A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC)
Condition: Solid Tumor; Anaplastic Thyroid Cancer
MeSH terms: Thyroid Neoplasms; Thyroid Carcinoma, Anaplastic; Thyroid Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      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. Early
      clinical studies with combretastatin, from which crolibulin is derived, demonstrated efficacy
      in a subset of patients with ATC.

      Objectives:

      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
      combination.

      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 Response
      Evaluation Criteria in Solid Tumors (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 epidermal growth factor receptor
      (EGFR), vascular endothelial growth factor receptor (VEGFR), BRAF, excision repair
      cross-complementation group 1 (ERCC1) and tumor protein p53 (TP53). Where sufficient tissue
      is available we will also perform gene expression analysis, micro ribonucleic acid (microRNA)
      array analysis, and compare these with 3-deoxy-3 -[(18)F] fluorothymidine (FLT)-positron
      emission tomography (PET) and tumor growth rate constant.

      Eligibility:

      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.

      Design:

      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.

      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 the
      opportunity to cross over to the crolibulin arm in the event of tumor progression.

      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 cisplatin 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.
    

Detailed description: 
      Background:

      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.

      Objectives:

      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
      combination.

      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 Response
      Evaluation Criteria in Solid Tumors (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 epidermal growth factor receptor
      (EGFR), vascular endothelial growth factor receptor (VEGFR), BRAF, ERCC1 and tumor protein
      p53 (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.

      Eligibility:

      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.

      Design:

      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 achieving
      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 achieving 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.

      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 cisplatin 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.
    

Intervention name(s): Crolibulin; Cisplatin
Intervention type(s): Drug; Drug
Intervention description(s): Phase I:Dose Level (DL) 1 - 13 mg/m(2) intravenous (IV),DL 2 - 13 mg/m(2) IV, DL 3 - 20 mg/m(2) IV. Phase II: 20 mg/m(2); Phase I:Dose Level (DL) 1- 75 mg/m(2) intravenous (IV),DL 2 - 100 mg/m(2),DL 3 - 100 mg/m(2). Phase II: 100 mg/m(2)
Other intervention name(s): EPC2407; CDDP
Intervention MeSH terms: Cisplatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anaplastic Thyroid Cancer; Crolibulin; Solid Tumors; ATC