1756P - A phase I/II trial of gemcitabine, docetaxel, and hydroxychloroquine in advanced/metastatic osteosarcoma

Background

Gemcitabine + Docetaxel (G/D) is frequently used in the treatment of advanced/metastatic osteosarcoma (OS) and has been shown to induce autophagy, a proposed mechanism of chemoresistance. Hydroxychloroquine (HCQ) is a lysosome inhibitor that blocks chemotherapy-induced autophagy in multiple tumor types. We conducted a phase I/II clinical trial of G/D with HCQ to evaluate safety, tolerability, and preliminary efficacy in patients with advanced/metastatic OS.

Methods

Adolescent and adult patients (>/= 12 y.o.) with metastatic or advanced unresectable OS were enrolled in cohorts of 3 using a 3+3 dose escalation design to evaluate G/D with HCQ at 2 dose levels. Patients received G/D at standard doses of G=900mg/m2 IV d1 and d8 and D=75mg/m2 IV d8 every 21 days. HCQ was given at 600mg PO daily or 600mg PO BID until disease progression (PD), unacceptable toxicity, or consent withdrawal. Tumor response assessments occurred every 6 weeks. Additional patients were enrolled at the RP2D (G/D + HCQ 600mg PO BID) to estimate the event free survival at 4 months (4mo EFS), objective response rate (ORR), and overall survival. Archival tumor and on-treatment tumor biopsies were collected for autophagy biomarker analysis.

Results

31 OS patients aged 12-71 years were enrolled (Ph 1 n=13, Ph 2 n=25 all patients treated at RP2D). The 4mo EFS was 44% and 39% for all patients and those treated at RP2D, respectively. The median overall survival was 12.7 mo (all patients) and 9.5 mo (RP2D). Best response was 1 CR, 3 PR, 13 SD, and 11 PD by RECIST 1.1 (ORR = 13%). 7 patients had prolonged benefit with PR/SD > 9 mo. Study treatment was discontinued due to patient preference without PD (n=14), PD (n=15), death due to PD (n=1), or treatment delay (n=1). The most common grade 3/4 adverse events were hematologic toxicity (anemia n=15, neutropenia n=10, thrombocytopenia n=12), and nausea (n=10). 3 patients underwent resection of metastatic lesions on study after >4 months of G/D+HCQ and demonstrated pathologic complete response (CR).

Conclusions

The combination of G/D + HCQ is well tolerated in adolescents and adults with OS and demonstrated efficacy with prolonged SD and pathologic CRs observed. The contribution of HCQ to chemotherapy efficacy warrants further investigation.

Clinical trial identification

NCT03598595.

Editorial acknowledgement

Legal entity responsible for the study

J. A. Livingston.

Funding

Cures Within Reach.

Disclosure

J.A. Livingston: Financial Interests, Personal, Other, Nonprofit Strategic Advisory Board: Osteosarcoma Institute; Financial Interests, Institutional, Funding, Clinical trial funding and drug support: Genentech, Exelixis. All other authors have declared no conflicts of interest.