known bone marrow involvement)
9. Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (for patients with solid tumors without known bone marrow involvement)
10. Hemoglobin >= 8.0 g/dL at baseline (Red Blood Cell transfusion is not allowed within 1 week prior to screening assessment) (for patients with solid tumors without known bone marrow involvement)
11. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: * Age: 12 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) * Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) * Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) ** For participants less than 18 years of age that screen fail only based on creatinine, a 24 hour urine collection may be used instead to confirm eligibility. A calculated GFR > 60 mL/min/1.73 m^2 using a 24 hour collection will meet criteria for inclusion on this trial
12. Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal (ULN) for age. For patients with documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) bilirubin must be < 3 x ULN for age (patients with solid tumors)
13. Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN. (if liver metastases present =< 5 x ULN). For the purpose of this study, the ULN for ALT is 45 U/L regardless of baseline and the ULN for AST is 50 U/L regardless of baseline (patients with solid tumors)
14. Serum albumin >= 2.5 g/dL (patients with solid tumors)
15. International normalized ratio (INR)/prothrombin time (PT) and either partial thromboplastin or activated partial thromboplastin time (aPTT) =< 1.5 x ULN (patients with solid tumors)
16. Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before Step 1 enrollment
17. Corrected QT interval (QTc) prolongation to < 470 ms (females) or < 450 ms (males) based on average triplicate 12-lead electrocardiogram (ECG)
18. Pulse oximetry > 93% on room air
19. Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days
20. Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) resulting from prior chemotherapy, surgery, and/or radiation must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
21. All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines