Dome, Jeffrey S.

ABSTRACTBackgroundThe Pediatric Oncology Group P9262 Phase 2 study of single‐agent paclitaxel demonstrated one complete response (CR), one partial response (PR), and four with stable disease (SD) among 15 patients with recurrent Wilms tumor (WT). Based on this activity, paclitaxel‐containing regimens have been used as salvage therapy for treatment‐refractory WT. We conducted a multi‐institutional retrospective study to further characterize the clinical activity of paclitaxel‐containing regimens in recurrent WT.MethodsTwelve institutions submitted anonymized data from patients with relapsed WT treated with paclitaxel. Response after one or two cycles of a paclitaxel‐containing regimen was reported according to Response Evaluation Criteria in Solid Tumors.ResultsTwenty‐eight patients with a median age at diagnosis of 5.5 years (range: 3 months to 31.9 years) were reported. Twenty had non‐anaplastic WT; eight had diffuse anaplasia (DA). Stage at diagnosis was I (n = 1), II (n = 1), III (n = 11), IV (n = 14), and V (n = 1). Patients received a mean of 8.5 anticancer drugs (range: 6–12) before paclitaxel, including eight who received high‐dose therapy/stem cell transplant. Paclitaxel (n = 13) or nab‐paclitaxel (n = 15) were predominantly administered in combination with other agents, most commonly doxorubicin and/or gemcitabine. Eleven of 26 patients with measurable disease had a partial response (7 = non‐anaplastic; 4 = DA), four had stable disease, and 11 had progressive disease. Two patients without measurable disease maintained a complete response for 12 and 16 months. The mean duration without progression was 7.6 months (range: 1–35 months).ConclusionsPaclitaxel‐containing regimens appear to be active against heavily pretreated WT with either non‐anaplastic or DA histology. Prospective studies are warranted to formally evaluate the efficacy of paclitaxel‐based therapies.

Background Lorvotuzumab mertansine (IMGN901) is an antibody‐drug conjugate linking an antimitotic agent (DM1) to an anti‐CD56 antibody (lorvotuzumab). Preclinical efficacy has been noted in Wilms tumor, rhabdomyosarcoma, and neuroblastoma. Synovial sarcoma, malignant peripheral nerve sheath tumor (MPNST), and pleuropulmonary blastoma also express CD56. A phase 2 trial of lorvotuzumab mertansine was conducted to assess its efficacy, recommended phase 2 dose, and toxicities. Methods Eligible patients had relapsed after or progressed on standard therapy for their tumor type. Lorvotuzumab mertansine (110 mg/m 2 per dose) was administered at the adult recommended phase 2 dose intravenously on days 1 and 8 of 21‐day cycles. Dexamethasone premedication was used. Pharmacokinetic samples, peripheral blood CD56‐positive cell counts, and tumor CD56 expression were assessed. Results Sixty‐two patients enrolled. The median age was 14.3 years (range, 2.8‐29.9 years); 35 were male. Diagnoses included Wilms tumor (n = 17), rhabdomyosarcoma (n = 17), neuroblastoma (n = 12), synovial sarcoma (n = 10), MPNST (n = 5), and pleuropulmonary blastoma (n = 1). Five patients experienced 9 dose‐limiting toxicities: hyperglycemia (n = 1), colonic fistula (n = 1) with perforation (n = 1), nausea (n = 1) with vomiting (n = 1), increased alanine aminotransferase in cycle 1 (n = 2), and increased alanine aminotransferase in cycle 2 (n = 1) with increased aspartate aminotransferase (n = 1). Non–dose‐limiting toxicities (grade 3 or higher) attributed to lorvotuzumab mertansine were rare. The median values of the maximum concentration, half‐life, and area under the curve from zero to infinity for DM1 were 0.87 µg/mL, 35 hours, and 27.9 µg/mL h, respectively. Peripheral blood CD56+ leukocytes decreased by 71.9% on day 8. One patient with rhabdomyosarcoma had a partial response, and 1 patient with synovial sarcoma achieved a delayed complete response. Conclusions Lorvotuzumab mertansine (110 mg/m 2 ) is tolerated in children at the adult recommended phase 2 dose; clinical activity is limited.

10537 Background: Lorvotuzumab mertansine (IMGN901; LM) is an antibody-drug conjugate, linking anti-mitotic agent (DM1) to an anti-CD56 antibody. Preclinical data show effects in Wilms tumor (WT), rhabdomyosarcoma (RMS), and neuroblastoma (NBL). Synovial sarcoma (SS), MPNST and pleuropulmonary blastoma (PPB) also express CD56. A phase 2 trial assessing the efficacy and tolerability of LM administered at the adult recommended phase 2 dose (RP2D) was conducted in children with relapsed tumors. Methods: LM (110 mg/m2/dose) was administered IV on days (d) 1 and 8 of 21 d cycles, with dexamethasone pre-medication. The tolerability of LM was assessed in 6 patients prior to trial activation group-wide. Dose limiting toxicity (DLT) was assessed using CTCAE. Response was assessed by RECIST. Pharmacokinetics (PK) were obtained during cycle 1. Peripheral blood CD56-positive cells were measured d1 and d8 pre-dose. Tumor CD56 expression by immunohistochemistry in archival tissue was scored (0-3+). Results: Sixty-two patients were enrolled. The median (range) age was 14.3 y (2.8–29.9); 35 were male. Diagnoses included WT (17), RMS (17), NBL (12), SS (10), MPNST (5) and PPB (1). One patient was ineligible due to lack of measurable disease. Of 61 eligible patients, 47 were evaluable for toxicity, 50 for response, 50 for tumor CD56 expression; and 18 consented to optional PK. Five patients experienced 9 DLTs: hyperglycemia (1), colonic fistula (1) with perforation (1), nausea (1) with vomiting (1), increased ALT (2 in cycle 1; 1 in cycle 2 with increased AST (1)). Non-dose limiting toxicities (Grade ≥3) attributed to LM included lymphopenia, anemia, vomiting, dehydration, hypokalemia, hyperuricemia, hypophosphatemia. Mean DM1 Cmax, t1/2 and AUC0-∞values were 922 ng/ml, 33 h and 27400 ng/ml*h, respectively. Tumor CD56 expression was 0 (8%), 1+(4%), 2+(12%), 3+(76%). LM and CD56 antibody PK, and response, will be reported. Conclusions: LM (110 mg/m2) is tolerated in children at the adult RP2D. Clinical trial information: NCT 02452554.