A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC)
Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors;
chemotherapy and surgery have had no impact on local control or survival of patients, with a
median survival of 3-7 months.
Crolibulin (EPC2407) is a microtubulin inhibitor that has been shown to have direct
antitumor effects in vivo and in vitro, destabilizing spindles and inducing apoptosis,
resulting in the disruption of neovascular endothelial cells with disruption of blood flow
to the tumor.
The primary objective in the Phase I portion is to assess the safety and tolerability of
cisplatin and crolibulin given in a 21-day cycle in dose-seeking cohorts.
We will assess the toxicities of crolibulin coadministered with cisplatin, evaluate
dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) for the
The primary objective in the Phase II portion is to compare the combination crolibulin plus
cisplatin versus cisplatin alone in adults with ATC by assessing the duration of
progression-free survival (PFS); comparison of the response rates as evaluated by RECIST
will be an important secondary objective.
We plan on biochemical and immunohistochemical analysis of several tumor parameters
including mitotic index, expression of several proteins including EGFR, VEGFR, BRAF, ERCC1
and TP53. Where sufficient tissue is available we will also perform gene expression
analysis, microRNA array analysis, and compare these with 3'-deoxy-3'-[(18)F]
fluorothymidine (FLT)-positron emission tomography (PET) and tumor growth rate constant.
Phase I: adults age 18 and older with unresectable, recurrent or metastatic solid tumors.
Phase II: adults age 18 and older with anaplastic thyroid cancer.
In the phase II portion disease must be evaluable by RECIST.
All patients must have adequate hepatic, renal, and bone marrow function.
The Phase I component consists of dose-escalation cohorts of three to six patients, in which
all patients receive both the study drug crolibulin with cisplatin. The MTD and DLT will be
determined based on toxicities during the first three weeks of combined therapy. After a
minimum of four cycles of concurrent cisplatin and crolibulin, if the patient is acheiving
clinical benefit in the opinion of the investigator but can no longer tolerate cisplatin,
the patient may receive crolibulin alone until he or she experiences unacceptable toxicity
or progressive disease.
The Phase II component will be a randomization study, to either crolibulin with cisplatin or
cisplatin monotherapy. Patients randomized to cisplatin alone will have the opportunity to
cross over to the crolibulin arm in the event of tumor progression. After a minimum of four
cycles of concurrent cisplatin and crolibulin, if the patient is acheiving clinical benefit
in the opinion of the investigator but can no longer tolerate cisplatin, the patient may
receive crolibulin alone until he or she experiences unacceptable toxicity or progressive
Drug administration will take place on days 1, 2, and 3 for crolibulin, and on day 1 for
cisplatin, on a 21-day cycle.
Maximum number of patients for planned enrollment is 70. During the Phase I portion of the
study, dose-seeking cohorts of three to six patients will be enrolled until MTD / DLT is
reached for a maximum of three dose cohorts [up to 24 patients if one assumes an expansion
cohort to twelve patients at the recommended phase 2 (RP2) dose]. During the randomized
Phase II trial comparing the activity of the combination of crolibulin plus cislplatin with
cisplatin alone it is estimated that a maximum of 40 patients will be enrolled [1:1
randomization 20 + 20 = 40 patients], and we will allow for 6 extra patients to be enrolled
to compensate for a small number of non-evaluable patients.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Dose limiting toxicity
Ann W Gramza, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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