4 Discussion
This study is the first combination trial of cabozantinib, topotecan and
cyclophosphamide in patients with relapsed or refractory Ewing sarcoma
or osteosarcoma. Concomitant therapy was not tolerable but an
interrupted schedule was tolerable. The recommended phase 2 schedule
administers cabozantinib only on days 8-21 of each cycle. Most patients
had stable disease with this combination, including three patients with
disease control for more than 4 months. One partial response was
observed in a patient with Ewing sarcoma. Decreasing ctDNA levels were
observed in patients with stable disease.
Discontinuous dosing of cabozantinib was necessary with this combination
based upon the observed toxicity profile with concomitant dosing.
Previous studies involving mTKIs and cytotoxic therapies in pediatric
patients with solid tumors have shown mixed results with regard to
schedule. A phase 1 study of pazopanib in combination with irinotecan
and temozolomide in relapsed/refractory sarcomas found concomitant
dosing was not tolerable[19]. Likewise, in a phase 1 study of
regorafenib in combination with vincristine/irinotecan, concomitant
dosing of regorafenib with the cytotoxic backbone was discontinued due
to toxicity. Discontinuous administration of regorafenib during weeks
without vincristine/irinotecan was the recommended phase 2
schedule[20]. In contrast, a randomized phase 2 study of pazopanib
added to doxorubicin and ifosfamide for patients with soft tissue
sarcoma found concomitant dosing to be tolerable. While grade 3/4
toxicity rates were higher in the pazopanib arm and 60% of patients on
the pazopanib arm experienced a pazopanib-related serious adverse event,
the regimen met predefined feasibility rules[21]. A phase 2 study of
lenvatinib in combination with ifosfamide and etoposide for patients
with relapsed or refractory osteosarcoma also found that concomitant
dosing was feasible[22]. Our results add to this growing body of
literature that suggest that considerations for scheduling mTKIs around
chemotherapy is likely dependent upon the specific chemotherapy regimen
and specific mTKI. In prior adult studies, concomitant cabozantinib was
tolerable with temozolomide but not with gemcitabine[14, 15]. It now
seems clear that it should not be assumed that mTKIs can simply be added
to backbone chemotherapy.
Previous studies have demonstrated efficacy of cabozantinib monotherapy
and separately of the topotecan plus cyclophosphamide regimen in this
same population. The primary objective of this phase 1 trial was safety
and the study was not designed to evaluate efficacy. Further, as both
cabozantinib monotherapy and topotecan plus cyclophosphamide have shown
activity in this patient population, the individual contribution or
possible synergy of the agents is unclear. In particular, prior
experience with topotecan/cyclophosphamide in Ewing sarcoma demonstrated
~20-30% response rate compared to the 14% observed in
the current dose finding study [17] [23]. Nevertheless, this
novel combination may warrant further exploration given the observed
disease control, including stable disease for >4 months in
3 patients. In addition, several patients with stable disease had
reductions in ctDNA burden by ULP-WGS and TranSS-Seq, suggesting
possible benefit in these patients.
A limitation to this study was the lack of long-term efficacy and
adverse effects data. Given that all agents were commercially available,
multiple patients opted to come off trial once their dose was
established to be treated as per this regimen at an institution closer
to home, limiting our ability to report on longer term toxicity or
disease control. An additional limitation of this trial was the lack
adequate sample size within each disease group to assess efficacy.
However, a strength is establishing a dose that is applicable to both
relapsed Ewing sarcoma and osteosarcoma.
In summary, we demonstrate the safety and tolerability of interrupted
dosing cabozantinib, cyclophosphamide and topotecan for patients with
relapsed Ewing sarcoma and osteosarcoma. Combinations of mTKIs with
chemotherapy are either being studied or under development as part of
front-line therapy for newly diagnosed Ewing sarcoma and osteosarcoma.