2.2 Study Design
This was a prospective, open-label, single arm, phase 1 clinical trial (NCT04661852). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 doses (RP2D) of cabozantinib when combined with topotecan and cyclophosphamide in patients with relapsed or refractory Ewing sarcoma and osteosarcoma. Secondary objectives were to describe the toxicities of the combination administered on this schedule, and to estimate the objective response rate.
The trial used a modified 3+3 design which permitted dose de-escalation in addition to escalation (Supplemental Table 1) ; the MTD was defined as per the standard 3+3 design. If dose level 1 was not tolerable, dose de-escalation depended upon the toxicity profile observed to decide whether to evaluate dose level -1A (dose reduced chemotherapy due primarily to hematologic toxicity) or dose level -1B (interrupted cabozantinib dosing due primarily to non-hematologic toxicity).
Treatment
Patients received therapy in 21-day cycles as shown inSupplemental Table 1. The cabozantinib tablet dose began at 62.5% of the recommended pediatric phase 2 monotherapy dose (25mg/m2/day PO instead of 40mg/m2/day) while topotecan and cyclophosphamide began at their standard pediatric doses (0.75mg/m2/day IV and 250mg/m2/day IV, respectively). Likewise, a step-up dosing regimen was employed in cycle 1 for all dose levels in an effort to improve mTKI tolerability (Supplemental Table 2 ). Myeloid growth factor (filgrastim or pegfilgrastim) was started on days 6-8 of each cycle.
Patients were allowed local control measures (surgery and/or radiotherapy to sites of disease) after a minimum of four cycles of protocol therapy without disease progression. Protocol therapy was held for at least 1 week prior to surgery and for a minimum of 2 weeks following surgery, at least 24 hours prior to radiation, during radiation, and for a minimum of 1 week following radiation.
Dose-Limiting Toxicities
The primary endpoint was the occurrence of a dose-limiting toxicity (DLT) within the cycle 1 DLT observation window (from the first dose in cycle 1 until the first dose of cycle 2). DLTs were defined as events that were possibly, probably or definitely attributable to the treatment regimen. DLTs occurring in the first cycle were used to guide dose escalation decisions. Hematologic DLT was defined as not meeting neutrophil or platelet criteria for subsequent cycle within 14 days of planned cycle start date. For non-hematological toxicity, any toxicity ≥ grade 3 attributable to the treatment regimen was classified as a DLT with the exceptions of the following: grade 3 nausea, vomiting, anorexia, diarrhea or dehydration resolving to ≤ grade 2 within 72 hours; grade 3 weight loss unless persistent for >21 days despite optimal nutrition support; grade 3 liver enzyme elevation that returns to levels that meet eligibility criteria within 7 days of holding cabozantinib and that do not recur upon re-challenge; asymptomatic grade 3 lipase or elevation that returns to levels that meet the eligibility criterion within 7 days of holding cabozantinib and that does not recur upon re-challenge; grade 3 febrile neutropenia in the absence of clinical or laboratory documentation of infection; grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral supplementation; grade 3 proteinuria (urine protein/creatine (UPC) ratio >1.9) unless it is confirmed with a second measurement within 72 hours; and QTc prolongation >500ms unless it persists beyond 72 hours despite correction of serum electrolyte abnormalities. In addition, non-hematologic toxicities that delayed start of subsequent cycle by > 14 days were considered DLTs.