A Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC)

Phase 1

Completed

Conditions: Anaplastic Thyroid Cancer
Solid Tumor

Interventions: Drug: Cisplatin
Drug: Crolibulin

Registration Number: NCT01240590

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ph II Level 4: Cisplatin	Cisplatin	100mg/m(2) Cisplatin
Ph I Level -1: Cisplatin + Crolibulin	Cisplatin	75mg/m(2) Cisplatin + 8 mg/m(2) Crolibulin
Ph I Level 1: Cisplatin + Crolibulin	Cisplatin	75mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin
Ph II Level 3: Cisplatin + Crolibulin	Cisplatin	100mg/m(2) Cisplatin + 20 mg/m(2) Crolibulin
Ph I Level -1: Cisplatin + Crolibulin	Crolibulin	75mg/m(2) Cisplatin + 8 mg/m(2) Crolibulin
Ph I Level 2: Cisplatin + Crolibulin	Cisplatin	100mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin
Ph I Level 1: Cisplatin + Crolibulin	Crolibulin	75mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin
Ph I Level 2: Cisplatin + Crolibulin	Crolibulin	100mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin
Ph II Level 3: Cisplatin + Crolibulin	Crolibulin	100mg/m(2) Cisplatin + 20 mg/m(2) Crolibulin

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Cisplatin (Phase I)	3 weeks	MTD is defined as the dose level immediately preceding the dose level at which 2 dose limiting toxicities (DLT) occurred. A DLT is defined as a hematologic or non-hematologic adverse event judged to be possibly, probably, or definitely related to cisplatin per the Common Terminology Criteria in Adverse Events (CTCAE).
Maximum Tolerated Dose (MTD) of Crolibulin (Phase I)	3 weeks	MTD is defined as the dose level immediately preceding the dose level at which 2 dose limiting toxicities (DLT) occurred. A DLT is defined as a hematologic or non-hematologic adverse event judged to be possibly, probably, or definitely related to cisplatin per the Common Terminology Criteria in Adverse Events (CTCAE).
Number of Participants With Serious and Non-Serious Adverse Events (Phase I & II)	4 years, 6 months and 26 days	Here is the number of participants with serious and non-serious adverse events. For a detailed list of adverse events, see the adverse event module.
Progression Free Survival (Phase II)	6 weeks	Progression free survival (PFS) is defined as the duration of time from start of study treatment to time of progression. Response is determined by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; and stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Underwent Medically-Necessary Interventions	4.5 years	Enrolled participants who had surgical procedures deemed medically necessary for their clinical care.
Tumor Growth Rate Constant	21 days	Difference in time (days) required for the treated tumors to reach a predetermined target size.