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

 Pathologic confirmation of cancer by the Laboratory of Pathology, National Cancer Institute
 (NCI)

 Phase I: Diagnosis of recurrent, metastatic or primary unresectable solid tumor that does
 not have curative standard treatment.

 Phase II: Diagnosis of recurrent, metastatic or primary unresectable anaplastic thyroid
 cancer (ATC), including ATC as part of a thyroid carcinoma of another histologic subtype.

 Measurable disease at presentation with disease measurable by Response Evaluation Criteria
 in Solid Tumors (RECIST) required in the phase II cohort.

 A life expectance of at least 3 months as evidenced by Eastern Cooperative Oncology Group
 (ECOG) performance status 0-1.

 Age greater than or equal to 18 years

 Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the case of
 nitrosourea) prior to enrollment date; unless the last therapy consisted of an oral agent
 whose average half life is known to be less than 48 hours in which case only 2 weeks need
 to have elapsed. Regardless of the therapy, any toxicity greater than Common Terminology
 Criteria in Adverse Events (CTCAE) grade 1 from previous anti-cancer therapy must have been
 resolved.

 Last radiotherapy treatment 4 weeks prior to starting treatment with this protocol with the
 exception of palliative radiotherapy and there must be sites of measurable disease that did
 not receive radiation.

 -  Organ and marrow function as defined:

 -  total bilirubin < 1.5 times the upper limit of reference range (ULRR), unless the
 patient meets the criteria for Gilbert's Syndrome

 -  alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline
 phosphatase (ALP) all three < 2.5 times the ULRR, or < 5 times the ULRR if judged by
 the investigator to be related to liver metastases

 -  serum creatinine ULRR or creatinine clearance greater than or equal to 50 mL/minute
 (calculated by Cockcroft-Gault formula or measured in a timed urine collection)

 -  serum calcium below the CTCAE grade 1 upper limit (11.5mg/dL or 2.9 mmol/L). In cases
 where the serum calcium is below the normal range, the calcium adjusted for albumin is
 calculated and substituted for the measured value.

 -  Serum potassium greater than the lower limit of normal (LLN) and < 5.5 mmol/L.

 -  Serum magnesium greater than the LLN and < 3.0 mg/dL or 1.23 mmol/L.

 -  absolute neutrophil count greater than or equal to 1000/mm(3)

 -  platelet count (Bullet) 100,000/m m(3)

 -  Prothrombin time (PT) less than or equal to 4 seconds above ULN and partial
 thromboplastin time (PTT) less than or equal to 10 seconds above ULN.

 Ability to understand and sign an informed consent document.

 Provision of informed consent prior to any study-related procedures

 Negative pregnancy test for women of childbearing potential

 Ability and willingness to follow the guidelines of the clinical protocol including visits
 to NCI, Bethesda, Maryland for treatment and follow up visits.

 Because the effects of chemotherapy on the developing human fetus are potentially harmful,
 female patients must be one year post-menopausal, surgically sterile, or using an
 acceptable method of contraception during and continued after the last dose of study
 medications (oral contraceptives, barrier methods, approved contraceptive implant,
 long-term injectable contraception, intrauterine device or tubal ligation). Male patients
 must be surgically sterile or using an acceptable method of contraception during their
 participation in this study. Contraceptive use will continue for at least two months after
 the last dose of study medication.

 EXCLUSION CRITERIA:

 Patients with cancer potentially curable by surgical excision alone or patients who have
 not received therapy that might be considered standard and potentially curable.

 Evidence of severe or uncontrolled systemic disease or any concurrent condition including,
 but not limited to symptomatic congestive heart failure, unstable angina pectoris, unstable
 hypertension, seizure disorder, or psychiatric illness which in the Investigators opinion
 makes it undesirable for the patient to participate in the trial or which would jeopardize
 compliance with the protocol.

 Untreated brain metastases (or local treatment of brain metastases within the last three
 months) due to the poor prognosis of these patients and difficulty ascertaining the cause
 of neurologic toxicities.

 During Phase II enrollment: Prior therapy with cisplatin. (Cisplatin will be allowed as
 prior therapy during Phase I enrollment.)

 Women who are currently pregnant or breast-feeding, due to the possible adverse effects on
 the developing fetus and infant.

 During Phase II enrollment: The presence of a second malignancy within the last 2 years,
 other than squamous cell carcinoma of the skin or in situ cervical cancer because it will
 complicate the primary objective of the study. Cancer survivors who have been free of
 disease for at least two years can be enrolled in this study.

 Patients with evidence of a bleeding diathesis that cannot be corrected with standard
 therapy or factor replacement.

 Any unresolved toxicity greater than CTCAE grade 1 (except alopecia, and certain other
 unresolved CTCAE Grade 2 toxicities including bone marrow hypocellularity, lymphopenia,
 infusion-related reaction, infusion site extravasation, injection site reaction, portal
 vein hypertension, obesity) from previous anti-cancer therapy. Patients with grade 1
 neuropathy will be evaluated on a case by case basis for entry into study. Pre-chemotherapy
 medical conditions will be taken into consideration.

 Major surgery with incompletely healed surgical incision before starting study therapy.

 Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava
 syndrome (SVC), New York Heart Association (NYHA) classification of heart disease greater
 than or equal to 2 (see Appendix C) within 3 months before entry; or presence of cardiac
 disease that, in the opinion of the Investigator, increases the risk of ventricular
 arrhythmia.

 History of arrhythmia (multifocal premature ventricular contractions PVCs), bigeminy,
 trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is
 symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular
 tachycardia. Atrial fibrillation, controlled on medication is not excluded.

 Patients with a left ventricular ejection fraction less than the institutional lower limit
 of normal.

 History (within the last 6 months) or presence of stroke/cerebrovascular accident.

 Corrected QT interval (QTc) prolongation with other medications. If the medication can be
 discontinued and an alternative medication started that does not cause QTc prolongation,
 the patient would be eligible. If no alternative medication is available and the medication
 can not be discontinued for medical reasons, then the patient would not be eligible.

 Congenital long Q wave, T wave (QT) syndrome, or 1st degree relative with unexplained
 sudden death under 40 years of age.

 Presence of left bundle branch block (LBBB).

 QTc with Bazett's correction that is not measurable, or greater than or equal to 480 msec
 on screening electrocardiogram (ECG). (Note: If a patient has a QTc interval greater than
 or equal to 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24
 hours apart). The average QTc from the three screening ECGs must be < 480 msec in order for
 the patient to be eligible for the study). Patients who are receiving a drug that has a
 risk of QTc prolongation (see Appendix C of the protocol) are excluded if QTc is greater
 than or equal to 460 msec.

 Concurrent medication that may cause QTc prolongation or induce Torsades de Pointes: Those
 medications in Group One of Appendix C of the protocol will not be allowed. Those
 medications in Group Two of Appendix C of the protocol will be allowed.

 Crolibulin is a substrate of cytochrome P450 2C8 (CYP2C8), P450 2C9(CYP2C9), P450 2C19
 (CYP2C19) and P450 3A4 (CYP3A4). Strong inducers and inhibitors of these enzymes will
 constitute concomitant medications that are prohibited during the study (See protocol for
 the complete list). These medications include but are not limited to: for CYP2C8,
 montelukast and trimethoprim, for CYP2C9, lovastatin and sertraline, for CYP2C19,
 fluoxetine, ketoconazole, pantoprazole, omeprazole, rabeprazole, and ticlopidine, for
 CYP3A4, itraconazole, clarithromycin, erythromycin, telithromycin, and verapamil.

 Hypertension not controlled by medical therapy (systolic blood pressure greater than 150 mm
 Hg or diastolic blood pressure greater than 100 mm Hg).