Terminé

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

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Ce qui est testé

Crolibulin

+ Cisplatin
Médicament
Qui peut participer

Carcinome
+8

+ Maladies du système endocrinien
+ Néoplasmes des glandes endocrines
De 18 à 90 ans
Voir tous les critères d'éligibilité
Comment se déroule l'étude

Étude thérapeutique

Phase 1 & 2
Interventionnel
Date de début : janvier 2011
Voir le détail du protocole

Résumé

Sponsor principalNational Cancer Institute (NCI)
Dernière mise à jour : 18 janvier 2026
Issu d'une base de données validée par les autorités. Revendiquer cette étude
Date de début de l'étude : 26 janvier 2011Date à laquelle le premier participant a commencé l'étude.

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.

Titre officielA Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults With Solid Tumors With a Focus on Anaplastic Thyroid Cancer (ATC) 
NCT01240590
Sponsor principalNational Cancer Institute (NCI)
Dernière mise à jour : 18 janvier 2026
Issu d'une base de données validée par les autorités. Revendiquer cette étude

Protocole

Cette section fournit des détails sur le plan de l'étude, y compris la manière dont l'étude est conçue et ce qu'elle évalue.
Détails du design
27 participants à inclureNombre total de participants que l'essai clinique vise à recruter.
Traitement
Cette étude teste un ou plusieurs traitements pour évaluer leur efficacité contre une maladie ou un problème de santé spécifique. L'objectif est de voir si un nouveau médicament ou une thérapie fonctionne mieux, ou provoque moins d'effets secondaires que les options existantes.

Comment les participants sont répartis entre les groupes de l'étude
Dans cette étude clinique, les participants sont répartis de manière aléatoire, comme lors d'un tirage au sort. Cela garantit l'équité et réduit les biais, rendant les résultats plus fiables. En attribuant les participants au hasard, les chercheurs peuvent comparer les traitements sans influence extérieure.

Autres méthodes de répartition
Répartition non aléatoire
: basée sur des critères spécifiques comme l'état de santé ou la décision du médecin.

Aucune (un seul groupe de participants)
: tous les participants reçoivent le même traitement, aucune répartition n'est nécessaire.

Comment les traitements sont administrés aux participants
Les participants sont répartis en groupes distincts, chaque groupe recevant un traitement différent en même temps. Cela permet de comparer directement l'efficacité de plusieurs traitements.

Autres façons d'administrer les traitements
Groupe unique
: tous les participants reçoivent le même traitement.

Affectation croisée
: les participants passent d'un traitement à un autre au cours de l'étude.

Plan factoriel
: les participants reçoivent des combinaisons de traitements pour évaluer leurs interactions.

Plan séquentiel
: les traitements sont administrés successivement selon un ordre prédéterminé, pouvant varier selon la réaction du participant.

Autre type d'attribution
: L'attribution des traitements ne suit pas de schéma standard ni de protocole prédéfini.

Comment l'efficacité du traitement est contrôlée
Dans ce type d’étude, aucun participant ne reçoit de placebo. Tous reçoivent soit le traitement expérimental, soit un autre traitement actif, souvent le traitement de référence. Ce modèle permet de comparer les effets de deux interventions réelles, sans inclure de substance inactive.

Autres options possibles
Contrôlée par placebo
: un placebo est utilisé pour comparer les effets du traitement expérimental à ceux d'une substance inactive, ce qui permet d'évaluer son efficacité réelle.

Comment la nature du traitement est tenue confidentielle
Dans une étude en ouvert, tous les participants ainsi que les chercheurs savent quel traitement est administré. Ce type de protocole est utilisé lorsqu'il n'est pas nécessaire ou pas possible de masquer les traitements.

Autres méthodes de masquage
Simple aveugle
: les participants ignorent le traitement reçu, mais les chercheurs le connaissent.

Double aveugle
: ni les participants ni les chercheurs ne savent quel traitement est administré.

Triple aveugle
: Les participants, les chercheurs et les personnes qui analysent les résultats ne savent pas quel traitement est administré.

Quadruple aveugle
: Les participants, les chercheurs, les personnes qui analysent les résultats et les professionnels de santé en charge du suivi ne savent pas non plus quel traitement est administré.

Éligibilité

Les chercheurs recherchent des patients correspondant à une certaine description appelée critères d'éligibilité : état de santé général ou traitements antérieurs du patient.
Conditions
Critères
Tout sexeLe sexe biologique des participants éligibles à s'inscrire.
De 18 à 90 ansTranche d'âge des participants éligibles à participer.
Volontaires sains non autorisésIndique si les individus en bonne santé et ne présentant pas la condition étudiée peuvent participer.
Conditions
Pathologie
Carcinome
Maladies du système endocrinien
Néoplasmes des glandes endocrines
Néoplasmes de la tête et du cou
Néoplasmes par type histologique
Néoplasmes par site
Néoplasmes
Tumeurs glandulaires et épithéliales
Néoplasmes Thyroïdiens
Maladies de la thyroïde
Carcinome anaplasique de la thyroïde
Critères

* 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).

Plan de l'étude

Découvrez tous les traitements administrés dans cette étude, leur description détaillée et ce qu'ils impliquent.
Groupes de traitement
Objectifs de l'étude
5 groupes d'intervention 

sont désignés dans cette étude

Cette étude ne comporte pas de groupe placebo. 

Groupes de traitement
Groupe I
Expérimental
75mg/m(2) Cisplatin + 8 mg/m(2) Crolibulin

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)
Groupe II
Comparateur actif
75mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin

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)
Groupe III
Comparateur actif
100mg/m(2) Cisplatin + 13 mg/m(2) Crolibulin

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)
Groupe IV
Comparateur actif
100mg/m(2) Cisplatin + 20 mg/m(2) Crolibulin

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)
Groupe 5
Comparateur actif
100mg/m(2) Cisplatin

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)
Objectifs de l'étude
Objectifs principaux

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).

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).

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.

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.
Objectifs secondaires

Enrolled participants who had surgical procedures deemed medically necessary for their clinical care.

Difference in time (days) required for the treated tumors to reach a predetermined target size.

Centres d'étude

Ce sont les hôpitaux, cliniques ou centres de recherche où l'essai est conduit. Vous pouvez trouver le site le plus proche de vous ainsi que son statut.
Cette étude comporte 1 site
Suspendu
National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, United StatesVoir le site
Terminé1 Centres d'Étude